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Sample records for factors influencing neurotrophic

  1. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are curre......Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies...

  2. Trophic and neurotrophic factors in human pituitary adenomas (Review).

    Science.gov (United States)

    Spoletini, Marialuisa; Taurone, Samanta; Tombolini, Mario; Minni, Antonio; Altissimi, Giancarlo; Wierzbicki, Venceslao; Giangaspero, Felice; Parnigotto, Pier Paolo; Artico, Marco; Bardella, Lia; Agostinelli, Enzo; Pastore, Francesco Saverio

    2017-10-01

    The pituitary gland is an organ that functionally connects the hypothalamus with the peripheral organs. The pituitary gland is an important regulator of body homeostasis during development, stress, and other processes. Pituitary adenomas are a group of tumors arising from the pituitary gland: they may be subdivided in functional or non-functional, depending on their hormonal activity. Some trophic and neurotrophic factors seem to play a key role in the development and maintenance of the pituitary function and in the regulation of hypothalamo-pituitary-adrenocortical axis activity. Several lines of evidence suggest that trophic and neurotrophic factors may be involved in pituitary function, thus suggesting a possible role of the trophic and neurotrophic factors in the normal development of pituitary gland and in the progression of pituitary adenomas. Additional studies might be necessary to better explain the biological role of these molecules in the development and progression of this type of tumor. In this review, in light of the available literature, data on the following neurotrophic factors are discussed: ciliary neurotrophic factor (CNTF), transforming growth factors β (TGF‑β), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), vascular endothelial growth factor (VEGF), vascular endothelial growth inhibitor (VEGI), fibroblast growth factors (FGFs) and epidermal growth factor (EGF) which influence the proliferation and growth of pituitary adenomas.

  3. Synaptic modulation by neurotrophic factors: differential and synergistic effects of brain-derived neurotrophic factor and ciliary neurotrophic factor.

    Science.gov (United States)

    Stoop, R; Poo, M M

    1996-05-15

    Extracellular application of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) to developing neuromuscular junctions in Xenopus nerve-muscle cultures resulted in an increase in the frequency of spontaneous synaptic currents (SSCs) and in the amplitude of nerve-evoked synaptic currents. Analyses of the amplitude and time course of the SSCs suggest that these effects are attributable to elevation of presynaptic transmitter release. The actions of these two factors on the transmitter secretion process, however, are distinctly different. Fura-2 Ca2+ imaging showed that an increase in presynaptic cytosolic Ca2+ ([Ca2+]i) accompanied the synaptic potentiation by BDNF, whereas no change in [Ca2+]i was observed during synaptic potentiation by CNTF. Removing external Ca2+ also abolished the potentiating effect of BDNF but did not influence the CNTF effect. Moreover, the two factors exerted different effects on the short-term synaptic plasticity. Paired-pulse facilitation normally found at these synapses was reduced by BDNF but unaffected by CNTF; CNTF, but not BDNF, reduced the extent of synaptic depression during high-frequency tetanic stimulation. Finally, the potentiation effect of BDNF and CNTF on spontaneous transmitter release was additive when both factors were applied together to the synapse at saturating concentrations (100 ng/ml) and was highly synergistic when low doses (1 and 10 ng/ml) of both factors were used. These results suggest that because of their differential effects on the secretory machinery, BDNF and CNTF may act cooperatively in modulating the development and functioning of synapses.

  4. Measurements of brain-derived neurotrophic factor

    DEFF Research Database (Denmark)

    Trajkovska, Viktorija; Klein, Anders Bue; Vinberg, Maj

    2007-01-01

    Although numerous studies have dealt with changes in blood brain-derived neurotrophic factor (BDNF), methodological issues about BDNF measurements have only been incompletely resolved. We validated BDNF ELISA with respect to accuracy, reproducibility and the effect of storage and repeated freezing...

  5. Influence of brain-derived neurotrophic factor on pathfinding of dentate granule cell axons, the hippocampal mossy fibers

    Directory of Open Access Journals (Sweden)

    Tamura Makoto

    2009-01-01

    Full Text Available Abstract Mossy fibers, the dentate granule cell axons, are generated throughout an animal's lifetime. Mossy fiber paths and synapses are primarily restricted to the stratum lucidum within the CA3 region. Brain-derived neurotrophic factor (BDNF, a neurotrophin family protein that activates Trk neurotrophin receptors, is highly expressed in the stratum lucidum in an activity-dependent manner. The addition of a Trk neurotrophin receptor inhibitor, K252a, to cultured hippocampal slices induced aberrant extension of mossy fibers into ectopic regions. BDNF overexpression in granule cells ameliorated the mossy fiber pathway abnormalities caused by a submaximal dose of K252a. A similar rescue was observed when BDNF was expressed in CA3 pyramidal cells, most notably in mossy fibers distal to the expression site. These findings are the first to clarify the role of BDNF in mossy fiber pathfinding, not as an attractant cue but as a regulator, possibly acting in a paracrine manner. This effect of BDNF may be as a signal for new fibers to fasciculate and extend further to form synapses with neurons that are far from active BDNF-expressing synapses. This mechanism would ensure the emergence of new independent dentate gyrus-CA3 circuits by the axons of new-born granule cells.

  6. The Brain Derived Neurotrophic Factor and Personality

    OpenAIRE

    Christian Montag

    2014-01-01

    The study of the biological basis of personality is a timely research endeavor, with the aim of deepening our understanding of human nature. In recent years, a growing body of research has investigated the role of the brain derived neurotrophic factor (BDNF) in the context of individual differences across human beings, with a focus on personality traits. A large number of different approaches have been chosen to illuminate the role of BDNF for personality, ranging from the measurement of BDNF...

  7. Influence of Maternal Undernutrition and Overfeeding on Cardiac Ciliary Neurotrophic Factor Receptor and Ventricular Size in Fetal Sheep

    Science.gov (United States)

    Dong, Feng; Ford, Stephen P.; Nijland, Mark J.; Nathanielsz, Peter W.; Ren, Jun

    2008-01-01

    Intrauterine nutrition status is reported to correlate with risk of cardiovascular diseases in adulthood. Either under- or over-nutrition during early to mid gestation contributes to altered fetal growth and ventricular geometry. This study was designed to examine myocardial expression of ciliary neurotrophic factor receptor α (CTNFRα) and its down-stream mediator signal transducer and activator of transcription 3 (STAT3) on maternal under- or over-nutrition-induced changes in fetal heart weight. Multiparous ewes were fed with 50% (nutrient-restricted, NR), 100% (control) or 150% (overfed, OF) of NRC requirements from 28 to 78 days of gestation (dG; Term 148 dG). Ewes were euthanized on day 78, and the gravid uteri and fetuses recovered. Ventricular protein expression of CTNFRα, STAT3, phosphorylated STAT3, insulin-like growth factor I receptor (IGF-1R) and IGF binding protein 3 (IGFBP3) were quantitated using western blot. Plasma cortisol levels were higher in both NR and OF fetuses whereas plasma IGF-1 levels were lower and higher, in NR and OF fetuses. Fetal weights were reduced by 29.9% in NR ewes and were increased by 22.2% in fetuses from OF ewes compared to control group. Nutrient restriction did not affect fetal heart or ventricular weights whereas overfeeding increased heart and ventricular weights. Protein expression of CTNFRα in fetal ventricular tissue was reduced in OF group whereas STAT3 and pSTAT3 levels were reduced in both NR and OF groups. Expression of IGF-1R and IGFBP3 was unaffected in either NR or OF group. These data suggested that compared with maternal undernutrition, intrauterine overfeeding during early to mid gestation is associated with increases fetal blood concentrations of cortisol and IGF-1 in association with ventricular hypertrophy where reduced expression of CNTFRα and STAT3 may play a role. PMID:17869083

  8. Comparing brain-derived neurotrophic factor and ciliary neurotrophic factor secretion of induced neurotrophic factor secreting cells from human adipose and bone marrow-derived stem cells.

    Science.gov (United States)

    Razavi, Shahnaz; Razavi, Mohamad Reza; Zarkesh Esfahani, Hamid; Kazemi, Mohammad; Mostafavi, Fatemeh Sadat

    2013-08-01

    Adipose derived stem cells (ADSCs) and bone marrow stem cells (BMSCs) may be equally beneficial in treating neurodegenerative diseases. However, ADSCs have practical advantages. In this study, we aimed to induce neurotrophic factors secreting cells in human ADSCs. Then, we compared the level of brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) secretion in neurotrophic factors secreting cells from human adipose and bone marrow-derived stem cells. Isolated human ADSCs and BMSCs were induced to neurotrophic factor (NTF)-secreting cells. The levels of expression and secretion of BDNF and CTNF of induced cells were assessed using immunocytochemical, Real-Time polymerase chain reaction, and enzyme linked immunosorbent assay (ELISA). The level of BDNF significantly increased in both the induced mesenchymal stem cells (MSCs) relative to ADSCs and the BMSCs (P < 0.01). Moreover, ELISA analysis showed that the release of BDNF in the induced BMSCs was almost twofold more than the induced ADSCs. Overall, NTF-secreting factor cells derived BMSCs and ADSCs could secret a range of different growth factors. Therefore, the variation in neurotrophic factors of different induced MSC populations suggest the possible beneficial effect of each specific kind of neurotrophic factor secreting cells for the treatment of a particular neurodegenerative disease. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

  9. Neurotrophic factor control of adult SVZ neurogenesis.

    Science.gov (United States)

    Bath, Kevin G; Lee, Francis S

    2010-04-01

    Neurogenesis is the process by which cells divide, migrate, and subsequently differentiate into a neuronal phenotype. Significant rates of neurogenesis persist into adulthood in two brain regions, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) of the lateral ventricles. Cells of the SVZ divide and migrate via the rostral migratory stream (RMS) to the olfactory bulb (OB) where they differentiate into granule and periglomerular cells. With the discovery of large-scale neurogenesis in the adult brain, there have been significant efforts to identify the mechanisms that control this process as well as the role of these cells in neuronal functioning. Neurotrophic factors are a family of molecules that serve critical roles in the survival and differentiation of neurons during development, as well as contribute to continued plasticity throughout life. Several members of the neurotrophin family have been implicated in the control of adult postnatal SVZ neurogenesis. In this review we will address what is currently known regarding neurotrophic factor-dependent control of SVZ neurogenesis and place these findings in the context of what is known regarding other growth factors.

  10. Supplementation with eicosapentaenoic omega-3 fatty acid does not influence serum brain-derived neurotrophic factor in diabetes mellitus patients with major depression: a randomized controlled pilot study

    NARCIS (Netherlands)

    Bot, Mariska; Pouwer, François; Assies, Johanna; Jansen, Eugène H. J. M.; Beekman, Aartjan T. F.; de Jonge, Peter

    2011-01-01

    Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients with major

  11. Supplementation with eicosapentaenoic omega-3 fatty acid does not influence serum brain-derived neurotrophic factor in diabetes mellitus patients with major depression: a randomized controlled pilot study

    NARCIS (Netherlands)

    Bot, M; Pouwer, F.; Assies, J.; Jansen, E.H.; Beekman, A.T.F.; de Jonge, P.

    2011-01-01

    Background: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients

  12. Supplementation with Eicosapentaenoic Omega-3 Fatty Acid Does Not Influence Serum Brain-Derived Neurotrophic Factor in Diabetes Mellitus Patients with Major Depression : A Randomized Controlled Pilot Study

    NARCIS (Netherlands)

    Bot, Mariska; Pouwer, Francois; Assies, Johanna; Jansen, Eugene H. J. M.; Beekman, Aartjan T. F.; de Jonge, Peter

    2011-01-01

    Background: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients

  13. The Brain Derived Neurotrophic Factor and Personality

    Directory of Open Access Journals (Sweden)

    Christian Montag

    2014-01-01

    Full Text Available The study of the biological basis of personality is a timely research endeavor, with the aim of deepening our understanding of human nature. In recent years, a growing body of research has investigated the role of the brain derived neurotrophic factor (BDNF in the context of individual differences across human beings, with a focus on personality traits. A large number of different approaches have been chosen to illuminate the role of BDNF for personality, ranging from the measurement of BDNF in the serum/plasma to molecular genetics to (genetic brain imaging. The present review provides the reader with an overview of the current state of affairs in the context of BDNF and personality.

  14. Neurotrophic factors in tension-type headache

    Directory of Open Access Journals (Sweden)

    Renan B. Domingues

    2015-05-01

    Full Text Available Neurotrophic factors (NF are involved in pain regulation and a few studies have suggested that they may play a pathophysiological role in primary headaches. The aim of this study was to investigate NF levels in patients with tension type headache (TTH. We carried out a cross sectional study including 48 TTH patients and 48 age and gender matched controls. Beck Depression and Anxiety Inventories, and Headache Impact Test were recorded. Serum levels of NF were determined by ELISA. There were not significant differences between NF levels between TTH patients and controls. Patients with chronic and episodic TTH had not significant differences in NF levels. The presence of headache at the time of evaluation did not significantly alter the levels of NF. Depression and anxiety scores as well as headache impact did not correlate with NF levels. Our study suggest that the serum levels of NF are not altered in TTH.

  15. Neurotrophic Factor Control of Satiety and Body Weight

    Science.gov (United States)

    Xu, Baoji; Xie, Xiangyang

    2016-01-01

    Energy balance, the relationship between energy intake and expenditure, is regulated by a complex interplay of hormones, brain circuits and peripheral tissues. Leptin is an adipocyte-derived cytokine that suppresses appetite and increases energy expenditure. Ironically, obese individuals have high levels of plasma leptin and are resistant to leptin treatment. Neurotrophic factors, particularly ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF), are also important for the control of body weight. CNTF can overcome leptin resistance to reduce body weight, although CNTF and leptin activate similar signalling cascades. Mutations in the gene for BDNF lead to insatiable appetite and severe obesity. PMID:27052383

  16. Reduced serum levels of oestradiol and brain derived neurotrophic factor in both diabetic women and HFD-feeding female mice.

    Science.gov (United States)

    Zhang, Yi; Zhang, Shan-Wen; Khandekar, Neeta; Tong, Shi-Fei; Yang, He-Qin; Wang, Wan-Ru; Huang, Xu-Feng; Song, Zhi-Yuan; Lin, Shu

    2017-04-01

    The estrogen levels in the pre and post menstrual phases interact with brain-derived neurotrophic factor in a complex manner, which influences the overall state of the body. To study the role of oestradiol and brain-derived neurotrophic factor in modulating obesity related type 2 diabetes and the interactions between two factors, we enrolled 15 diabetic premenopausal women and 15 diabetic postmenopausal women respectively, the same number of healthy pre and postmenopausal women were recruited as two control groups. The fasting blood glucose, insulin, lipids, estrogen, and brain-derived neurotrophic factor levels were measured through clinical tests. Additionally, we set up obese female mouse model to mimic human trial stated above, to verify the relationship between estrogen and brain-derived neurotrophic factor. Our findings revealed that there is a moderately positive correlation between brain-derived neurotrophic factor and oestradiol in females, and decreased brain-derived neurotrophic factor may worsen impaired insulin function. The results further confirmed that high fat diet-fed mice which exhibited impaired glucose tolerance, showed lower levels of oestradiol and decreased expression of brain-derived neurotrophic factor mRNA in the ventromedial hypothalamus. The level of brain-derived neurotrophic factor reduced on condition that the level of oestradiol is sufficiently low, such as women in postmenopausal period, which aggravates diabetes through feeding-related pathways. Increasing the level of brain-derived neurotrophic factor may help to alleviate the progression of the disease in postmenopausal women with diabetes.

  17. Influence of brain-derived neurotrophic factor-tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure.

    Science.gov (United States)

    Becker, Bryan K; Tian, Changhai; Zucker, Irving H; Wang, Han-Jun

    2016-10-01

    Impairment of baroreflex function is associated with the progression of chronic heart failure (CHF) and a poor prognosis. The baroreflex desensitization in CHF is at least partly the result of central neuronal network dysfunction. The dorsal medial nucleus tractus solitarius (dmNTS) has long been appreciated as a primary site of baroreceptor afferent termination in the central nervous system. However, the influence of neurotransmitters and neuromodulators in the dmNTS on baroreflex function both in normal and CHF states is not fully understood. The present study provides the first evidence showing a tonic sympatho-inhibitory role for brain-derived neurotrophic factor (BDNF) neurotransmission in the dmNTS. Most importantly, BDNF- tyrosine receptor kinase B (TrkB) signalling in the dmNTS is integral for normal baroreflex function as indicated by the blunting of baroreflex sensitivity (BRS) following the antagonization of TrkB, which inhibited baroreflex gain and range. Furthermore, we found that the tonic sympatho-inhibition of BDNF was withdrawn in the CHF state, thus contributing to the increased sympathetic tone associated with CHF. Consistent with this finding, BDNF/TrkB antagonism had little effect on reducing BRS in CHF animals, which is corroborated by the observation of decreased TrkB expression in the dmNTS during CHF. Taken together, these results implicate a reduction in BDNF-TrkB signalling in the dmNTS during CHF that contributes to sympatho-excitation and baroreflex desensitization. The observation that the BDNF/TrkB pathway is impaired in the dmNTS during CHF provides a novel mechanism for understanding the central alterations that contribute to baroreflex desensitization during CHF. Chronic heart failure (CHF) results in blunting of arterial baroreflex sensitivity (BRS), which arises from alterations to both peripheral baroreceptors and central autonomic nuclei such as the nucleus tractus solitarius (NTS). Although glutamate is known to be an

  18. Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival

    OpenAIRE

    Sendtner, Michael; Arakawa, Yoshihiro; Stöckli, Kurt A.; Kreutzberg, Georg W.; Thoenen, Hans

    2010-01-01

    We have demonstrated that the extensive degeneration of motoneurons in the rat facial nucleus after transection of the facial nerve in newborn rats can be prevented by local ciliary neurotrophic factor (CNTF) administration. CNTF differs distinctly from known neurotrophic molecules such as NGF, BDNF and NT-3 in both its molecular characteristics (CNTF is a cytosolic rather than a secretory molecule) and its broad spectrum of biological activities. CNTF is expressed selectively by Schwann cell...

  19. Supplementation with eicosapentaenoic omega-3 fatty acid does not influence serum brain-derived neurotrophic factor in diabetes mellitus patients with major depression

    DEFF Research Database (Denmark)

    Bot, Mariska; Pouwer, Francois; Assies, Johanna

    2011-01-01

    BACKGROUND: Low brain-derived neurotrophic factor (BDNF) levels are observed in both depressed and diabetes patients. Animal research has shown that omega-3 polyunsaturated fatty acids increase BDNF levels. In this exploratory randomized double-blind placebo-controlled study in diabetes patients......, in addition to ongoing antidepressant therapy. At baseline and 12-week follow-up, we determined serum BDNF levels and depression severity, using the Montgomery-Åsberg Depression Rating Scale. RESULTS: We found no effect of E-EPA on BDNF levels (t = -0.144, p = 0.887), and changes in BDNF levels and depression...... with major depression, we tested whether (a) omega- 3 ethyl-eicosapentaenoic acid (E-EPA) leads to increased serum BDNF levels and (b) whether changes in BDNF levels are associated with corresponding changes in depression. METHODS: Patients received 1 g/day E-EPA (n = 13) or placebo (n = 12) for 12 weeks...

  20. Determinants of serum brain-derived neurotrophic factor

    NARCIS (Netherlands)

    Bus, B. A. A.; Molendijk, M. L.; Penninx, B. J. W. H.; Buitelaar, J. K.; Kenis, G.; Prickaerts, J.; Elzinga, B. M.; Voshaar, R. C. Oude

    Background: Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and plasticity of neurons in the adult central nervous system. The high correlation between cortical and serum BDNF levels has led to many human studies on BDNF levels

  1. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease

    Science.gov (United States)

    Mattson, Mark P.

    2008-01-01

    Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders. PMID:19076369

  2. Brain-derived neurotrophic factor in asthmatic children | Salama ...

    African Journals Online (AJOL)

    Background: Brain-derived neurotrophic factor (BDNF) regulates the cross-talk between the immune and nervous systems which may play an important role in asthma pathophysiology. Objective: This study was aimed to investigate the relation between BDNF and asthma exacerbation and severity, and to study its possible ...

  3. Possible involvement of brain-derived neurotrophic factor in male ...

    African Journals Online (AJOL)

    Brain-derived neurotrophic factor (BDNF) plays a role in the development of various non-neuronal tissues, as the reproductive system. BDNF transcript and protein has been detected in testis and sperms. The present work aimed to assess the possible involvement of BDNF mRNA expression in sperm functions, hormonal ...

  4. Brain-derived neurotrophic factor in asthmatic children.

    African Journals Online (AJOL)

    Ehab

    Background: Brain-derived neurotrophic factor (BDNF) regulates the cross- talk between the immune and nervous systems which may play an important role in asthma pathophysiology. Objective: This study was aimed to investigate the relation between BDNF and asthma exacerbation and severity, and to study its possible ...

  5. Loneliness in Relation to Depression: The Moderating Influence of a Polymorphism of the Brain Derived Neurotrophic Factor Gene on Self-efficacy and Coping Strategies

    Science.gov (United States)

    Bedard, Marc; Woods, Robbie; Crump, Carly; Anisman, Hymie

    2017-01-01

    Disturbances of brain derived neurotrophic factor (BDNF) signaling, which may occur among those with a polymorphism of the Val66Met gene, comprising a Met substitution for the Val allele, may be associated with depressive cognitions. However, presumed elevated BDNF levels among individuals with the Val/Val genotype, might confer increased responsivity to contextual challenges, thus fostering vulnerability to depression. In Study 1, among undergraduate students (N = 252), increased loneliness perceptions were accompanied with depressive symptoms. This relationship was moderated by self-efficacy and BDNF genotype, such that when individuals appraised high self-efficacy, those with the Val/Val genotype, compared to Met carriers, reported greater depression scores when they perceived feeling lonely. Study 2 revealed that among undergraduate students (N = 178), lower depressive scores were associated with increased problem-focused coping among Val/Val individuals, but not Met carriers. Moreover, with increased perceived loneliness, Val/Val carriers endorsed lower problem-focused coping. Findings suggest that Val/Val individuals may have adverse neurocognitive vulnerability to loneliness experiences. PMID:28769852

  6. Nerve growth factor, brain-derived neurotrophic factor, and the chronobiology of mood: a new insight into the "neurotrophic hypothesis"

    Directory of Open Access Journals (Sweden)

    Tirassa P

    2015-10-01

    Full Text Available Paola Tirassa,1 Adele Quartini,2 Angela Iannitelli2–4 1National Research Council (CNR, Institute of Cell Biology and Neurobiology (IBCN, 2Department of Medical-Surgical Sciences and Biotechnologies, Faculty of Pharmacy and Medicine – "Sapienza" University of Rome, 3Italian Psychoanalytical Society (SPI, Rome, Italy; 4International Psychoanalytical Association (IPA, London, UKAbstract: The light information pathways and their relationship with the body rhythms have generated a new insight into the neurobiology and the neurobehavioral sciences, as well as into the clinical approaches to human diseases associated with disruption of circadian cycles. Light-based strategies and/or drugs acting on the circadian rhythms have widely been used in psychiatric patients characterized by mood-related disorders, but the timing and dosage use of the various treatments, although based on international guidelines, are mainly dependent on the psychiatric experiences. Further, many efforts have been made to identify biomarkers able to disclose the circadian-related aspect of diseases, and therefore serve as diagnostic, prognostic, and therapeutic tools in clinic to assess the different mood-related symptoms, including pain, fatigue, sleep disturbance, loss of interest or pleasure, appetite, psychomotor changes, and cognitive impairments. Among the endogenous factors suggested to be involved in mood regulation, the neurotrophins, nerve growth factor, and brain-derived neurotrophic factor show anatomical and functional link with the circadian system and mediate some of light-induced effects in brain. In addition, in humans, both nerve growth factor and brain-derived neurotrophic factor have showed a daily rhythm, which correlate with the morningness–eveningness dimensions, and are influenced by light, suggesting their potential role as biomarkers for chronotypes and/or chronotherapy. The evidences of the relationship between the diverse mood-related disorders

  7. The effect of regular aerobic exercise on urinary brain-derived neurotrophic factor in children

    OpenAIRE

    Yunita Fediani; Masayu Rita Dewi; Muhammad Irfannuddin; Masagus Irsan Saleh; Safri Dhaini

    2014-01-01

    Background Nervous system development in early life influences the quality of cognitive ability during adulthood. Neuronal development and neurogenesis are highly influenced by neurotrophins. The most active neurotrophin is brain-derived neurotrophic factor (BDNF). Physical activity has a positive effect on cognitive function. However, few experimental studies have been done on children to assess the effect of aerobic regular exercise on BDNF levels. Objective To asses...

  8. The effect of regular aerobic exercise on urinary brain-derived neurotrophic factor in children

    OpenAIRE

    Yunita Fediani; Masayu Rita Dewi; Muhammad Irfannuddin; Masagus Irsan Saleh; Safri Dhaini

    2014-01-01

    Background Nervous system development in early life influences the quality of cognitive ability during adulthood. Neuronal development and neurogenesis are highly influenced by neurotrophins. The most active neurotrophin is brain-derived neurotrophic factor (BDNF). Physical activity has a positive effect on cognitive function. However, few experimental studies have been done on children to assess the effect of aerobic regular exercise on BDNF levels. Objective To assess the effect of regu...

  9. The Effect of Repeated Electroacupuncture Analgesia on Neurotrophic and Cytokine Factors in Neuropathic Pain Rats

    Directory of Open Access Journals (Sweden)

    Junying Wang

    2016-01-01

    Full Text Available Chronic pain is a common disability influencing quality of life. Results of previous studies showed that acupuncture has a cumulative analgesic effect, but the relationship with spinal cytokines neurotrophic factors released by astrocytes remains unknown. The present study was designed to observe the effect of electroacupuncture (EA treatment on spinal cytokines neurotrophic factors in chronic neuropathic pain rats. The chronic neuropathic pain was established by chronic constrictive injury (CCI. EA treatment was applied at Zusanli (ST36 and Yanglingquan (GB34 (both bilateral once a day, for 30 min. IL-1β mRNA, TNF-α mRNA, and IL-1 mRNA were detected by quantitative real-time PCR, and the proteins of BDNF, NGF, and NT3/4 were detected by Western blot. The expression levels of cytokines such as IL-1β mRNA, TNF-α mRNA, IL-6 mRNA, and neurotrophic factors such as BDNF, NGF, and NT3/4 in the spinal cord were increased significantly after CCI. The astrocytes released more IL-1β and BDNF after CCI. Repeated EA treatment could suppress the elevated expression of IL-1β mRNA, TNFα mRNA, and BDNF, NGF, and NT3/4 but had no effect on IL-6 mRNA. It is suggested that cytokines and neurotrophic factors which may be closely associated with astrocytes participated in the process of EA relieving chronic pain.

  10. Early Life Stressors and Genetic Influences on the Development of Bipolar Disorder: The Roles of Childhood Abuse and Brain-Derived Neurotrophic Factor

    Science.gov (United States)

    Liu, Richard T.

    2010-01-01

    Objectives: Although there is increasing research exploring the psychosocial influences and biological underpinnings of bipolar disorder, relatively few studies have specifically examined the interplay between these factors in the development of this illness. Social-biological models within a developmental psychopathology perspective are necessary…

  11. Astrocytes produce an insulin-like neurotrophic factor

    International Nuclear Information System (INIS)

    Kadle, R.; Suksang, C.; Fellows, R.E.

    1986-01-01

    They have previously reported that survival of dissociated neurons from fetal rat telencephalon plated at low density in serum-free, hormone-free defined medium is enhanced in the presence of insulin. In the absence of insulin a similar effect on neuronal survival is observed if cells are grown in medium conditioned by glial cells. The present study was carried out to characterize the insulin-like neurotrophic activity present in the glial conditioned medium (GLCM). Conditioned medium from confluent cultures of astrogial cells maintained in a serum free defined medium without insulin was collected every two or three days. A 5 to 30kDa fraction of this medium was obtained by filtering it sequentially through YM30 and YM5 membrane filters. Binding of 125 I-insulin to high density neuronal cultures was inhibited 43% by this fraction. Radioimmunoassay for insulin indicated that 1-2 ng of immuno-reactive insulin were present per ml of GLCM. Immunosequestration of the factor by insulin antibodies bound to protein A agarose gel resulted in loss of neurotrophic activity of the 5 to 30 kDa fraction. These results indicate that cultured astrocytes produce a factor immunologically and biochemically similar to insulin. This factor enhances the survival of neurons in culture and may be important for their normal development and differentiation

  12. Delayed onset muscle soreness: Involvement of neurotrophic factors.

    Science.gov (United States)

    Mizumura, Kazue; Taguchi, Toru

    2016-01-01

    Delayed-onset muscle soreness (DOMS) is quite a common consequence of unaccustomed strenuous exercise, especially exercise containing eccentric contraction (lengthening contraction, LC). Its typical sign is mechanical hyperalgesia (tenderness and movement related pain). Its cause has been commonly believed to be micro-damage of the muscle and subsequent inflammation. Here we present a brief historical overview of the damage-inflammation theory followed by a discussion of our new findings. Different from previous observations, we have observed mechanical hyperalgesia in rats 1-3 days after LC without any apparent microscopic damage of the muscle or signs of inflammation. With our model we have found that two pathways are involved in inducing mechanical hyperalgesia after LC: activation of the B2 bradykinin receptor-nerve growth factor (NGF) pathway and activation of the COX-2-glial cell line-derived neurotrophic factor (GDNF) pathway. These neurotrophic factors were produced by muscle fibers and/or satellite cells. This means that muscle fiber damage is not essential, although it is sufficient, for induction of DOMS, instead, NGF and GDNF produced by muscle fibers/satellite cells play crucial roles in DOMS.

  13. Brain-Derived Neurotrophic Factor in Chronic Periodontitis

    Directory of Open Access Journals (Sweden)

    Jôice Dias Corrêa

    2014-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is a member of the neurotrophic factor family. Outside the nervous system, BDNF has been shown to be expressed in various nonneural tissues, such as periodontal ligament, dental pulp, and odontoblasts. Although a role for BDNF in periodontal regeneration has been suggested, a function for BDNF in periodontal disease has not yet been studied. The aim of this study was to analyze the BDNF levels in periodontal tissues of patients with chronic periodontitis (CP and periodontally healthy controls (HC. All subjects were genotyped for the rs4923463 and rs6265 BDNF polymorphisms. Periodontal tissues were collected for ELISA, myeloperoxidase (MPO, and microscopic analysis from 28 CP patients and 29 HC subjects. BDNF levels were increased in CP patients compared to HC subjects. A negative correlation was observed when analyzing concentration of BDNF and IL-10 in inflamed periodontium. No differences in frequencies of BDNF genotypes between CP and HC subjects were observed. However, BDNF genotype GG was associated with increased levels of BDNF, TNF-α, and CXCL10 in CP patients. In conclusion, BDNF seems to be associated with periodontal disease process, but the specific role of BDNF still needs to be clarified.

  14. Neonatal levels of neurotrophic factors and risk of autism spectrum disorders

    DEFF Research Database (Denmark)

    Abdallah, Morsi; Mortensen, E L; Greaves-Lord, K

    2013-01-01

    To examine levels of 3 neurotrophic factors (NTFs): Brain derived neurotrophic factor (BDNF), Neurotrophin-4 (NT-4), and transforming growth factor-β (TGF-β) in dried blood spot samples of neonates diagnosed with autism spectrum disorders (ASD) later in life and frequency-matched controls....

  15. Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans

    Directory of Open Access Journals (Sweden)

    Aren Bezdjian

    2016-11-01

    Full Text Available Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53% was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%. Ciliary neurotrophic factor (50%, nerve growth factor (24% and insulin-like growth factor (21% were most often used. Injection site reaction was a frequently occurring adverse event (61% followed by asthenia (24% and gastrointestinal disturbances (20%. Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.

  16. A functional brain-derived neurotrophic factor (BDNF) gene variant increases the risk of moderate-to-severe allergic rhinitis

    NARCIS (Netherlands)

    Jin, Peng; Andiappan, Anand Kumar; Quek, Jia Min; Lee, Bernett; Au, Bijin; Sio, Yang Yie; Irwanto, Astrid; Schurmann, Claudia; Grabe, Hans Joergen; Suri, Bani Kaur; Matta, Sri Anusha; Westra, Harm-Jan; Franke, Lude; Esko, Tonu; Sun, Liangdan; Zhang, Xuejun; Liu, Hong; Zhang, Furen; Larbi, Anis; Xu, Xin; Poidinger, Michael; Liu, Jianjun; Chew, Fook Tim; Rotzschke, Olaf; Shi, Li; Wang, De Yun

    Background: Brain-derived neurotrophic factor (BDNF) is a secretory protein that has been implicated in the pathogenesis of allergic rhinitis (AR), atopic asthma, and eczema, but it is currently unknown whether BDNF polymorphisms influence susceptibility to moderate-to-severe AR. Objective: We

  17. Peripheral blood brain-derived neurotrophic factor in bipolar disorder

    DEFF Research Database (Denmark)

    Munkholm, K; Vinberg, M; Kessing, L V

    2016-01-01

    subjects and between affective states in bipolar disorder patients, including assessment of the effect of treatment of acute episodes on BDNF levels. A systematic review of English language studies without considering publication status was conducted in PubMed (January 1950-November 2014), Embase (1974......Peripheral blood brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in bipolar disorder, speculated to mirror alterations in brain expression of BDNF. The research area is rapidly evolving; however, recent...... investigations have yielded conflicting results with substantial variation in outcomes, highlighting the need to critically assess the state of current evidence. The aims of the study were to investigate differences in peripheral blood BDNF concentrations between bipolar disorder patients and healthy control...

  18. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes

    DEFF Research Database (Denmark)

    Krabbe, K. S.; Nielsen, A. R.; Krogh-Madsen, R.

    2006-01-01

    Aims/hypothesis  Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore...... explored whether BDNF plays a role in human glucose metabolism. Subjects and methods  We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic...... and a hyperinsulinaemic-euglycaemic clamp. Results  Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism...

  19. Brain-derived neurotrophic factor: role in depression and suicide

    Directory of Open Access Journals (Sweden)

    Yogesh Dwivedi

    2009-08-01

    Full Text Available Yogesh DwivediPsychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USAAbstract: Depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF, one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF. This has led to the proposal of the “neurotrophin hypothesis of depression”. Increasing evidence demonstrates that suicidal behavior is also associated with lower expression of BDNF, which may be independent from depression. Recent genetic studies also support a link of BDNF to depression/suicidal behavior. Not only BDNF, but abnormalities in its cognate receptor tropomycin receptor kinase B (TrkB and its splice variant (TrkB.T1 have also been reported in depressed/suicidal patients. It has been suggested that epigenetic modulation of the Bdnf and Trkb genes may contribute to their altered expression and functioning. More recently, impairment in the functioning of pan75 neurotrophin receptor has been reported in suicide brain specimens. pan75 neurotrophin receptor is a low-affinity neurotrophin receptor that, when expressed in conjunction with low availability of neurotropins/Trks, induces apoptosis. Overall, these studies suggest the possibility that BDNF and its mediated signaling may participate in the pathophysiology of depression and suicidal behavior. This review focuses on the critical evidence demonstrating the involvement of BDNF in depression and suicide.Keywords: BDNF, neurotrophins, p75NTR, Trk receptor, depression, antidepressants, suicide, genetics, epigenetics

  20. Serum brain-derived neurotrophic factor levels and cocaine-induced transient psychotic symptoms

    OpenAIRE

    Corominas-Roso, M.; Roncero, C.; Eiroá Orosa, Francisco José; Ribasés, M.; Barral, C.; Daigre, C.; Martínez-Luna, N.; Sánchez-Mora, C.; Ramos-Quiroga,J.A.; Casas, Miquel

    2013-01-01

    Background: Cocaine-induced psychosis (CIP) is among the most serious adverse effects of cocaine. Reduced serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the involvement of BDNF in CIP are lacking. Methods: A total of 22 cocaine-dependent patients (aged 33.65 ± 6.85) who had never experienced psychotic symptoms under the influence of cocaine (non-CIP) and 18 patients (aged 34.18 ± 8.54) with a history of CIP c...

  1. Association Between Brain-Derived Neurotrophic Factor Genotype and Upper Extremity Motor Outcome After Stroke.

    Science.gov (United States)

    Chang, Won Hyuk; Park, Eunhee; Lee, Jungsoo; Lee, Ahee; Kim, Yun-Hee

    2017-06-01

    The identification of intrinsic factors for predicting upper extremity motor outcome could aid the design of individualized treatment plans in stroke rehabilitation. The aim of this study was to identify prognostic factors, including intrinsic genetic factors, for upper extremity motor outcome in patients with subacute stroke. A total of 97 patients with subacute stroke were enrolled. Upper limb motor impairment was scored according to the upper limb of Fugl-Meyer assessment score at 3 months after stroke. The prediction of upper extremity motor outcome at 3 months was modeled using various factors that could potentially influence this impairment, including patient characteristics, baseline upper extremity motor impairment, functional and structural integrity of the corticospinal tract, and brain-derived neurotrophic factor genotype. Multivariate ordinal logistic regression models were used to identify the significance of each factor. The independent predictors of motor outcome at 3 months were baseline upper extremity motor impairment, age, stroke type, and corticospinal tract functional integrity in all stroke patients. However, in the group with severe motor impairment at baseline (upper limb score of Fugl-Meyer assessment stroke. Brain-derived neurotrophic factor genotype may be a potentially useful predictor of upper extremity motor outcome in patients with subacute stroke with severe baseline motor involvement. © 2017 American Heart Association, Inc.

  2. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain.

    Science.gov (United States)

    Afzalpour, Mohammad Esmaiel; Chadorneshin, Hossein Taheri; Foadoddini, Mohsen; Eivari, Hossein Abtahi

    2015-08-01

    The research literature suggests that oxidative stress and pro-inflammatory factors influence neurotrophins in vitro. However, there is insufficient information about their effects on exercise training conditions, especially during high intensity trainings. This study aimed to compare the effects of 6weeks of high intensity interval and continuous training regimens on brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), hydrogen peroxide (H2O2), and tumor necrosis factor alpha (TNF-α) in the rat brain. For this purpose, twenty-four Albino Wistar rats were divided into sedentary control (SC), high intensity interval training (HIIT), and continuous training (CT) groups. Both HIIT and CT regimens increased H2O2 level and TNF-α concentration in the brain, and the alterations made were greater following HIIT than CT. In addition, both HIIT and CT regimens increased BDNF and GDNF concentrations significantly, with a higher elevation following HIIT than CT. Furthermore, H2O2 level and TNF-α concentration correlated positively with both BDNF and GDNF concentrations. Generally, high intensity interval training regimen, rather than continuous training regimen, is highly potential to improve BDNF and GDNF through a greater increase in H2O2 and TNF-α as oxidative stress and pro-inflammatory factors. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Ciliary neurotrophic factor reduces the proliferation and promotes the differentiation of TH- MYCN transformed sympathoadrenal progenitors.

    Science.gov (United States)

    DeWitt, John; Pappas, Anthony; Nishi, Rae

    2014-01-01

    Neuroblastoma is a childhood cancer caused by the transformation of sympathoadrenal progenitors. By following the formation of tumors in homozygous TH-MYCN mice, an established mouse model of neuroblastoma, we were able to capture transformed cells prior to the formation of large, vascularized tumors in order to determine the responsiveness of cells to neurotrophic factors. We discovered that the ciliary neurotrophic factor (CNTF) receptor is abundantly expressed in tumor cells from these mice. Furthermore, CNTF - but not nerve growth factor, brain-derived nerve growth factor, neurotrophin 3, or glial cell line-derived neurotrophic factor - promoted neuronal differentiation and withdrawal from the cell cycle. Thus, the transformation of sympathoadrenal progenitors by MYCN overexpression differentially affects responsiveness to neurotrophic molecules. © 2014 S. Karger AG, Basel.

  4. Endogenous ciliary neurotrophic factor modulates anxiety and depressive-like behavior.

    Science.gov (United States)

    Peruga, Isabella; Hartwig, Silvia; Merkler, Doron; Thöne, Jan; Hovemann, Bernhard; Juckel, Georg; Gold, Ralf; Linker, Ralf A

    2012-04-15

    On a molecular level, depression is characterized by an altered monoaminergic neurotransmission as well as a modulation of cytokines and other mediators in the central nervous system. In particular, neurotrophic factors may influence affective behavior including depression and anxiety. Ciliary neurotrophic factor (CNTF) plays an important role in the regulation of neuronal development, neuroprotection and may also influence cognitive processes. Here we investigate the affective behavior in mice deficient for CNTF (CNTF -/- mice) at young age of 10-20 weeks. CNTF -/- mice displayed an increased anxiety-like behavior with a 30% reduction of the time spent in the bright compartment of the light/dark box as well as a significantly increased startle response. In the learned helplessness paradigm, CNTF -/- mice are more prone to depressive-like behavior. In the hippocampus of 20 weeks old, but not 10 weeks old, CNTF -/- mice, these changes correlated with a loss of parvalbumin immunoreactive GABAergic interneurons and a reduction of serotonin levels as well as 5-HT receptor 1A expression. Modulation of monoaminergic neurotransmitter levels via chronic application of the antidepressants amitriptyline and citalopram did not exert beneficial effects. These data imply that endogenous CNTF plays a pivotal role for the structural maintenance of hippocampal functions and thus has an important impact on the modulation of affective behavior in rodent models of anxiety and depression. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Kuhlmann, Tanja; Remington, Leah; Cognet, Isabelle

    2006-01-01

    Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a surv......Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described...... it was withdrawn. After cessation of CNTF treatment, inflammation and symptoms returned to control levels. However, slight but significantly higher numbers of oligodendrocytes, NG2-positive cells, axons, and neurons were observed in mice that had been treated with high concentrations of CNTF. Our results show...

  6. Association analysis between polymorphisms in the conserved dopamine neurotrophic factor (CDNF) gene and cocaine dependence

    OpenAIRE

    Lohoff, Falk W.; Bloch, Paul J.; Ferraro, Thomas N.; Berrettini, Wade H.; Pettinati, Helen M.; Dackis, Charles A.; O’Brien, Charles P.; Kampman, Kyle M.; Oslin, David W.

    2009-01-01

    Cocaine induced neuroplasticity changes in the mesocorticolimbic dopamine systems are thought to be involved in the pathophysiology of cocaine dependence. Since neurotrophic factors have been observed to prevent/reverse and mimic cocaine-induced neurobiological changes in the brain, related genes are plausible candidates for susceptibility to cocaine dependence. The novel conserved dopamine neurotrophic factor protein (CDNF) promotes the survival, growth, and function of dopamine-specific neu...

  7. Constitutive expression of ciliary neurotrophic factor in mouse hypothalamus.

    Science.gov (United States)

    Severi, Ilenia; Carradori, Maria Rita; Lorenzi, Teresa; Amici, Adolfo; Cinti, Saverio; Giordano, Antonio

    2012-06-01

    Ciliary neurotrophic factor (CNTF) is a potent survival molecule for a large number of neuronal and glial cells in culture; its expression in glial cells is strongly upregulated after a variety of nerve tissue injuries. Exogenously administered CNTF produces an anorectic effect via activation of hypothalamic neurons and stimulates neurogenesis in mouse hypothalamus. To determine whether CNTF is produced endogenously in the hypothalamus, we sought cellular sources and examined their distribution in adult mouse hypothalamus by immunohistochemistry. CNTF immunoreactivity (IR) was predominantly detected in the ependymal layer throughout the rostrocaudal extension of the third ventricle, where numerous ependymocytes and tanycytes exhibited specific staining. Some astrocytes in the grey matter of the anterior hypothalamus and in the median eminence of the hypothalamic tuberal region were also positive. Stimulation of cells bearing CNTF receptor α (CNTFRα) induces specific activation of the signal transducer and activator of transcription 3 (STAT3) signalling system. Treatment with recombinant CNTF and detection of the nuclear expression of phospho-STAT3 (P-STAT3) showed that CNTF-producing ependymal cells and tanycytes were intermingled with, or very close to, P-STAT3-positive, CNTFRα-bearing cells. A fraction of CNTF-producing ependymal cells and tanycytes and some median eminence astrocytes also exhibited P-STAT3 IR. Thus, in normal adult mice the ependyma of the third ventricle is both a source of and a target for CNTF, which may play hitherto unknown roles in hypothalamic function in physiological conditions. © 2012 The Authors. Journal of Anatomy © 2012 Anatomical Society.

  8. Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis.

    Science.gov (United States)

    Lee, Nancy; Batt, Myra K; Cronier, Brigitte A; Jackson, Michele C; Bruno Garza, Jennifer L; Trinh, Dennis S; Mason, Carter O; Spearry, Rachel P; Bhattacharya, Shayon; Robitz, Rachel; Nakafuku, Masato; MacLennan, A John

    2013-01-16

    Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B "stem" cells are highly responsive, whereas type C "transit-amplifying" cells and type A neuroblasts are remarkably unresponsive, as are GFAP(+) astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a "floxed" CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype-specific, adult-onset increase in olfactory bulb neuron populations. Adult-onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype-specific manner.

  9. Effect of neurotrophic factor, MDP, on rats’ nerve regeneration

    Directory of Open Access Journals (Sweden)

    A.A. Fornazari

    2011-04-01

    Full Text Available Our objective was to determine the immune-modulating effects of the neurotrophic factor N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP on median nerve regeneration in rats. We used male Wistar rats (120-140 days of age, weighing 250-332 g and compared the results of three different techniques of nerve repair: 1 epineural neurorrhaphy using sutures alone (group S - 10 rats, 2 epineural neurorrhaphy using sutures plus fibrin tissue adhesive (FTA; group SF - 20 rats, and 3 sutures plus FTA, with MDP added to the FTA (group SFM - 20 rats. Functional assessments using the grasp test were performed weekly for 12 weeks to identify recovery of flexor muscle function in the fingers secondary to median nerve regeneration. Histological analysis was also utilized. The total number and diameter of myelinated fibers were determined in each proximal and distal nerve segment. Two indices, reported as percentage, were calculated from these parameters, namely, the regeneration index and the diameter change index. By the 8th week, superiority of group SFM over group S became apparent in the grasping test (P = 0.005. By the 12th week, rats that had received MDP were superior in the grasping test compared to both group S (P < 0.001 and group SF (P = 0.001. Moreover, group SF was better in the grasping test than group S (P = 0.014. However, no significant differences between groups were identified by histological analysis. In the present study, rats that had received MDP obtained better function, in the absence of any significant histological differences.

  10. Paroxetine increases brain-derived neurotrophic factor in postmenopausal women.

    Science.gov (United States)

    Cubeddu, Alessandra; Giannini, Andrea; Bucci, Fiorella; Merlini, Sara; Casarosa, Elena; Pluchino, Nicola; Luisi, Stefano; Luisi, Michele; Genazzani, Andrea R

    2010-03-01

    Menopause is marked by a decline in ovarian function resulting in one or more climacteric symptoms. In the last few years, attention has been focused on the use of selective serotonin reuptake inhibitors (SSRIs) in the treatment of vasomotor symptoms associated with the menopausal transition. Thanks to the recent findings on the interaction between the serotoninergic system and neurotrophins, it has been suggested that brain-derived neurotrophic factor (BDNF) could contribute to the activity of SSRIs. Moreover, because endogenous gonadal hormones modulate both BDNF expression and serotonin biosynthesis and bioavailability and regulate brain functions like affective and cognitive functions, we proposed to evaluate the effects of a treatment with paroxetine, an SSRI, in a group of postmenopausal women and to clarify the possible relationship between paroxetine, plasma BDNF levels, and climacteric symptoms. A total of 119 postmenopausal women (age, 46-60 y; menopause age, 1-20 y) were included; 89 took paroxetine 10 mg/day for 6 months and 30 took estrogen + progestogen therapy (EPT) for 6 months. Blood samples were taken before the beginning of the therapy and at 3 and 6 months. The Green Climacteric Scale questionnaire was used to follow up women's clinical conditions. Plasma BDNF levels significantly increased after 3 and 6 months of therapy (P menopause age persisted throughout the treatment. Moreover, a significant reduction in the Greene Climacteric Scale score was observed. In the EPT group, the plasma BDNF level significantly increased after 6 months of therapy. The plasma BDNF levels after 6 months of paroxetine were significantly lower than those after 6 months of EPT. The present data suggest that a low dose of paroxetine is effective in enhancing plasma BDNF levels, and this increase might have a role in improving climacteric symptoms, highlighting the possible role of BDNF in endocrinological and cognitive functions.

  11. Brain-Derived Neurotrophic Factor Predicts Mortality Risk in Older Women

    DEFF Research Database (Denmark)

    Krabbe, K.S.; Mortensen, E.L.; Avlund, K.

    2009-01-01

    OBJECTIVES To test the hypothesis that low circulating brain-derived neurotrophic factor (BDNF), a secretory member of the neurotrophin family that has a protective role in neurodegeneration and stress responses and a regulatory role in metabolism, predicts risk of all-cause mortality in 85-year...... was measured in plasma and serum. The Danish National Register of Patients was used to collect data on morbidity. The primary outcome in Cox regression analyses was all-cause mortality. RESULTS Women with low plasma BDNF (lowest tertile) had greater all-cause mortality risk than women with high plasma BDNF......-grade inflammation. No association was found between plasma BDNF and mortality in men, and serum BDNF did not influence mortality in either sex. CONCLUSION Low plasma BDNF is a novel, independent, and robust biomarker of mortality risk in old women. BDNF may be a central factor in the network of multimorbidity...

  12. The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer.

    Science.gov (United States)

    Wang, Kun; Demir, Ihsan Ekin; D'Haese, Jan G; Tieftrunk, Elke; Kujundzic, Kristina; Schorn, Stephan; Xing, Baocai; Kehl, Timo; Friess, Helmut; Ceyhan, Güralp O

    2014-01-01

    Neurotrophic factors possess an emerging role in the pathophysiology of several gastrointestinal disorders, regulating innervation, pain sensation and disease-associated neuroplasticity. Here, we aimed at characterizing the role of the neurotrophic factor neurturin (NRTN) and its receptor glial-cell-line-derived neurotrophic factor receptor alpha-2 (GFRα-2) in pancreatic cancer (PCa) and pancreatic neuropathy. For this purpose, NRTN and GFRα-2 were studied in normal human pancreas and PCa tissues via immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, immunoblotting and correlated to abdominal pain. The impact of NRTN/GFRα-2 on PCa cell (PCC) biology was investigated via exposure to hypoxia, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide viability and matrigel invasion assays in native and specific small interfering RNA-silenced PCCs. To assess the influence of NRTN on pancreatic neuroplasticity and neural invasion (NI), its impact was explored via an in vitro 'neuroplasticity assay' and a 3D neural migration assay. NRTN and GFRα-2 demonstrated a site-specific upregulation in PCa, predominantly in nerves, PCCs and extracellular matrix. Patients with severe pain demonstrated higher intraneural GFRα-2 immunoreactivity than patients with no pain. PCa tissue and PCCs contained increased amounts of NRTN, which was suppressed under hypoxia. NRTN promoted PCC invasiveness, and silencing of NRTN limited both PCC proliferation and invasion. Depletion of NRTN from PCa tissue extracts and PCC supernatants decreased axonal sprouting in neuronal cultures but did not influence glial density. Silencing of NRTN in PCCs boosted NI. We conclude that increased NRTN/GFRα-2 in PCa seems to promote an aggressive PCC phenotype and neuroplasticity in PCa. Accelerated NI following NRTN suppression constitutes a novel explanation for the attraction of PCC to nerves in the hypoxic PCa tumor microenvironment. PCa is characterized by

  13. Biomaterial-based drug delivery systems for the controlled release of neurotrophic factors

    International Nuclear Information System (INIS)

    Mohtaram, Nima Khadem; Montgomery, Amy; Willerth, Stephanie M

    2013-01-01

    This review highlights recent work on the use of biomaterial-based drug delivery systems to control the release of neurotrophic factors as a potential strategy for the treatment of neurological disorders. Examples of neurotrophic factors include the nerve growth factor, the glial cell line-derived neurotrophic factor, the brain-derived neurotrophic factor and neurotrophin-3. In particular, this review focuses on two methods of drug delivery: affinity-based and reservoir-based systems. We review the advantages and challenges associated with both types of drug delivery system and how these systems can be applied to neurological diseases and disorders. While a limited number of affinity-based delivery systems have been developed for the delivery of neurotrophic factors, we also examine the broad spectrum of reservoir-based delivery systems, including microspheres, electrospun nanofibers, hydrogels and combinations of these systems. Finally, conclusions are drawn about the current state of such drug delivery systems as applied to neural tissue engineering along with some thoughts on the future direction of the field. (topical review)

  14. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans

    DEFF Research Database (Denmark)

    Huang, T; Larsen, K T; Ried-Larsen, M

    2014-01-01

    The purpose of this study was to summarize the effects of physical activity and exercise on peripheral brain-derived neurotrophic factor (BDNF) in healthy humans. Experimental and observational studies were identified from PubMed, Web of Knowledge, Scopus, and SPORT Discus. A total of 32 articles...... met the inclusion criteria. Evidence from experimental studies suggested that peripheral BDNF concentrations were elevated by acute and chronic aerobic exercise. The majority of the studies suggested that strength training had no influence on peripheral BDNF. The results from most observational...... studies suggested an inverse relationship between the peripheral BDNF level and habitual physical activity or cardiorespiratory fitness. More research is needed to confirm the findings from the observational studies....

  15. Ciliary neurotrophic factor reduces proliferation and promotes differentiation of TH-MYCN transformed sympathoadrenal progenitors

    Science.gov (United States)

    DeWitt, John; Pappas, Anthony; Nishi, Rae

    2014-01-01

    Neuroblastoma is a childhood cancer caused by transformation of sympathoadrenal progenitors. By following the formation of tumors in homozygous TH-MYCN mice, an established mouse model of neuroblastoma, we were able to capture transformed cells prior to the formation of large, vascularized tumors in order to determine the responsiveness of cells to neurotrophic factors. We discovered that the CNTF receptor is abundantly expressed in tumor cells from these mice. Furthermore, CNTF, but not nerve growth factor, brain-derived nerve growth factor, NT-3, or glial cell line derived neurotrophic factor, promoted neuronal differentiation and withdrawal from the cell cycle. Thus, transformation of sympathoadrenal progenitors by MYCN overexpression differentially affects responsiveness to neurotrophic molecules. PMID:25171250

  16. Randomized trial of ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for retinitis pigmentosa.

    Science.gov (United States)

    Birch, David G; Weleber, Richard G; Duncan, Jacque L; Jaffe, Glenn J; Tao, Weng

    2013-08-01

    To evaluate the safety and effect on visual function of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa (RP). Ciliary neurotrophic factor for late-stage retinitis pigmentosa study 3 (CNTF3; n = 65) and ciliary neurotrophic factor for early-stage retinitis pigmentosa study 4 (CNTF4; n = 68) were multicenter, sham-controlled dose-ranging studies. Patients were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoints were change in best-corrected visual acuity (BCVA) at 12 months for CNTF3 and change in visual field sensitivity at 12 months for CNTF4. Patients had the choice of retaining or removing the implant at 12 months for CNTF3 and 24 months for CNTF4. There were no serious adverse events related to either the encapsulated cell implant or the surgical procedure. In CNTF3, there was no change in acuity in either ciliary neurotrophic factor- or sham-treated eyes at 1 year. In CNTF4, eyes treated with the high-dose implant showed a significant decrease in sensitivity while no change was seen in sham- and low dose-treated eyes at 12 months. The decrease in sensitivity was reversible upon implant removal. In both studies, ciliary neurotrophic factor treatment resulted in a dose-dependent increase in retinal thickness. Long-term intraocular delivery of ciliary neurotrophic factor is achieved by the encapsulated cell implant. Neither study showed therapeutic benefit in the primary outcome variable. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Brain-derived neurotrophic factor and ciliary neurotrophic factor in maternal plasma and umbilical cord blood from pre-eclamptic and physiological pregnancies.

    Science.gov (United States)

    Bienertova-Vasku, J; Bienert, P; Zlamal, F; Splichal, Z; Tomandl, J; Tomandlova, M; Hodicka, Z; Ventruba, P; Vasku, A

    2013-05-01

    The aim of the study was to investigate the circulating levels of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in maternal serum and umbilical cord blood from respective pregnancies in pre-eclampsia (PE) cases and a control cohort. A total of 12 pre-eclampsia cases and 34 healthy controls were enrolled and the maternal peripheral blood - umbilical cord blood duos, were examined for BDNF and CNTF levels. BNDF levels were significantly higher in umbilical cord blood from pre-eclamptic pregnancies; there was also significant difference between maternal plasma and umbilical cord blood levels of BDNF (p CNTF levels in umbilical cord blood (CNTF-UCB) were significantly higher in PE cases than in the controls (p = 0.03). Significant differences were observed in expression of BDNF and CNTF proteins in maternal peripheral blood and umbilical cord blood between pre-eclampsia cases and healthy controls.

  18. Potentiation of transmitter release by ciliary neurotrophic factor requires somatic signaling.

    Science.gov (United States)

    Stoop, R; Poo, M M

    1995-02-03

    Neurotrophic factors participate in the development and maintenance of the nervous system. Application of ciliary neurotrophic factor (CNTF), a protein that promotes survival of motor neurons, resulted in an immediate potentiation of spontaneous and impulse-evoked transmitter release at developing neuromuscular synapses in Xenopus cell cultures. When CNTF was applied at the synapse, the onset of the potentiation was slower than that produced by application at the cell body of the presynaptic neuron. The potentiation effect was abolished when the neurite shaft was severed from the cell body. Thus, transmitter secretion from the nerve terminals is under immediate somatic control and can be regulated by CNTF.

  19. Flavonoids Induce the Synthesis and Secretion of Neurotrophic Factors in Cultured Rat Astrocytes: A Signaling Response Mediated by Estrogen Receptor

    Directory of Open Access Journals (Sweden)

    Sherry L. Xu

    2013-01-01

    Full Text Available Neurotrophic factors are playing vital roles in survival, growth, and function of neurons. Regulation of neurotrophic factors in the brain has been considered as one of the targets in developing drug or therapy against neuronal disorders. Flavonoids, a family of multifunctional natural compounds, are well known for their neuronal beneficial effects. Here, the effects of flavonoids on regulating neurotrophic factors were analyzed in cultured rat astrocytes. Astrocyte is a major secreting source of neurotrophic factors in the brain. Thirty-three flavonoids were screened in the cultures, and calycosin, isorhamnetin, luteolin, and genistein were identified to be highly active in inducing the synthesis and secretion of neurotrophic factors, including nerve growth factor (NGF, glial-derived neurotrophic factor (GDNF, and brain-derived neurotrophic factor (BDNF. The inductions were in time- and dose-dependent manners. In cultured astrocytes, the phosphorylation of estrogen receptor was triggered by application of flavonoids. The phosphorylation was blocked by an inhibitor of estrogen receptor, which in parallel reduced the flavonoid-induced expression of neurotrophic factors. The results proposed the role of flavonoids in protecting brain diseases, and therefore these flavonoids could be developed for health food supplement for patients suffering from neurodegenerative diseases.

  20. [Polymorphism of brain derived neurotrophic factor and recovery of functions after ischemic stroke].

    Science.gov (United States)

    Liepert, J; Heller, A; Behnisch, G; Schoenfeld, A

    2015-10-01

    After ischemic stroke, many factors influence the restitution of functions. In particular they include the patient age, the initial stroke severity and the presence of cognitive and neuropsychological deficits. In this study we investigated whether a polymorphism in the gene encoding for brain derived neurotrophic factor (BDNF) influences improvements of motor functions and everyday activities. Patients with subacute ischemic stroke (n = 67) were examined at the beginning of an inpatient neurological rehabilitation, after 4 weeks of treatment and after 6 months. The Barthel index (BI) and the Rivermead motor assessment (RMA) were used to measure motor functions and everyday activities. Patients were allocated to three groups (valine [Val]/valine, val/methionine [Met] and Met/Met) depending on the BDNF polymorphism at codon 66. The 3 groups (Val/Val, n = 34 patients, Val/Met, n = 26 and Met/Met, n = 7) showed significant improvements in BI and RMA after 4 weeks and after 6 months as compared to the preceding measurements. The BI and RMA were positively correlated. The three groups did not differ with respect to the extent of improvement. After ischemic stroke, motor functions and everyday activities improved continuously over a period of at least 6 months. The BDNF polymorphism did not influence this development.

  1. Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis

    DEFF Research Database (Denmark)

    Kuhlmann, Tanja; Remington, Leah; Cognet, Isabelle

    2006-01-01

    Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a surv......Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described...... as a survival and differentiation factor for neurons and oligodendrocytes, significantly ameliorates the clinical course of a mouse model of multiple sclerosis. In the acute phase of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein peptide 35-55, treatment with CNTF did...... not change the peripheral immune response but did reduce the number of perivascular infiltrates and T cells and the level of diffuse microglial activation in spinal cord. Blood brain barrier permeability was significantly reduced in CNTF-treated animals. Beneficial effects of CNTF did not persist after...

  2. Correlates of early pregnancy serum brain-derived neurotrophic factor in a Peruvian population.

    Science.gov (United States)

    Yang, Na; Levey, Elizabeth; Gelaye, Bizu; Zhong, Qiu-Yue; Rondon, Marta B; Sanchez, Sixto E; Williams, Michelle A

    2017-12-01

    Knowledge about factors that influence serum brain-derived neurotrophic factor (BDNF) concentrations during early pregnancy is lacking. The aim of the study is to examine the correlates of early pregnancy serum BDNF concentrations. A total of 982 women attending prenatal care clinics in Lima, Peru, were recruited in early pregnancy. Pearson's correlation coefficient was calculated to evaluate the relation between BDNF concentrations and continuous covariates. Analysis of variance and generalized linear models were used to compare the unadjusted and adjusted BDNF concentrations according to categorical variables. Multivariable linear regression models were applied to determine the factors that influence early pregnancy serum BDNF concentrations. In bivariate analysis, early pregnancy serum BDNF concentrations were positively associated with maternal age (r = 0.16, P pregnancy body mass index (BMI) (r = 0.17, P pregnancy BMI (β = 1.58, P pregnancy serum BDNF concentrations. Participants with moderate antepartum depressive symptoms (Patient Health Questionnaire-9 (PHQ-9) score ≥ 10) had lower serum BDNF concentrations compared with participants with no/mild antepartum depressive symptoms (PHQ-9 score pregnancy BMI, gestational age, and the presence of moderate antepartum depressive symptoms were statistically significantly associated with early pregnancy serum BDNF concentrations in low-income Peruvian women. Biological changes of CRP during pregnancy may affect serum BDNF concentrations.

  3. Serum brain-derived neurotrophic factor levels and cocaine-induced transient psychotic symptoms.

    Science.gov (United States)

    Corominas-Roso, Margarida; Roncero, Carlos; Eiroa-Orosa, Francisco-Jose; Ribasés, Marta; Barral, Carmen; Daigre, Constanza; Martínez-Luna, Nieves; Sánchez-Mora, Cristina; Ramos-Quiroga, Josep Antoni; Casas, Miguel

    2013-01-01

    Cocaine-induced psychosis (CIP) is among the most serious adverse effects of cocaine. Reduced serum brain-derived neurotrophic factor (BDNF) levels have been reported in schizophrenia and psychosis; however, studies assessing the involvement of BDNF in CIP are lacking. A total of 22 cocaine-dependent patients (aged 33.65 ± 6.85) who had never experienced psychotic symptoms under the influence of cocaine (non-CIP) and 18 patients (aged 34.18 ± 8.54) with a history of CIP completed a 2-week detoxification program in an inpatient facility. Two serum samples were collected from each patient at baseline and at the end of the protocol. Demographic, consumption and clinical data were recorded for all patients. A paired group of healthy controls was also included. At the beginning of the detoxification treatment, serum BDNF levels were similar in both the non-CIP and the CIP groups. During early abstinence, the non-CIP group exhibited a significant increase in serum BDNF levels (p = 0.030), whereas the CIP group exhibited a decrease. Improvements in depression (Beck Depression Inventory, BDI, p = 0.003) and withdrawal symptoms (Cocaine Selective Severity Assessment, CSSA, p = 0.013) show a significant positive correlation with serum BDNF levels in the non-CIP group, whereas no correlation between the same variables was found in the CIP group. This study suggests that BDNF plays a role in the transient psychotic symptoms associated with cocaine consumption. In the non-CIP group, the increase in serum BDNF appears to be driven by the effects of chronic cocaine consumption and withdrawal. In contrast, patients with CIP share some of the neurotrophic deficiencies that characterize schizophrenia and psychosis. Copyright © 2013 S. Karger AG, Basel.

  4. Axon Guidance of Sympathetic Neurons to Cardiomyocytes by Glial Cell Line-Derived Neurotrophic Factor (GDNF)

    NARCIS (Netherlands)

    Miwa, Keiko; Lee, Jong-Kook; Takagishi, Yoshiko; Opthof, Tobias; Fu, Xianming; Hirabayashi, Masumi; Watabe, Kazuhiko; Jimbo, Yasuhiko; Kodama, Itsuo; Komuro, Issei

    2013-01-01

    Molecular signaling of cardiac autonomic innervation is an unresolved issue. Here, we show that glial cell line-derived neurotrophic factor (GDNF) promotes cardiac sympathetic innervation in vitro and in vivo. In vitro, ventricular myocytes (VMs) and sympathetic neurons (SNs) isolated from neonatal

  5. Brain-derived neurotrophic factor and early-life stress: Multifaceted ...

    Indian Academy of Sciences (India)

    The brain-derived neurotrophic factor (BDNF) is a key regulator of neural development and plasticity. Longtermchanges in the BDNF pathway are associated with childhood adversity and adult depression symptoms.Initially, stress-induced decreases in the BDNF pathway were found in some studies, but subsequent ...

  6. Human obesity associated with an intronic SNP in the brain-derived neurotrophic factor locus

    Science.gov (United States)

    Brain-derived neurotrophic factor (BDNF) plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 ...

  7. Circulating brain-derived neurotrophic factor has diagnostic and prognostic value in traumatic brain injury

    NARCIS (Netherlands)

    F.K. Korley (Frederick K.); R. Diaz-Arrastia (Ramon); A.H.B. Wu (Alan H. B.); J.K. Yue (John); G. Manley (Geoffrey); H.I. Sair (Haris I.); J.E. van Eyk (Jennifer); A.D. Everett (Allen D.); D. Okonkwo (David); A.B. Valadka (Alex); W.A. Gordon (Wayne A.); A.I.R. Maas (Andrew I.R.); P. Mukherjee (Pratik); E.L. Yuh (Esther); H.F. Lingsma (Hester); A.M. Puccio (Ava); D.M. Schnyer (David)

    2016-01-01

    textabstractBrain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency

  8. Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

    NARCIS (Netherlands)

    Barker, J.M.; Taylor, J.R.; de Vries, T.J.; Peters, J.

    2015-01-01

    Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural

  9. Decreased levels of brain-derived neurotrophic factor in the remitted state of unipolar depressive disorder

    DEFF Research Database (Denmark)

    Hasselbalch, Jacob; Knorr, U; Bennike, B

    2012-01-01

    Decreased levels of peripheral brain-derived neurotrophic factor (BDNF) have been associated with depression. It is uncertain whether abnormally low levels of BDNF in blood are present beyond the depressive state and whether levels of BDNF are associated with the course of clinical illness....

  10. The Impact of the Brain-Derived Neurotrophic Factor Gene on Trauma and Spatial Processing

    Directory of Open Access Journals (Sweden)

    Jessica K. Miller

    2017-11-01

    Full Text Available The influence of genes and the environment on the development of Post-Traumatic Stress Disorder (PTSD continues to motivate neuropsychological research, with one consistent focus being the Brain-Derived Neurotrophic Factor (BDNF gene, given its impact on the integrity of the hippocampal memory system. Research into human navigation also considers the BDNF gene in relation to hippocampal dependent spatial processing. This speculative paper brings together trauma and spatial processing for the first time and presents exploratory research into their interactions with BDNF. We propose that quantifying the impact of BDNF on trauma and spatial processing is critical and may well explain individual differences in clinical trauma treatment outcomes and in navigation performance. Research has already shown that the BDNF gene influences PTSD severity and prevalence as well as navigation behaviour. However, more data are required to demonstrate the precise hippocampal dependent processing mechanisms behind these influences in different populations and environmental conditions. This paper provides insight from recent studies and calls for further research into the relationship between allocentric processing, trauma processing and BDNF. We argue that research into these neural mechanisms could transform PTSD clinical practice and professional support for individuals in trauma-exposing occupations such as emergency response, law enforcement and the military.

  11. Decreased plasma brain-derived neurotrophic factor and vascular endothelial growth factor concentrations during military training.

    Directory of Open Access Journals (Sweden)

    Go Suzuki

    Full Text Available Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep.

  12. Mimicking the neurotrophic factor profile of embryonic spinal cord controls the differentiation potential of spinal progenitors into neuronal cells.

    Directory of Open Access Journals (Sweden)

    Masaya Nakamura

    Full Text Available Recent studies have indicated that the choice of lineage of neural progenitor cells is determined, at least in part, by environmental factors, such as neurotrophic factors. Despite extensive studies using exogenous neurotrophic factors, the effect of endogenous neurotrophic factors on the differentiation of progenitor cells remains obscure. Here we show that embryonic spinal cord derived-progenitor cells express both ciliary neurotrophic factor (CNTF and brain-derived neurotrophic factor (BDNF mRNA before differentiation. BDNF gene expression significantly decreases with their differentiation into the specific lineage, whereas CNTF gene expression significantly increases. The temporal pattern of neurotrophic factor gene expression in progenitor cells is similar to that of the spinal cord during postnatal development. Approximately 50% of spinal progenitor cells differentiated into astrocytes. To determine the effect of endogenous CNTF on their differentiation, we neutralized endogenous CNTF by administration of its polyclonal antibody. Neutralization of endogenous CNTF inhibited the differentiation of progenitor cells into astrocytes, but did not affect the numbers of neurons or oligodendrocytes. Furthermore, to mimic the profile of neurotrophic factors in the spinal cord during embryonic development, we applied BDNF or neurotrophin (NT-3 exogenously in combination with the anti-CNTF antibody. The exogenous application of BDNF or NT-3 promoted the differentiation of these cells into neurons or oligodendrocytes, respectively. These findings suggest that endogenous CNTF and exogenous BDNF and NT-3 play roles in the differentiation of embryonic spinal cord derived progenitor cells into astrocytes, neurons and oligodendrocytes, respectively.

  13. Experimental neurotrophic factor therapy leads to cortical synaptic remodeling and compensates for behavioral deficits.

    OpenAIRE

    Cuello, A C

    1997-01-01

    This brief review discusses experimental therapy with neurotrophic factors in a model of central nervous system (CNS) neural atrophy and synaptic loss resulting from unilateral cortical infarctions. It discusses the trophic factor protection of the cholinergic phenotype of neurons belonging to the forebrain-to-neocortex projection, as well as the capacity of trophic therapy to elicit synaptogenesis in the cerebral cortex of adult animals. Finally, it addresses the behavioral consequences of t...

  14. More inflammation but less brain-derived neurotrophic factor in antisocial personality disorder.

    Science.gov (United States)

    Wang, Tzu-Yun; Lee, Sheng-Yu; Hu, Ming-Chuan; Chen, Shiou-Lan; Chang, Yun-Hsuan; Chu, Chun-Hsien; Lin, Shih-Hsien; Li, Chia-Ling; Wang, Liang-Jen; Chen, Po See; Chen, Shih-Heng; Huang, San-Yuan; Tzeng, Nian-Sheng; Lee, I Hui; Chen, Kao Chin; Yang, Yen Kuang; Hong, Jau-Shyong; Lu, Ru-Band

    2017-11-01

    Antisocial personality disorder (ASPD) is highly comorbid with substance use disorders (SUDs). We hypothesize that chronic neuroinflammation and the loss of neurotrophic factors prompts the pathogenesis of both disorders. We used ELISA to measure plasma levels of proinflammatory (tumor necrosis factor-α [TNF-α], C-reactive protein [CRP]) and anti-inflammatory factors (transforming growth factor-β1 [TGF-β1] and interleukin-10 [IL-10]), and brain-derived neurotrophic factor (BDNF) in male patients with ASPD (n=74), SUDs (n=168), ASPD comorbid with SUDs (ASPD+SUDs) (n=438), and Healthy Controls (HCs) (n=81). A multivariate analysis of covariance (MANCOVA) controlled for possible confounders was used to compare cytokines and BDNF levels between groups. The results of MANCOVA adjusted for age showed a significant (pdisorder (OUD) and other SUDs groups showed that the IL-10 levels were specifically higher in OUD and ASPD±OUD groups than other SUDs (P≤0.001). We conclude that uncontrolled inflammation and losing neurotrophic factors, with or without comorbid SUDs, underlies ASPD. IL-10 expression might be more specifically associated with OUD. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. EGR3 Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Bianca Pfaffenseller

    2018-02-01

    Full Text Available Bipolar disorder (BD is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3 of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.

  16. Effect of brain-derived neurotrophic factor on the formation of psycho-vegetative syndrome with brain injury

    Directory of Open Access Journals (Sweden)

    Selyanina N.V.

    2016-09-01

    Full Text Available Aim: to determine the role of brain-derived neurotrophic factor in the formation and forecasting of psycho-vegetative syndrome in patients with cerebral mild to moderate injury. Material and Methods. There have been 150 patients with contusion of the brain, examined. Indicators of neurological, psycho-vegetative status, quantitative content of brain-derived neurotrophic factor (BDNF and nerve growth factor (NGF in the serum were studied. Results. At patients with brain contusion neurological, psycho-vegetative disturbances and decrease neurotrophic factors are determined. It was found to depend of the content of BDNF and psycho-vegetative indicators. Conclusion. The level of brain-derived neurotrophic factor serum (less than 300 pg/ml is a predictor of psycho-vegetative syndrome in the long term of the brain injury.

  17. Role of ciliary neurotrophic factor in the proliferation and differentiation of neural stem cells.

    Science.gov (United States)

    Ding, Jun; He, Zhili; Ruan, Juan; Ma, Zilong; Liu, Ying; Gong, Chengxin; Iqbal, Khalid; Sun, Shenggang; Chen, Honghui

    2013-01-01

    Ciliary neurotrophic factor (CNTF) is a pleiotropic cytokine that has been fully studied for its structure, receptor, and signaling pathways and its multiplex effects on neural system, skeletal muscle, and weight control. Recent research demonstrates that CNTF also plays an important role in neurogenesis and the differentiation of neural stem cells. In this article, we summarize the general characteristics of CNTF and its function on neural stem cells, which could be a valuable therapeutic strategy in treating neurological disorders.

  18. Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice

    OpenAIRE

    Yoneda, Mitsugu; Sugimoto, Naotoshi; Katakura, Masanori; Matsuzaki, Kentaro; Tanigami, Hayate; Yachie, Akihiro; Ohno-Shosaku, Takako; Shido, Osamu

    2017-01-01

    Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Theobromine works as a phosphodiesterase (PDE) inhibitor to increase intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the cAMP-response element-binding protein (CREB), which is involved in a large variety of brain processes, including the induction of the brain-derived neurotrophic factor (BDNF). BDNF supports cell survival and neuronal functions, including learning and m...

  19. Glial cell line-derived neurotrophic factor (GDNF) enhances sympathetic neurite growth in rat hearts at early developmental stages

    NARCIS (Netherlands)

    Miwa, Keiko; Lee, Jong-Kook; Takagishi, Yoshiko; Opthof, Tobias; Fu, Xianming; Kodama, Itsuo

    2010-01-01

    Molecular signaling of sympathetic innervation of myocardium is an unresolved issue. The purpose of this study was to investigate the effect of neurotrophic factors on sympathetic neurite growth towards cardiomyocytes. Cardiomyocytes (CMs) and sympathetic neurons (SNs) were isolated from neonatal

  20. Serum glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction after surgery for rheumatic heart disease.

    Science.gov (United States)

    Duan, Xiaoxia; Zhu, Tao; Chen, Chan; Zhang, Guanpeng; Zhang, Junhui; Wang, Lin; Zhang, Luye; Wang, Maohua; Wang, Xiaobin

    2018-03-01

    Postoperative cognitive dysfunction is an important complication of cardiac surgery with poor outcomes. Serum glial cell line-derived neurotrophic factor levels are decreased in patients with Alzheimer's disease, but the association between glial cell line-derived neurotrophic factor levels and postoperative cognitive dysfunction is poorly understood. The present study aimed to investigate the prognostic value of postoperative serum glial cell line-derived neurotrophic factor levels to predict postoperative cognitive dysfunction in patients with rheumatic heart disease undergoing heart valve replacement. This was a prospective observational study of 80 patients undergoing elective heart valve replacement surgery from June 2015 to June 2016 at the Affiliated Hospital of Southeast Medical University. Cognitive functions were assessed 1 day before and 7 days after surgery. Serum glial cell line-derived neurotrophic factor levels were measured by an enzyme-linked immunosorbent assay before (T1) and 1 (T2), 2 (T3), and 7 (T4) days after surgery. Perioperative parameters were evaluated to assess the relationship between glial cell line-derived neurotrophic factors and postoperative cognitive dysfunction. Postoperative cognitive dysfunction was identified in 38 patients (47.5%) 7 days after surgery. Average glial cell line-derived neurotrophic factor levels at 2 and 7 days after surgery in the postoperative cognitive dysfunction group were lower than in the nonpostoperative cognitive dysfunction group at the same time points (P derived neurotrophic factor (T1-T3) and Δglial cell line-derived neurotrophic factor (T1-T4) were identified as good predictors of postoperative cognitive dysfunction with threshold for postoperative cognitive dysfunction detection of 49.10 and 60.90, respectively. The perioperative glial cell line-derived neurotrophic factor levels in patients with postoperative cognitive dysfunction were lower than in patients without postoperative

  1. Neural Progenitor Cell Implants Modulate Vascular Endothelial Growth Factor and Brain-Derived Neurotrophic Factor Expression in Rat Axotomized Neurons

    Science.gov (United States)

    Talaverón, Rocío; Matarredona, Esperanza R.; de la Cruz, Rosa R.; Pastor, Angel M.

    2013-01-01

    Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs) are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and nerve growth factor (NGF) on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group) or vehicle injections (axotomized group) in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons, which might

  2. Neural progenitor cell implants modulate vascular endothelial growth factor and brain-derived neurotrophic factor expression in rat axotomized neurons.

    Directory of Open Access Journals (Sweden)

    Rocío Talaverón

    Full Text Available Axotomy of central neurons leads to functional and structural alterations which largely revert when neural progenitor cells (NPCs are implanted in the lesion site. The new microenvironment created by NPCs in the host tissue might modulate in the damaged neurons the expression of a high variety of molecules with relevant roles in the repair mechanisms, including neurotrophic factors. In the present work, we aimed to analyze changes in neurotrophic factor expression in axotomized neurons induced by NPC implants. For this purpose, we performed immunofluorescence followed by confocal microscopy analysis for the detection of vascular endothelial growth factor (VEGF, brain-derived neurotrophic factor (BDNF, neurotrophin-3 (NT-3 and nerve growth factor (NGF on brainstem sections from rats with axotomy of abducens internuclear neurons that received NPC implants (implanted group or vehicle injections (axotomized group in the lesion site. Control abducens internuclear neurons were strongly immunoreactive to VEGF and BDNF but showed a weak staining for NT-3 and NGF. Comparisons between groups revealed that lesioned neurons from animals that received NPC implants showed a significant increase in VEGF content with respect to animals receiving vehicle injections. However, the immunoreactivity for BDNF, which was increased in the axotomized group as compared to control, was not modified in the implanted group. The modifications induced by NPC implants on VEGF and BDNF content were specific for the population of axotomized abducens internuclear neurons since the neighboring abducens motoneurons were not affected. Similar levels of NT-3 and NGF immunolabeling were obtained in injured neurons from axotomized and implanted animals. Among all the analyzed neurotrophic factors, only VEGF was expressed by the implanted cells in the lesion site. Our results point to a role of NPC implants in the modulation of neurotrophic factor expression by lesioned central neurons

  3. Effect of glial cell line-derived neurotrophic factor on retinal function after experimental branch retinal vein occlusion

    DEFF Research Database (Denmark)

    Ejstrup, Rasmus; Dornonville de la Cour, Morten; Kyhn, Maria Voss

    2012-01-01

    The objective of the study was to investigate the effect of glial cell line-derived neurotrophic factor (GDNF) on the multifocal electroretinogram (mfERG) following an induced branch retinal vein occlusion (BRVO) in pigs.......The objective of the study was to investigate the effect of glial cell line-derived neurotrophic factor (GDNF) on the multifocal electroretinogram (mfERG) following an induced branch retinal vein occlusion (BRVO) in pigs....

  4. Modulation of visceral hypersensitivity by glial cell line-derived neurotrophic factor family receptor α-3 in colorectal afferents

    OpenAIRE

    Tanaka, T.; Shinoda, M.; Feng, B.; Albers, K. M.; Gebhart, G. F.

    2010-01-01

    Irritable bowel syndrome is characterized by colorectal hypersensitivity and contributed to by sensitized mechanosensitive primary afferents and recruitment of mechanoinsensitive (silent) afferents. Neurotrophic factors are well known to orchestrate dynamic changes in the properties of sensory neurons. Although pain modulation by proteins in the glial cell line-derived neurotrophic factor (GDNF) family has been documented in various pathophysiological states, their role in colorectal hypersen...

  5. Ageing of enteric neurons: oxidative stress, neurotrophic factors and antioxidant enzymes

    Directory of Open Access Journals (Sweden)

    Korsak Kris

    2012-08-01

    Full Text Available Abstract Background Ageing is associated with gastrointestinal dysfunction, which can have a major impact on quality of life of the elderly. A number of changes in the innervation of the gut during ageing have been reported, including neuronal loss and degenerative changes. Evidence indicates that reactive oxygen species (ROS are elevated in ageing enteric neurons, but that neurotrophic factors may reduce generation of neuronal ROS. Two such factors, glial cell line derived neurotrophic factor (GDNF and neurotrophin-3 (NT-3 have also been found to protect enteric neurons against oxidative stress induced cell death of enteric ganglion cells in vitro. We have investigated the possible roles of neurotrophic factors further, by examining their expression in the gut during ageing, and by analysing their effects on antioxidant enzyme production in cultures of enteric ganglion cells. Results Analysis of the expression of GDNF and its receptors c-Ret and GFR α − 1 in rat gut by RT-PCR showed that expression continues throughout life and into ageing, in both ad libitum(AL and calorically-restricted (CR animals. Levels of expression of GDNF and GFR α − 1 were elevated in 24 month AL animals compared to 24 month CR animals, and to 24 CR and 6 month control animals respectively. The related factor Neurturin and its receptor GFR α − 2 were also expressed throughout life, the levels of the GFR – α-2(b isoform were reduced in 24 m AL animals. Immunolabelling showed that c-Ret and GFR α − 1 proteins were expressed by myenteric neurons in ageing animals. GDNF, but not NT-3, was found to increase expression of Cu/Zn superoxide dismutase and catalase by cultured enteric ganglion cells. Conclusions The neurotrophic factors GDNF and neurturin and their receptors continue to be expressed in the ageing gut. Changes in the levels of expression of GDNF , GFR α-1 and GFR α-2(b isoform occurred in 24 m AL animals. GDNF, but not

  6. A small peptide mimetic of brain-derived neurotrophic factor promotes peripheral myelination.

    Science.gov (United States)

    Xiao, Junhua; Hughes, Richard A; Lim, Joe Y; Wong, Agnes W; Ivanusic, Jason J; Ferner, Anita H; Kilpatrick, Trevor J; Murray, Simon S

    2013-05-01

    The expression of the neurotrophins and their receptors is essential for peripheral nervous system development and myelination. We have previously demonstrated that brain-derived neurotrophic factor (BDNF) exerts contrasting influences upon Schwann cell myelination in vitro - promoting myelination via neuronally expressed p75NTR, but inhibiting myelination via neuronally expressed TrkB. We have generated a small peptide called cyclo-dPAKKR that structurally mimics the region of BDNF that binds p75NTR. Here, we have investigated whether utilizing cyclo-dPAKKR to selectively target p75NTR is an approach that could exert a unified promyelinating response. Like BDNF, cyclo-dPAKKR promoted myelination of nerve growth factor-dependent neurons in vitro, an effect dependent on the neuronal expression of p75NTR. Importantly, cyclo-dPAKKR also significantly promoted the myelination of tropomyosin-related kinase receptor B-expressing neurons in vitro, whereas BDNF exerted a significant inhibitory effect. This indicated that while BDNF exerted a contrasting influence upon the myelination of distinct subsets of dorsal root ganglion (DRG) neurons in vitro, cyclo-dPAKKR uniformly promoted their myelination. Local injection of cyclo-dPAKKR adjacent to the developing sciatic nerve in vivo significantly enhanced myelin protein expression and significantly increased the number of myelinated axons. These results demonstrate that cyclo-dPAKKR promotes peripheral myelination in vitro and in vivo, suggesting it is a strategy worthy of further investigation for the treatment of peripheral demyelinating diseases. © 2013 International Society for Neurochemistry.

  7. Sequential process in brain-derived neurotrophic factor-induced functional periodontal tissue regeneration.

    Science.gov (United States)

    Konishi, Akihiro; Takeda, Katsuhiro; Fujita, Tsuyoshi; Kajiya, Mikihito; Matsuda, Shinji; Kittaka, Mizuho; Shiba, Hideki; Kurihara, Hidemi

    2016-04-01

    We recently demonstrated that brain-derived neurotrophic factor (BDNF) promotes periodontal tissue regeneration. The purpose of this study was to establish an essential component of a rational approach for the clinical application of BDNF in periodontal regenerative therapy. Here, we assessed the sequence of early events in BDNF-induced periodontal tissue regeneration, especially from the aspect of cementum regeneration. Brain-derived neurotrophic factor was applied into experimental periodontal defects in Beagle dogs. The localization of cells positive for neurotrophic tyrosine kinase, receptor, type 2, proliferating cell nuclear antigen, osteopontin, integrin αVβ3, and integrin α2β1 was evaluated by immunohistochemistry. The effects of BDNF on adhesion of cultured human periodontal ligament cells was examined by an in vitro study. The results suggest that BDNF could induce rapid cementum regeneration by stimulating adhesion, proliferation, and differentiation of periodontal ligament cells in the early regenerative phase, resulting in enhancement of periodontal tissue regeneration. © 2016 Eur J Oral Sci.

  8. Brain-derived neurotrophic factor in asthmatic children.

    African Journals Online (AJOL)

    Ehab

    asthma by neurogenic inflammation. This pathway could be triggered by immune cells with the potential to release neurotrophins in allergic inflammation. Vice versa, immune cells are widely influenced by BDNF which is able to induce degranulation and differentiation of mast cells, the key cells of the early allergic ...

  9. In vitro assessment of TAT — Ciliary Neurotrophic Factor therapeutic potential for peripheral nerve regeneration

    International Nuclear Information System (INIS)

    Barbon, Silvia; Stocco, Elena; Negro, Alessandro; Dalzoppo, Daniele; Borgio, Luca; Rajendran, Senthilkumar; Grandi, Francesca; Porzionato, Andrea; Macchi, Veronica; De Caro, Raffaele

    2016-01-01

    In regenerative neurobiology, Ciliary Neurotrophic Factor (CNTF) is raising high interest as a multifunctional neurocytokine, playing a key role in the regeneration of injured peripheral nerves. Despite its promising trophic and regulatory activity, its clinical application is limited by the onset of severe side effects, due to the lack of efficient intracellular trafficking after administration. In this study, recombinant CNTF linked to the transactivator transduction domain (TAT) was investigated in vitro and found to be an optimized fusion protein which preserves neurotrophic activity, besides enhancing cellular uptake for therapeutic advantage. Moreover, a compelling protein delivery method was defined, in the future perspective of improving nerve regeneration strategies. Following determination of TAT-CNTF molecular weight and concentration, its specific effect on neural SH-SY5Y and PC12 cultures was assessed. Cell proliferation assay demonstrated that the fusion protein triggers PC12 cell growth within 6 h of stimulation. At the same time, the activation of signal transduction pathway and enhancement of cellular trafficking were found to be accomplished in both neural cell lines after specific treatment with TAT-CNTF. Finally, the recombinant growth factor was successfully loaded on oxidized polyvinyl alcohol (PVA) scaffolds, and more efficiently released when polymer oxidation rate increased. Taken together, our results highlight that the TAT domain addiction to the protein sequence preserves CNTF specific neurotrophic activity in vitro, besides improving cellular uptake. Moreover, oxidized PVA could represent an ideal biomaterial for the development of nerve conduits loaded with the fusion protein to be delivered to the site of nerve injury. - Highlights: • TAT-CNTF is an optimized fusion protein that preserves neurotrophic activity. • In neural cell lines, TAT-CNTF triggers the activation of signal transduction. • Fast cellular uptake of TAT-CNTF was

  10. Myokines (muscle-derived cytokines and chemokines) including ciliary neurotrophic factor (CNTF) inhibit osteoblast differentiation.

    Science.gov (United States)

    Johnson, Rachelle W; White, Jason D; Walker, Emma C; Martin, T John; Sims, Natalie A

    2014-07-01

    Muscle and bone are intimately linked by bi-directional signals regulating both muscle and bone cell gene expression and proliferation. It is generally accepted that muscle cells secrete factors (myokines) that influence adjacent bone cells, but these myokines are yet to be identified. We have previously shown that osteocyte-specific deletion of the co-receptor subunit utilized by IL-6 family cytokines, glycoprotein 130 (gp130), resulted in impaired bone formation in the trabecular bone, but enhanced periosteal expansion, suggesting a gp130-dependent periosteum-specific inhibition of osteoblast function, potentially induced by the local muscle fibres. We report here that differentiated primary calvarial osteoblasts cultured in myotube-conditioned media (CM) from myogenic C2C12 cells show reduced mRNA levels of genes associated with osteoblast differentiation. Alkaline phosphatase protein activity and all mRNA markers of osteoblast differentiation in the tested panel (runx2, osterix, alkaline phosphatase, parathyroid hormone (PTH) receptor, osteoprotegerin, osteocalcin, sclerostin) were reduced following culture with myotube CM. The exception was RANKL, which was significantly elevated in differentiated primary osteoblast cultures expressing osteocytic genes. A cytokine array of the C2C12 myotube-conditioned media identified TIMP-1 and MCP-1 as the most abundant myokines, but treatment with recombinant TIMP-1 or MCP-1 did not inhibit osteoblast gene expression. Rather, the IL-6 family cytokine ciliary neurotrophic factor (CNTF), which we found abundantly expressed by mouse muscle at the transcript and protein level, reduced osteoblast gene expression, although not to the same extent as the myotube-conditioned media. These data indicate that muscle cells secrete abundant TIMP-1, MCP-1, and CNTF, and that of these, only CNTF has the ability to suppress osteoblast function and gene expression in a similar manner to myotube-conditioned medium. This suggests that CNTF is

  11. Ciliary neurotrophic factor (CNTF) activation of astrocytes decreases spreading depolarization susceptibility and increases potassium clearance.

    Science.gov (United States)

    Seidel, Jessica L; Faideau, Mathilde; Aiba, Isamu; Pannasch, Ulrike; Escartin, Carole; Rouach, Nathalie; Bonvento, Gilles; Shuttleworth, C William

    2015-01-01

    Waves of spreading depolarization (SD) have been implicated in the progressive expansion of acute brain injuries. SD can persist over several days, coincident with the time course of astrocyte activation, but little is known about how astrocyte activation may influence SD susceptibility. We examined whether activation of astrocytes modified SD threshold in hippocampal slices. Injection of a lentiviral vector encoding Ciliary neurotrophic factor (CNTF) into the hippocampus in vivo, led to sustained astrocyte activation, verified by up-regulation of glial fibrillary acidic protein (GFAP) at the mRNA and protein levels, as compared to controls injected with vector encoding LacZ. In acute brain slices from LacZ controls, localized 1M KCl microinjections invariably generated SD in CA1 hippocampus, but SD was never induced with this stimulus in CNTF tissues. No significant change in intrinsic excitability was observed in CA1 neurons, but excitatory synaptic transmission was significantly reduced in CNTF samples. mRNA levels of the predominantly astrocytic Na(+) /K(+) -ATPase pump α2 subunit were higher in CNTF samples, and the kinetics of extracellular K(+) transients during matched synaptic activation were consistent with increased K(+) uptake in CNTF tissues. Supporting a role for the Na(+) /K(+) -ATPase pump in increased SD threshold, ouabain, an inhibitor of the pump, was able to generate SD in CNTF tissues. These data support the hypothesis that activated astrocytes can limit SD onset via increased K(+) clearance and suggest that therapeutic strategies targeting these glial cells could improve the outcome following acute brain injuries associated with SD. © 2014 Wiley Periodicals, Inc.

  12. The relationship between ciliary neurotrophic factor (CNTF genotype and motor unit physiology: preliminary studies

    Directory of Open Access Journals (Sweden)

    Ferrell Robert

    2005-09-01

    Full Text Available Abstract Background Ciliary neurotrophic factor (CNTF is important for neuronal and muscle development, and genetic variation in the CNTF gene has been associated with muscle strength. The effect of CNTF on nerve development suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. The purpose of this study is to examine whether CNTF genotype differentially affects motor unit activation in the vastus medialis with increasing isometric force during knee extension. Results Sixty-nine healthy subjects were genotyped for the presence of the G and A (null alleles in the CNTF gene (n = 57 G/G, 12 G/A. They were tested using a dynamometer during submaximal isometric knee extension contractions that were from 10–50% of their maximal strength. During the contractions, the vastus medialis was studied using surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP area and mean firing rates (mFR from identified motor units. CNTF genotyping was performed using standard PCR techniques from DNA obtained from leucocytes of whole blood samples. The CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The two groups used motor units with different size and activation characteristics with increasing force generation. While G/G subjects tended to utilize larger motor units with increasing force, G/A subjects showed relatively less increase in size by using relatively larger units at lower force levels. At higher force levels, G/A subjects were able to generate more force per motor unit size suggesting more efficient motor unit function with increasing muscle force. Conclusion Differential motor unit responses were observed between CNTF genotypes at force levels utilized in daily activities.

  13. The relationship between ciliary neurotrophic factor (CNTF) genotype and motor unit physiology: preliminary studies.

    Science.gov (United States)

    Conwit, Robin A; Ling, Shari; Roth, Stephen; Stashuk, Daniel; Hurley, Ben; Ferrell, Robert; Metter, E Jeffrey

    2005-09-23

    Ciliary neurotrophic factor (CNTF) is important for neuronal and muscle development, and genetic variation in the CNTF gene has been associated with muscle strength. The effect of CNTF on nerve development suggests that CNTF genotype may be associated with force production via its influence on motor unit size and firing patterns. The purpose of this study is to examine whether CNTF genotype differentially affects motor unit activation in the vastus medialis with increasing isometric force during knee extension. Sixty-nine healthy subjects were genotyped for the presence of the G and A (null) alleles in the CNTF gene (n = 57 G/G, 12 G/A). They were tested using a dynamometer during submaximal isometric knee extension contractions that were from 10-50% of their maximal strength. During the contractions, the vastus medialis was studied using surface and intramuscular electromyography with spiked triggered averaging to assess surface-detected motor unit potential (SMUP) area and mean firing rates (mFR) from identified motor units. CNTF genotyping was performed using standard PCR techniques from DNA obtained from leucocytes of whole blood samples. The CNTF G/A genotype was associated with smaller SMUP area motor units and lower mFR at higher force levels, and fewer but larger units at lower force levels than G/G homozygotes. The two groups used motor units with different size and activation characteristics with increasing force generation. While G/G subjects tended to utilize larger motor units with increasing force, G/A subjects showed relatively less increase in size by using relatively larger units at lower force levels. At higher force levels, G/A subjects were able to generate more force per motor unit size suggesting more efficient motor unit function with increasing muscle force. Differential motor unit responses were observed between CNTF genotypes at force levels utilized in daily activities.

  14. Chronically increased ciliary neurotrophic factor and fibroblast growth factor-2 expression after spinal contusion in rats.

    Science.gov (United States)

    Tripathi, Richa B; McTigue, Dana M

    2008-09-10

    Demyelination and oligodendrocyte loss following spinal cord injury (SCI) are well documented. Recently, we showed oligodendrocyte progenitor cell (OPC) accumulation and robust oligodendrocyte genesis occurring along SCI lesion borders. We have since begun investigating potential mechanisms for this endogenous repair response. Here, we examined ciliary neurotrophic factor (CNTF) and fibroblast growth factor-2 (FGF-2) expression, because both factors alter progenitor proliferation and differentiation and are increased in several CNS disorders. We hypothesized that CNTF and FGF-2 would increase after SCI, especially in regions of enhanced oligogenesis. First, CNTF protein was quantified using Western blots, which revealed that CNTF protein continually rose through 28 days post injury (dpi). Next, by using immunohistochemistry, we examined the spatiotemporal expression of CNTF in cross-sections spanning the injury site. CNTF immunoreactivity was observed on astrocytes and oligodendrocytes in naïve and contused spinal cords. Significantly increased CNTF was detected in spared white and gray matter between 5 and 28 dpi compared with uninjured controls. By 28 dpi, CNTF expression was significantly higher along lesion borders compared with outlying spared tissue; a similar distribution of phosphorylated STAT3, a transcription factor up-regulated by CNTF and to a lesser extent FGF-2, was also detected. Because CNTF can potentiate FGF-2 expression, we examined the distribution of FGF-2+ cells. Significantly more FGF-2+ cells were noted along lesion borders at 7 and 28 dpi. Thus, both CNTF and FGF-2 are present in regions of elevated OPC proliferation and oligodendrocyte generation after SCI and therefore may play a role in injury-induced gliogenesis. (c) 2008 Wiley-Liss, Inc.

  15. Concentrated growth factor increases Schwann cell proliferation and neurotrophic factor secretion and promotes functional nerve recovery in vivo.

    Science.gov (United States)

    Qin, Jie; Wang, Lin; Sun, Yue; Sun, Xiaolin; Wen, Chaoju; Shahmoradi, Mahdi; Zhou, Yanmin

    2016-02-01

    Concentrated growth factor (CGF) is a newly generated complex that comprises a fibrin matrix incorporating growth factors and plasmatic and leukocyte cytokines. It has been widely used in bone regenerative medicine. However, the effect of CGF on peripheral nerve regeneration had not been previously investigated. The aim of the present study was to evaluate the possibility of using CGF for nerve regeneration by i) investigating the effect of CGF on the proliferation of Schwann cells (SCs) and secretion of neurotrophic factors nerve growth factor (NGF) and glial cell line‑derived neurotrophic factor (GDNF) in vitro; and ii) analyzing the effect of CGF on functional nerve recovery after nerve injury in vivo. CGF was prepared from venous blood taken from rats, and using scanning electron microscopy (SEM) we noted that it featured a fiber‑like appearance with pore size ranging from 0.1 to 1.0 µm. The soluble component of CGF was used to produce conditioned media with which to treat the Schwann cell line. A cell counting kit-8 assay and cell cycle analysis were both used to study the proliferative effect of CGF on SCs. Reverse transcription-quantitative PCR and western blot analysis demonstrated that there was an increase in the mRNA and protein expression of NGF and GDNF, both of which are markers of SC neurotrophic secretion. A model of sciatic nerve crush injury was established for the in vivo experiment, and CGF was found to increase the sciatic functional index (indicative of nerve function). We noted that CGF increased SC proliferation and secretion of neurotrophic factors in vitro, and promoted functional recovery after peripheral nerve injuries in vivo. These results suggest that CGF is a promising candidate biomaterial for peripheral nerve regeneration, and may potentially be utilized to repair nerve injuries.

  16. Modulation of neurogenesis via neurotrophic factors in acupuncture treatments for neurological diseases.

    Science.gov (United States)

    Shin, Hwa Kyoung; Lee, Sae-Won; Choi, Byung Tae

    2017-10-01

    Acupuncture is one of the main healing arts in Oriental medicine. It has long been used in East Asian countries, including Korea and China, and is thought to be an effective alternative treatment for various neurological diseases. The therapeutic effects of acupuncture come from inserting a needle at specific acupoints on the body surface, with subsequent delivery of stimulation via manual rotation or electric pulses (electroacupuncture, EA). In various neurological disease models, peripheral nerve stimulation using acupuncture or EA may have protective effects on neural tissues by increasing expression of neurotrophic factors (NTFs), such as brain-derived neurotrophic factor and glial-derived neurotrophic factor, in the central nervous system, especially the brain. In addition, acupuncture may contribute to recovery from functional impairments following brain damage by encouraging neural stem cell proliferation, which is active at the initial stage of injury, and by further facilitating differentiation. Hence, acupuncture may act as a stimulator activating peripheral nerves at specific acupoints and inducing the expression of various NTFs in the brain. Subsequently, NTFs induced by this treatment trigger autocrine or paracrine signaling, which stimulates adult neurogenesis, thereby exerting therapeutic effects on functional impairments in neurological diseases. Acupuncture may offer an alternative treatment that promotes adult neurogenesis through the expression of NTFs in the brain. It may also have synergistic effects when combined with pharmacological interventions, again facilitating neurogenesis. This review examines recent studies concerning the effects of acupuncture and EA on adult neurogenesis associated with NTF expression in neurological diseases, in particular stroke, Alzheimer's disease, and Parkinson's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Molecular mechanisms underlying the regulation of brain-derived neurotrophic factor (BDNF) translation in dendrites

    OpenAIRE

    Pinheiro, Vera Lúcia Margarido

    2010-01-01

    Dissertação de mestrado em Biologia Celular e Molecular apresentada ao Departamento de Ciências da Vida da Faculdade de Ciências e Tecnologia da Universidade de Coimbra A especificidade espacial e temporal subjacente à diversidade de processos de plasticidade sináptica que ocorrem no sistema nervoso central está profundamente relacionada com a disponibilidade da proteína brain-derived neurotrophic factor (BDNF) em domínios sub-celulares distintos, especialmente na área pós-sinápti...

  18. Pharmacokinetics of intravitreal glial cell line-derived neurotrophic factor: experimental studies in pigs

    DEFF Research Database (Denmark)

    Ejstrup, Rasmus; Kiilgaard, J F; Tucker, B A

    2010-01-01

    a retinal ganglion cell line (RGC5) bioassay. Indirect ophthalmoscopy, intraocular pressure assessment, and fundus photography were performed before enucleation. There was initial variability in the cGDNF, but after 24h GDNF was cleared in a monoexponential fashion with a half-life of 37 h (CL 33-43 h......The purpose of this study was to establish the intravitreal (ITV) pharmacokinetics of glial cell line-derived neurotrophic factor (GDNF) and observe possible complications after ITV injection. Twenty Danish landrace pigs and 34 eyes were included in the study; 30 were injected with 100 ng of GDNF...

  19. Pharmacokinetics of intravitreal glial cell line-derived neurotrophic factor: experimental studies in pigs

    DEFF Research Database (Denmark)

    Ejstrup, Rasmus; Kiilgaard, J F; Tucker, B A

    2010-01-01

    The purpose of this study was to establish the intravitreal (ITV) pharmacokinetics of glial cell line-derived neurotrophic factor (GDNF) and observe possible complications after ITV injection. Twenty Danish landrace pigs and 34 eyes were included in the study; 30 were injected with 100 ng of GDNF...... a retinal ganglion cell line (RGC5) bioassay. Indirect ophthalmoscopy, intraocular pressure assessment, and fundus photography were performed before enucleation. There was initial variability in the cGDNF, but after 24h GDNF was cleared in a monoexponential fashion with a half-life of 37 h (CL 33-43 h...

  20. Brain Derived Neurotrophic Factor moderates associations between maternal smoking during pregnancy and offspring behavioral disorders

    Science.gov (United States)

    Talati, Ardesheer; Odgerel, Zagaa; Wickramaratne, Priya J; Weissman, Myrna M

    2016-01-01

    Maternal smoking during pregnancy is associated with a number of adverse offspring outcomes. In the present study, based on 209 offspring from a 3-generation family study of depression, we show that the effects of prenatal exposure on offspring externalizing psychopathology (conduct, substance use disorder) is more pronounced in the presence of lower-expressing brain derived neurotrophic factor (BDNF) gene variants. BDNF plays an important role in the development and survival of neural circuits. Individuals with low-expressing variants who are further exposed to prenatal tobacco smoke may be most vulnerable to a spectrum of behavioral disorders that depend on these circuits. PMID:27611068

  1. Expression of neurotrophic factors in diabetic muscle--relation to neuropathy and muscle strength.

    Science.gov (United States)

    Andreassen, C S; Jakobsen, J; Flyvbjerg, A; Andersen, H

    2009-10-01

    Diabetic polyneuropathy can lead to atrophy and weakness of distally located striated muscles due to denervation. Lack of neurotrophic support is believed to contribute to the development of diabetic neuropathy. In this study, we measured the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4) and ciliary neurotrophic factor (CNTF) in muscle biopsies taken from the gastrocnemic and deltoid muscles in 42 diabetic patients and 20 healthy control subjects. To express the distal neuropathic gradient and to reduce interindividual variation, a distal/proximal ratio between expression levels in the gastrocnemic and deltoid muscles was calculated for all neurotrophic factors. Neuropathic status was determined by clinical examination, electrophysiological studies and quantitative sensory examination in diabetic patients, and muscle strength at both the shoulder and ankle was assessed by isokinetic dynamometry. Distal/proximal ratios for NT-3 were lower in diabetic patients [median (range) 110.7 (39.8-546.8)] than in controls [157.6 (63.3-385.4); (P < 0.05)], and in neuropathic diabetic patients [107.1 (39.8-326.0)] versus patients without neuropathy [134.5 (46.6-546.8); (P < 0.005)]. Further, ratios for NT-3 were related to muscle strength (r(s) = 0.41, P < 0.01) and showed a tendency towards a negative relationship to the combined score of all measures of neuropathy [Neuropathy rank-sum score (NRSS)] (r(s) = -0.27, P = 0.09). Similar trends were observed for ratios for NT-4. Ratios for NGF (r(s) = -0.32, P < 0.05) and BDNF (r(s) = -0.32, P < 0.05) were related to NRSS, but not to muscle strength. Ratios for CNTF were higher in diabetic patients [64.6 (23.7-258.7)] compared with controls [50.2 (27.2-186.4); (P < 0.05)], but showed no relationship to neither NRSS nor muscle strength. Our results show that the expression of NT-3 is reduced in striated muscles in diabetic patients and is related to

  2. Brain-derived neurotrophic factor, impaired glucose metabolism, and bipolar disorder course

    DEFF Research Database (Denmark)

    Mansur, Rodrigo B; Santos, Camila M; Rizzo, Lucas B

    2016-01-01

    OBJECTIVES: The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism...... mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured. RESULTS: Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking...

  3. Transplants and neurotrophic factors increase regeneration and recovery of function after spinal cord injury.

    Science.gov (United States)

    Bregman, Barbara S; Coumans, Jean-Valery; Dai, Hai Ning; Kuhn, Penelope L; Lynskey, James; McAtee, Marietta; Sandhu, Faheem

    2002-01-01

    Earlier studies suggested that while after spinal cord lesions and transplants at birth, the transplants serve both as a bridge and as a relay to restore supraspinal input caudal to the injury (Bregman, 1994), after injury in the adult the spinal cord transplants serve as a relay, but not as a bridge. We show here, that after complete spinal cord transection in adult rats, delayed spinal cord transplants and exogenous neurotrophic factors, the transplants can also serve as a bridge to restore supraspinal input (Fig. 9). We demonstrate here that when the delivery of transplants and neurotrophins are delayed until 2 weeks after spinal cord transection, the amount of axonal growth and the amount of recovery of function are dramatically increased. Under these conditions, both supraspinal and propriospinal projections to the host spinal cord caudal to the transection are reestablished. The growth of supraspinal axons across the transplant and back into the host spinal cord caudal to the lesion was dependent upon the presence of exogenous neurotrophic support. Without the neurotrophins, only propriospinal axons were able to re-establish connections across the transplant. Studies using peripheral nerve or Schwann cell grafts have shown that some anatomical connectivity can be restored across the injury site, particularly under the influence of neurotrophins (Xu et al., 1995a,b; Cheng et al., 1996; Ye and Houle, 1997). Without neurotrophin treatment, brainstem axons do not enter [figure: see text] the graft (Xu et al., 1995a,b; Cheng et al., 1996; Ye and Houle, 1997). Similarly, cells genetically modified to secrete neurotrophins and transplanted into the spinal cord influence the axonal growth of specific populations of spinally projecting neurons (Tuszynski et al., 1996, 1997; Grill et al., 1997; Blesch and Tuszynski, 1997). Taken together, these studies support a role for neurotrophic factors in the repair of the mature CNS. The regrowth of supraspinal and propriospinal

  4. Impaired expression of ciliary neurotrophic factor in Charcot-Marie-Tooth type 1A neuropathy.

    Science.gov (United States)

    Nobbio, Lucilla; Fiorese, Fulvia; Vigo, Tiziana; Cilli, Michele; Gherardi, Gianfranco; Grandis, Marina; Melcangi, Roberto Cosimo; Mancardi, Gianluigi; Abbruzzese, Michele; Schenone, Angelo

    2009-05-01

    We investigated the contribution of Schwann cell-derived ciliary neurotrophic factor (CNTF) to the pathogenesis of Charcot-Marie-Tooth disease type 1A (CMT1A) and addressed the question as to whether it plays a role in the development of axonal damage observed in the disease, with aging. Ciliary neurotrophic factor was underexpressed in experimental CMT1A but not in other models of hereditary neuropathies. Sciatic nerve crush experiments and dosage of CNTF at different time points showed that expression of this trophic factor remained significantly lower in CMT1A rats than in normal controls; moreover, in uninjured CMT1A sciatic nerves CNTF levels further decreased with ageing, thus paralleling the molecular signs of axonal impairment, that is increased expression of non-phosphorylated neurofilaments and amyloid precursor protein. Administration of CNTF to dorsal root ganglia cultures reduced dephosphorylation of neurofilaments in CMT1A cultures, without improving demyelination. Taken together, these results provide further evidence that the production of CNTF by Schwann cells is markedly reduced in CMT1A. Moreover, the observations suggest that trophic support to the axon is impaired in CMT1A and that further studies on the therapeutic use of trophic factors or their derivatives in experimental and human CMT1A are warranted.

  5. Dysregulation of neurotrophic and haematopoietic growth factors in Alzheimer's disease: from pathophysiology to novel treatment strategies.

    Science.gov (United States)

    Sopova, Kateryna; Gatsiou, Katerina; Stellos, Konstantinos; Laske, Christoph

    2014-01-01

    Alzheimer's disease (AD) is the leading cause of dementia in the elderly. Growth factors have been demonstrated to act in a synergistic way in angiogenesis and neurogenesis contributing to self-healing powers of the adult human brain. A growing body of evidence demonstrates that levels of many growth factors (neurotrophins and hematopoietins) are altered in cerebrospinal fluid and peripheral blood from AD patients and in animal models of AD. The present review summarizes the role of several neurotrophic growth factors (e.g., BDNF, SCF, NGF, GDNF) and haematopoietic growth factors (e.g., G-CSF, VEGF, SDF-1) in AD. Moreover, we summarize recent studies evaluating the diagnostic and prognostic value of growth factor levels in blood and cerebrospinal fluid in patients with AD and discuss the potential role of these growth factors as a promising new therapeutic approach in AD.

  6. Exposure to Early Life Stress Results in Epigenetic Changes in Neurotrophic Factor Gene Expression in a Parkinsonian Rat Model

    Directory of Open Access Journals (Sweden)

    Thabisile Mpofana

    2016-01-01

    Full Text Available Early life adversity increases the risk of mental disorders later in life. Chronic early life stress may alter neurotrophic factor gene expression including those for brain derived neurotrophic factor (BDNF and glial cell derived neurotrophic factor (GDNF that are important in neuronal growth, survival, and maintenance. Maternal separation was used in this study to model early life stress. Following unilateral injection of a mild dose of 6-hydroxydopamine (6-OHDA, we measured corticosterone (CORT in the blood and striatum of stressed and nonstressed rats; we also measured DNA methylation and BDNF and GDNF gene expression in the striatum using real time PCR. In the presence of stress, we found that there was increased corticosterone concentration in both blood and striatal tissue. Further to this, we found higher DNA methylation and decreased neurotrophic factor gene expression. 6-OHDA lesion increased neurotrophic factor gene expression in both stressed and nonstressed rats but this increase was higher in the nonstressed rats. Our results suggest that exposure to early postnatal stress increases corticosterone concentration which leads to increased DNA methylation. This effect results in decreased BDNF and GDNF gene expression in the striatum leading to decreased protection against subsequent insults later in life.

  7. In vitro assessment of TAT - Ciliary Neurotrophic Factor therapeutic potential for peripheral nerve regeneration.

    Science.gov (United States)

    Barbon, Silvia; Stocco, Elena; Negro, Alessandro; Dalzoppo, Daniele; Borgio, Luca; Rajendran, Senthilkumar; Grandi, Francesca; Porzionato, Andrea; Macchi, Veronica; De Caro, Raffaele; Parnigotto, Pier Paolo; Grandi, Claudio

    2016-10-15

    In regenerative neurobiology, Ciliary Neurotrophic Factor (CNTF) is raising high interest as a multifunctional neurocytokine, playing a key role in the regeneration of injured peripheral nerves. Despite its promising trophic and regulatory activity, its clinical application is limited by the onset of severe side effects, due to the lack of efficient intracellular trafficking after administration. In this study, recombinant CNTF linked to the transactivator transduction domain (TAT) was investigated in vitro and found to be an optimized fusion protein which preserves neurotrophic activity, besides enhancing cellular uptake for therapeutic advantage. Moreover, a compelling protein delivery method was defined, in the future perspective of improving nerve regeneration strategies. Following determination of TAT-CNTF molecular weight and concentration, its specific effect on neural SH-SY5Y and PC12 cultures was assessed. Cell proliferation assay demonstrated that the fusion protein triggers PC12 cell growth within 6h of stimulation. At the same time, the activation of signal transduction pathway and enhancement of cellular trafficking were found to be accomplished in both neural cell lines after specific treatment with TAT-CNTF. Finally, the recombinant growth factor was successfully loaded on oxidized polyvinyl alcohol (PVA) scaffolds, and more efficiently released when polymer oxidation rate increased. Taken together, our results highlight that the TAT domain addiction to the protein sequence preserves CNTF specific neurotrophic activity in vitro, besides improving cellular uptake. Moreover, oxidized PVA could represent an ideal biomaterial for the development of nerve conduits loaded with the fusion protein to be delivered to the site of nerve injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. ERK-mediated production of neurotrophic factors by astrocytes promotes neuronal stem cell differentiation by erythropoietin.

    Science.gov (United States)

    Park, Mi Hee; Lee, Sang Min; Lee, Jae Woong; Son, Dong Ju; Moon, Dong Cheul; Yoon, Do Young; Hong, Jin Tae

    2006-01-27

    Erythropoietin (EPO), a hematopoietic factor, is also required for normal brain development, and its receptor is localized in brain. Our previous study showed that EPO promotes differentiation of neuronal stem cells into astrocytes. Since astrocytes have influence on the neuronal function, we investigated whether EPO-activated astrocytes could stimulate differentiation of neuronal stem cells into neurons. EPO did not promote neuronal differentiation of neuronal stem cells isolated from 17 day embryos, however, neuronal differentiation was promoted when the neuronal stem cells were co-cultured with astrocyte isolated from post neonatal (Day 1) rat brain. Moreover, neuronal differentiation was further promoted when the neuronal stem cells were cultured with astrocyte culture medium treated by EPO (10U/ml) showing increase of morphological differentiation, and expression of neuronal differentiation marker proteins, neurofilament, and tyrosine hydroxylase. The promoting effect of EPO-treated astrocyte medium was also found in the differentiation of PC12 cells. EPO-promoted morphological differentiation of neuronal stem cells as well as astrocytes was dose dependently reduced by treatment with anti-EPO receptor antibodies in culture with astrocyte culture medium. To clarify whether EPO itself or via production of well-known neurotropic factor could promote neuronal cell differentiation, we determined the level of neurotropic factors in the EPO-treated astrocytes. Compared to untreated astrocytes, EPO-treated astrocytes increased about 2-fold in beta-NGF and 3-4-fold in BMP2, but did not increase BNDF and NT-3 levels. Since the previous study showed that extracellular signal-regulated kinase (ERK) is involved in activation of astrocytes by EPO, we determined whether generation of neurotrophic factor may also be involved with the ERK pathway. In the presence of ERK inhibitor, PD98059, the generation of beta-NGF was diminished in a dose dependent manner consistent with the

  9. Brain Ciliary Neurotrophic Factor (CNTF and hypothalamic control of energy homeostasis

    Directory of Open Access Journals (Sweden)

    Vacher Claire-Marie

    2011-09-01

    Full Text Available Cytokines play an important role in energy-balance regulation. Notably leptin, an adipocyte-secreted cytokine, regulates the activity of hypothalamic neurons that are involved in the modulation of appetite. Leptin decreases appetite and stimulates weight loss in rodents. Unfortunately, numerous forms of obesity in humans seem to be resistant to leptin action. The ciliary neurotrophic factor (CNTF is a neurocytokine that belongs to the same family as leptin and that was originally characterized as a neurotrophic factor that promotes the survival of a broad spectrum of neuronal cell types and that enhances neurogenesis in adult rodents. It presents the advantage of stimulating weight loss in humans, despite the leptin resistance. Moreover, the weight loss persists several weeks after the cessation of treatment. Hence, CNTF has been considered as a promising therapeutic tool for the treatment of obesity and has prompted intense research aimed at identifying the cellular and molecular mechanisms underlying its potent anorexigenic properties. It has been found that CNTF shares signaling pathways with leptin and is expressed in the arcuate nucleus (ARC, a key hypothalamic region controlling food intake. Endogenous CNTF may also participate in the control of energy balance. Indeed, its expression in the ARC is inversely correlated to body weight in rats fed a high-sucrose diet. Thus hypothalamic CNTF may act, in some individuals, as a protective factor against weight gain during hypercaloric diet and could account for individual differences in the susceptibility to obesity.

  10. Axon guidance of sympathetic neurons to cardiomyocytes by glial cell line-derived neurotrophic factor (GDNF.

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    Keiko Miwa

    Full Text Available Molecular signaling of cardiac autonomic innervation is an unresolved issue. Here, we show that glial cell line-derived neurotrophic factor (GDNF promotes cardiac sympathetic innervation in vitro and in vivo. In vitro, ventricular myocytes (VMs and sympathetic neurons (SNs isolated from neonatal rat ventricles and superior cervical ganglia were cultured at a close distance. Then, morphological and functional coupling between SNs and VMs was assessed in response to GDNF (10 ng/ml or nerve growth factor (50 ng/ml. As a result, fractions of neurofilament-M-positive axons and synapsin-I-positive area over the surface of VMs were markedly increased with GDNF by 9-fold and 25-fold, respectively, compared to control without neurotrophic factors. Pre- and post-synaptic stimulation of β1-adrenergic receptors (BAR with nicotine and noradrenaline, respectively, resulted in an increase of the spontaneous beating rate of VMs co-cultured with SNs in the presence of GDNF. GDNF overexpressing VMs by adenovirus vector (AdGDNF-VMs attracted more axons from SNs compared with mock-transfected VMs. In vivo, axon outgrowth toward the denervated myocardium in adult rat hearts after cryoinjury was also enhanced significantly by adenovirus-mediated GDNF overexpression. GDNF acts as a potent chemoattractant for sympathetic innervation of ventricular myocytes, and is a promising molecular target for regulation of cardiac function in diseased hearts.

  11. CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium.

    Science.gov (United States)

    Li, Rong; Wen, Rong; Banzon, Tina; Maminishkis, Arvydas; Miller, Sheldon S

    2011-01-01

    Ciliary neurotrophic factor (CNTF) protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE) physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE). Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFRα, LIFRβ, gp130, and OsMRβ, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase). CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGFβ2. It also significantly increases fluid absorption (J(V)) across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease.

  12. CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium.

    Directory of Open Access Journals (Sweden)

    Rong Li

    Full Text Available Ciliary neurotrophic factor (CNTF protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE. Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFRα, LIFRβ, gp130, and OsMRβ, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase. CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGFβ2. It also significantly increases fluid absorption (J(V across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease.

  13. Regulation of neurotrophic factors and energy metabolism by antidepressants in astrocytes

    KAUST Repository

    Martin, Jean Luc

    2013-09-01

    There is growing evidence that astrocytes are involved in the neuropathology of major depression. In particular, decreases in glial cell density observed in the cerebral cortex of individuals with major depressive disorder are accompanied by a reduction of several astrocytic markers suggesting that astrocyte dysfunction may contribute to the pathophysiology of major depression. In rodents, glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors and antidepressant treatment prevents the stress-induced reduction of astrocyte number in the hippocampus. Collectively, these data support the existence of a link between astrocyte loss or dysfunction, depressive-like behavior and antidepressant treatment. Astrocytes are increasingly recognized to play important roles in neuronal development, neurotransmission, synaptic plasticity and maintenance of brain homeostasis. It is also well established that astrocytes provide trophic, structural, and metabolic support to neurons. In this article, we review evidence that antidepressants regulate energy metabolism and neurotrophic factor expression with particular emphasis on studies in astrocytes. These observations support a role for astrocytes as new targets for antidepressants. The contribution of changes in astrocyte glucose metabolism and neurotrophic factor expression to the therapeutic effects of antidepressants remains to be established. © 2013 Bentham Science Publishers.

  14. Brain-derived Neurotrophic Factor (BDNF) and gray matter volume in bipolar disorder.

    Science.gov (United States)

    Poletti, S; Aggio, V; Hoogenboezem, T A; Ambrée, O; de Wit, H; Wijkhuijs, A J M; Locatelli, C; Colombo, C; Arolt, V; Drexhage, H A; Benedetti, F

    2017-02-01

    Bipolar Disorder (BD) is a severe psychiatric condition characterized by grey matter (GM) volumes reduction. Neurotrophic factors have been suggested to play a role in the neuroprogressive changes during the illness course. In particular peripheral brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker related to disease activity and neuroprogression in BD. The aim of our study was to investigate if serum levels of BDNF are associated with GM volumes in BD patients and healthy controls (HC). We studied 36 inpatients affected by a major depressive episode in course of BD type I and 17 HC. Analysis of variance was performed to investigate the effect of diagnosis on GM volumes in the whole brain. Threshold for significance was Pbrain areas, encompassing the caudate head, superior temporal gyrus, insula, fusiform gyrus, parahippocampal gyrus, and anterior cingulate cortex. The interaction analysis between BDNF levels and diagnosis showed a significant effect in the middle frontal gyrus. HC reported higher BDNF levels associated with higher GM volumes, whereas no association between BDNF and GM volumes was observed in BD. Our study seems to suggest that although the production of BDNF is increased in BD possibly to prevent and repair neural damage, its effects could be hampered by underlying neuroinflammatory processes interfering with the neurodevelopmental role of BDNF. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  15. The intricacies of neurotrophic factor therapy for retinal ganglion cell rescue in glaucoma: a case for gene therapy

    Directory of Open Access Journals (Sweden)

    Marianna Foldvari

    2016-01-01

    Full Text Available Regeneration of damaged retinal ganglion cells (RGC and their axons is an important aspect of reversing vision loss in glaucoma patients. While current therapies can effectively lower intraocular pressure, they do not provide extrinsic support to RGCs to actively aid in their protection and regeneration. The unmet need could be addressed by neurotrophic factor gene therapy, where plasmid DNA, encoding neurotrophic factors, is delivered to retinal cells to maintain sufficient levels of neurotrophins in the retina. In this review, we aim to describe the intricacies in the design of the therapy including: the choice of neurotrophic factor, the site and route of administration and target cell populations for gene delivery. Furthermore, we also discuss the challenges currently being faced in RGC-related therapy development with special considerations to the existence of multiple RGC subtypes and the lack of efficient and representative in vitro models for rapid and reliable screening in the drug development process.

  16. Exploring Serum Levels of Brain Derived Neurotrophic Factor and Nerve Growth Factor Across Glaucoma Stages.

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    Francesco Oddone

    Full Text Available To investigate the serum levels of Brain Derived Neurotrophic Factor (BDNF and Nerve Growth Factor (NGF in patients affected by primary open angle glaucoma with a wide spectrum of disease severity compared to healthy controls and to explore their relationship with morphological and functional glaucoma parameters.45 patients affected by glaucoma at different stages and 15 age-matched healthy control subjects underwent visual field testing, peripapillary retinal nerve fibre layer thickness measurement using Spectral Domain Optical Coherence Tomography and blood collection for both neurotrophins detection by Enzyme-Linked Immunosorbent Assay. Statistical analysis and association between biostrumental and biochemical data were investigated.Serum levels of BDNF in glaucoma patients were significantly lower than those measured in healthy controls (261.2±75.0 pg/ml vs 313.6±79.6 pg/ml, p = 0.03. Subgroups analysis showed that serum levels of BDNF were significantly lower in early (253.8±40.7 pg/ml, p = 0.019 and moderate glaucoma (231.3±54.3 pg/ml, p = 0.04 but not in advanced glaucoma (296.2±103.1 pg/ml, p = 0.06 compared to healthy controls. Serum levels of NGF in glaucoma patients were significantly lower than those measured in the healthy controls (4.1±1 pg/mL vs 5.5±1.2 pg/mL, p = 0.01. Subgroups analysis showed that serum levels of NGF were significantly lower in early (3.5±0.9 pg/mL, p = 0.0008 and moderate glaucoma (3.8±0.7 pg/ml, p<0.0001 but not in advanced glaucoma (5.0±0.7 pg/ml, p = 0.32 compared to healthy controls. BDNF serum levels were not related to age, visual field mean deviation or retinal nerve fibre layer thickness either in glaucoma or in controls while NGF levels were significantly related to visual field mean deviation in the glaucoma group (r2 = 0.26, p = 0.004.BDNF and NGF serum levels are reduced in the early and moderate glaucoma stages, suggesting the possibility that both factors could be further investigated

  17. Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: Therapeutic implications for neurodegenerative disorders

    OpenAIRE

    Jana, Arundhati; Modi, Khushbu K.; Roy, Avik; Anderson, John A.; van Breemen, Richard B.; Pahan, Kalipada

    2013-01-01

    This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and as...

  18. Association study of a brain-derived neurotrophic factor polymorphism and short-term antidepressant response in major depressive disorders

    Directory of Open Access Journals (Sweden)

    Lung-Cheng Huang

    2008-10-01

    Full Text Available Eugene Lin1,7, Po See Chen2,6,7, Lung-Cheng Huang3,4, Sen-Yen Hsu51Vita Genomics, Inc., Wugu Shiang, Taipei, Taiwan; 2Department of Psychiatry, Hospital and College of Medicine, National Cheng Kung University, Tainan, Taiwan; 3Department of Psychiatry, National Taiwan University Hospital Yun-Lin Branch, Taiwan; 4Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; 5Department of Psychiatry, Chi Mei Medical Center, Liouying, Tainan, Taiwan; 6Department of Psychiatry, National Cheng Kung University Hospital, Dou-liou Branch, Yunlin, Taiwan; 7These authors contributed equally to this workAbstract: Major depressive disorder (MDD is one of the most common mental disorders worldwide. Single nucleotide polymorphisms (SNPs can be used in clinical association studies to determine the contribution of genes to drug efficacy. A common SNP in the brain-derived neurotrophic factor (BDNF gene, a methionine (Met substitution for valine (Val at codon 66 (Val66Met, is a candidate SNP for influencing antidepressant treatment outcome. In this study, our goal was to determine the relationship between the Val66Met polymorphism in the BDNF gene and the rapid antidepressant response to venlafaxine in a Taiwanese population with MDD. Overall, the BDNF Val66Met polymorphism was found not to be associated with short-term venlafaxine treatment outcome. However, the BDNF Val66Met polymorphism showed a trend to be associated with rapid venlafaxine treatment response in female patients. Future research with independent replication in large sample sizes is needed to confirm the role of the BDNF Val66Met polymorphism identified in this study.Keywords: antidepressant response, brain-derived neurotrophic factor, major depressive disorder, serotonin and norepinephrine reuptake inhibitor, single nucleotide polymorphisms

  19. Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone

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    Giesser Barbara S

    2008-07-01

    Full Text Available Abstract Background Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component. It has been suggested that novel treatment options are needed that target both aspects of the disease. Evidence from basic and clinical studies suggests that testosterone has an immunomodulatory as well as a potential neuroprotective effect that could be beneficial in MS. Methods Ten male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment. Blood samples were obtained at three-month intervals during the observation and the treatment period. Isolated blood peripheral mononuclear cells (PBMCs were used to examine lymphocyte subpopulation composition by flow cytometry and ex vivo protein production of cytokines (IL-2, IFNγ, TNFα, IL-17, IL-10, IL-12p40, TGFβ1 and growth factors (brain-derived neurotrophic factor BDNF, platelet-derived growth factor PDGF-BB, nerve growth factor NGF, and ciliary neurotrophic factor CNTF. Delayed type hypersensitivity (DTH skin recall tests were obtained before and during treatment as an in vivo functional immune measure. Results Testosterone treatment significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition by decreasing CD4+ T cell percentage and increasing NK cells. In addition, PBMC production of IL-2 was significantly decreased while TGFβ1 production was increased. Furthermore, PBMCs obtained during the treatment period produced significantly more BDNF and PDGF-BB. Conclusion These results are consistent with an immunomodulatory effect of testosterone treatment in MS. In addition, increased production of BDNF and PDGF-BB suggests a potential neuroprotective effect. Trial Registration NCT00405353 http://www.clinicaltrials.gov

  20. Downregulated Brain-Derived Neurotrophic Factor-Induced Oxidative Stress in the Pathophysiology of Diabetic Retinopathy.

    Science.gov (United States)

    Behl, Tapan; Kotwani, Anita

    2017-04-01

    Brain-derived neurotrophic factor (BDNF), a member of neurotrophin growth factor family, physiologically mediates induction of neurogenesis and neuronal differentiation, promotes neuronal growth and survival and maintains synaptic plasticity and neuronal interconnections. Unlike the central nervous system, its secretion in the peripheral nervous system occurs in an activity-dependent manner. BDNF improves neuronal mortality, growth, differentiation and maintenance. It also provides neuroprotection against several noxious stimuli, thereby preventing neuronal damage during pathologic conditions. However, in diabetic retinopathy (a neuromicrovascular disorder involving immense neuronal degeneration), BDNF fails to provide enough neuroprotection against oxidative stress-induced retinal neuronal apoptosis. This review describes the prime reasons for the downregulation of BDNF-mediated neuroprotective actions during hyperglycemia, which renders retinal neurons vulnerable to damaging stimuli, leading to diabetic retinopathy. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  1. Elevated levels of plasma brain derived neurotrophic factor in rapid cycling bipolar disorder patients

    DEFF Research Database (Denmark)

    Munkholm, Klaus; Pedersen, Bente Klarlund; Kessing, Lars Vedel

    2014-01-01

    Impaired neuroplasticity may be implicated in the pathophysiology of bipolar disorder, involving peripheral alterations of the neurotrophins brain derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3). Evidence is limited by methodological issues and is based primarily on case......-control designs. The aim of this study was to investigate whether BDNF and NT-3 levels differ between patients with rapid cycling bipolar disorder and healthy control subjects and whether BDNF and NT-3 levels alter with affective states in rapid cycling bipolar disorder patients. Plasma levels of BDNF and NT-3...... patients during a 6-12 months period and compared with repeated measurements in healthy control subjects. Careful attention was given to standardization of all procedures and adjustment for potential confounders of BDNF and NT-3. In linear mixed models, adjusting for demographical and lifestyle factors...

  2. The effects of fasting during Ramadan on the concentration of serotonin, dopamine, brainderived neurotrophic factor and nerve growth factor

    Directory of Open Access Journals (Sweden)

    Abdolhossein Bastani

    2017-06-01

    Full Text Available Neurotransmitters and neurotrophic factors are signaling molecules that play a crucial role in cell proliferation, differentiation, survival and functions of neurons. It is believed that caloric restriction could help the health of the nervous system by affecting the synthesis of neurotrophins and neurotransmitter and oxygen radical metabolism. The objective was to investigate the plasma levels of serotonin, dopamine, brain-derived neurotrophic factor (BDNF, and nerve growth factor (NGF in 29 healthy fasted subjects (22 women and 7 men during the month of fasting in Ramadan. The levels of these factors were measured (using ELISA method three times, 2 days before the fasting month as a control, on the 14th and 29th day of Ramadan as test groups. In addition, these factors were investigated in the group of women only. According to our investigation, the plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan. In detail, the levels of these factors were increased in 14th and 29th day test groups compared to controls (P<0.05. Moreover, these levels were significantly increased on the 29th day compared to the 14th day test groups, but there were no differences between dopamine levels in all groups. Furthermore, the results obtained in women’s groups were the same as those obtained in previous groups. Our findings suggest that plasma levels of serotonin, BDNF and NGF were significantly increased during fasting month of Ramadan.

  3. Possible Role of Brain-Derived Neurotrophic Factor (BDNF) in Autism Spectrum Disorder: Current Status

    International Nuclear Information System (INIS)

    Halepoto, D. M.; Bashir, S.; AL-Ayadhi, L.

    2014-01-01

    Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays a vital role in the growth, development, maintenance, and function of several neuronal systems. The purpose of this review is to document the support for the involvement of this molecule in the maintenance of normal cognitive, emotional functioning, and to outline recent developments in the content of Autism spectrum disorder (ASD). Current and future treatment development can be guided by developing understanding of this molecules actions in the brain and the ways the expression of BDNF can be planned. Over the years, research findings suggested a critical role played by BDNF in the development of autism including increased serum concentrations of BDNF in children with autism and identification of different forms of BDNF in families of autistic individuals. (author)

  4. Ciliary neurotrophic factor analogue aggravates CCl4-induced acute hepatic injury in rats.

    Science.gov (United States)

    Cui, Ming-Xia; Jiang, Jun-Feng; Min, Guang-Ning; Han, Wei; Wu, Yong-Jie

    2017-05-01

    Ciliary neurotrophic factor (CNTF) and CNTF analogs were reported to have hepatoprotective effect and ameliorate hepatic steatosis in db/db or high-fat-diet-fed mice. Because hepatic steatosis and injury are also commonly induced by hepatotoxin, the aim of the present study is to clarify whether CNTF could alleviate hepatic steatosis and injury induced by carbon tetrachloride (CCl 4 ). Unexpectedly, when combined with CCl 4 , CNTF aggravated hepatic steatosis and liver injury. The mechanism is associated with effects of CNTF that inhibited lipoprotein secretion and drastically impaired the ability of lipoproteins to act as transport vehicles for lipids from the liver to the circulation. While injected after CCl 4 cessation, CNTF could improve liver function. These data suggest that CNTF could be a potential hepatoprotective agent against CCl 4 -induced hepatic injury after the cessation of CCl 4 exposure. However, it is forbidden to combine recombinant mutant of human CNTF treatment with CCl 4 .

  5. Ciliary neurotrophic factor (CNTF) delivery to retina: an overview of current research advancements.

    Science.gov (United States)

    Ghasemi, Maryam; Alizadeh, Effat; Saei Arezoumand, Khatereh; Fallahi Motlagh, Behzad; Zarghami, Nosratollah

    2017-10-24

    The intraocular administration of the ciliary neurotrophic factor (CNTF) has been found to attenuate the photoreceptor degeneration and preserve retinal functions in the animal research models of the inherited or induced retinal disease. Studies with the aim of CNTF transfer to the posterior segment inside the eye have been directed to determine the best method for its administration. An ideal delivery method would overcome the eye drug elimination mechanisms or barriers and provide the sustained release of the CNTF into retina in the safest fashion with the minimum harm to the quality of life. This review focuses on the present state of CNTF delivery to retina, also provides an overview of available technologies and their challenges.

  6. Association between plasma brain-derived neurotrophic factor levels and personality traits in healthy Japanese subjects.

    Science.gov (United States)

    Yasui-Furukori, Norio; Tsuchimine, Shoko; Kaneda, Ayako; Sugawara, Norio; Ishioka, Masamichi; Kaneko, Sunao

    2013-11-30

    Although depression has been associated with decreased brain-derived neurotrophic factor (BDNF) levels for specific personality traits, there is a little information regarding the association between peripheral BDNF levels and such traits. The sample consisted of 178 healthy Japanese subjects (age range, 37.4 ± 11.5 years). All subjects filled out the Temperament and Character Inventory (TCI). Plasma BDNF levels were measured using the enzyme-linked immunosorbent assay. A simple regression analysis revealed that plasma BDNF levels were significantly correlated with harm avoidance (r=-0.177, p=0.018) and self-directedness scores (r=0.165, p=0.028). Our findings suggest that plasma BDNF levels are associated with depression-related personality traits. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise

    DEFF Research Database (Denmark)

    Rasmussen, Peter; Brassard, Patrice; Adser, Helle

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) has an important role in regulating maintenance, growth and survival of neurons. However, the main source of circulating BDNF in response to exercise is unknown. To identify whether the brain is a source of BDNF during exercise, eight volunteers rowed for 4...... h while simultaneous blood samples were obtained from the radial artery and the internal jugular vein. To further identify putative cerebral region(s) responsible for BDNF release, mouse brains were dissected and analysed for BDNF mRNA expression following treadmill exercise. In humans, a BDNF...... release from the brain was observed at rest (P exercise (P exercise, the brain contributed 70-80% of circulating BDNF, while that contribution decreased following 1 h of recovery. In mice, exercise induced a three...

  8. Increased basal plasma brain-derived neurotrophic factor levels in sprint runners.

    Science.gov (United States)

    Correia, Paulo Roberto; Scorza, Fulvio Alexandre; Gomes da Silva, Sérgio; Pansani, Aline; Toscano-Silva, Michelle; de Almeida, Antonio Carlos; Arida, Ricardo Mario

    2011-10-01

    Exercise is known to enhance circulating brain-derived neurotrophic factor (BDNF) levels in healthy humans. BDNF changes have been measured in endurance but not in strength exercise. The present study aimed to investigate whether anaerobic activity such as sprinting differentially alters basal plasma BDNF concentration. Brazilian sprinters (100 m) at either the international (Olympics and Outdoor World Championships) (n = 14) or the domestic level (n = 8), and sedentary subjects (n = 15), were recruited. Plasma BDNF concentrations were analyzed by enzyme-linked immunosorbent assay. The basal plasma BDNF concentrations were significantly higher in the international and the domestic sprinters than in the sedentary subjects. In addition, sprinters at the international level had higher plasma BDNF concentrations than those at the domestic level. Our findings suggest that increased basal plasma BDNF level is related to enhanced exercise performance.

  9. Serum concentrations of brain-derived neurotrophic factor in patients with gender identity disorder.

    Science.gov (United States)

    Fontanari, Anna-Martha V; Andreazza, Tahiana; Costa, Ângelo B; Salvador, Jaqueline; Koff, Walter J; Aguiar, Bianca; Ferrari, Pamela; Massuda, Raffael; Pedrini, Mariana; Silveira, Esalba; Belmonte-de-Abreu, Paulo S; Gama, Clarissa S; Kauer-Sant'Anna, Marcia; Kapczinski, Flavio; Lobato, Maria Ines R

    2013-10-01

    Gender Identity Disorder (GID) is characterized by a strong and persistent cross-gender identification that affects different aspects of behavior. Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF-signaling is thought to contribute to the pathogenesis of psychiatric disordersand is related to traumatic life events. To examine serum BDNF levels, we compared one group of DSM-IV GID patients (n = 45) and one healthy control group (n = 66). Serum BDNF levels were significantly decreased in GID patients (p = 0.013). This data support the hypothesis that the reduction found in serum BDNF levels in GID patients may be related to the psychological abuse that transsexuals are exposed during their life. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Activity-dependent brain-derived neurotrophic factor expression regulates cortistatin-interneurons and sleep behavior

    Directory of Open Access Journals (Sweden)

    Martinowich Keri

    2011-03-01

    Full Text Available Abstract Background Sleep homeostasis is characterized by a positive correlation between sleep length and intensity with the duration of the prior waking period. A causal role for brain-derived neurotrophic factor (BDNF in sleep homeostasis has been suggested, but the underlying mechanisms remain unclear. Cortistatin, a neuropeptide expressed primarily in a subset of cortical GABAergic interneurons, is another molecule implicated in sleep homeostasis. Results We confirmed that sleep deprivation leads to an increase in cortical cortistatin mRNA expression. Disruption of activity-dependent BDNF expression in a genetically modified mouse line impairs both baseline levels of cortistatin mRNA as well as its levels following sleep deprivation. Disruption of activity-dependent BDNF also leads to a decrease in sleep time during the active (dark phase. Conclusion Our studies suggest that regulation of cortistatin-expressing interneurons by activity-dependent BDNF expression may contribute to regulation of sleep behavior.

  11. Brain-Derived Neurotrophic Factor, Depression, and Physical Activity: Making the Neuroplastic Connection

    Directory of Open Access Journals (Sweden)

    Cristy Phillips

    2017-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is a neurotrophin that is vital to the survival, growth, and maintenance of neurons in key brain circuits involved in emotional and cognitive function. Convergent evidence indicates that neuroplastic mechanisms involving BDNF are deleteriously altered in major depressive disorder (MDD and animal models of stress. Herein, clinical and preclinical evidence provided that stress-induced depressive pathology contributes to altered BDNF level and function in persons with MDD and, thereby, disruptions in neuroplasticity at the regional and circuit level. Conversely, effective therapeutics that mitigate depressive-related symptoms (e.g., antidepressants and physical activity optimize BDNF in key brain regions, promote neuronal health and recovery of function in MDD-related circuits, and enhance pharmacotherapeutic response. A greater knowledge of the interrelationship between BDNF, depression, therapeutic mechanisms of action, and neuroplasticity is important as it necessarily precedes the derivation and deployment of more efficacious treatments.

  12. Antidepressant Effects of Pharmacopuncture on Behavior and Brain-Derived Neurotrophic Factor (BDNF Expression in Chronic Stress Model of Mice

    Directory of Open Access Journals (Sweden)

    Yunna Kim

    2017-12-01

    Conclusion: HJ11 improves depressive-like behaviors in the stress-induced mouse model of depression, and the results indicate that the neuroprotective effect of HJ11, identified by brain-derived neurotrophic factor expression, may play a critical role in its antidepressant effect.

  13. Effects of ciliary neurotrophic factor on retrograde cell reaction after facial nerve crush in young adults rats

    NARCIS (Netherlands)

    Gispen, W.H.; Ulenkate, H.J.L.M.; Jennekens, F.G.I.

    1996-01-01

    Locally applied ciliary neurotrophic factor (CNTF) has a powerful effect on retrograde axonal reaction following facial nerve crush in neonatal rats. We examined whether it also exerts a strong effect on retrograde axonal reaction in young adult rats when administered subcutaneously. The dose was 1

  14. Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals

    DEFF Research Database (Denmark)

    Pedersen, Bente K; Pedersen, Maria; Krabbe, Karen S

    2009-01-01

    Brain-derived neurotrophic factor (BDNF) has been shown to regulate neuronal development and plasticity and plays a role in learning and memory. Moreover, it is well established that BDNF plays a role in the hypothalamic pathway that controls body weight and energy homeostasis. Recent evidence...

  15. The brain-derived neurotrophic factor Val66Met polymorphism affects encoding of object locations during active navigation

    NARCIS (Netherlands)

    Wegman, J.B.T.; Tyborowska, A.B.; Hoogman, M.; Arias Vasquez, A.; Janzen, G.

    2017-01-01

    The brain-derived neurotrophic factor (BDNF) was shown to be involved in spatial memory and spatial strategy preference. A naturally occurring single nucleotide polymorphism of the BDNF gene (Val66Met) affects activity-dependent secretion of BDNF. The current event-related fMRI study on preselected

  16. Human umbilical cord blood stem cells and brain-derived neurotrophic factor for optic nerve injury: a biomechanical evaluation

    Science.gov (United States)

    Zhang, Zhong-jun; Li, Ya-jun; Liu, Xiao-guang; Huang, Feng-xiao; Liu, Tie-jun; Jiang, Dong-mei; Lv, Xue-man; Luo, Min

    2015-01-01

    Treatment for optic nerve injury by brain-derived neurotrophic factor or the transplantation of human umbilical cord blood stem cells has gained progress, but analysis by biomechanical indicators is rare. Rabbit models of optic nerve injury were established by a clamp. At 7 days after injury, the vitreous body received a one-time injection of 50 μg brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood stem cells. After 30 days, the maximum load, maximum stress, maximum strain, elastic limit load, elastic limit stress, and elastic limit strain had clearly improved in rabbit models of optical nerve injury after treatment with brain-derived neurotrophic factor or human umbilical cord blood stem cells. The damage to the ultrastructure of the optic nerve had also been reduced. These findings suggest that human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, improve biomechanical properties, and contribute to the recovery after injury. PMID:26330839

  17. Effects of maternal smoking and exposure to methylmercury on brain-derived neurotrophic factor concentrations in umbilical cord serum

    DEFF Research Database (Denmark)

    Spulber, Stefan; Rantamäki, Tomi; Nikkilä, Outi

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal survival and differentiation. We examined the concentration of BDNF in cord serum from newborns exposed to methylmercury (MeHg) and polychlorinated biphenyls (PCB) in utero by maternal consumption of whale meat. The...

  18. Brain derived neurotrophic factor gene (BDNF) and personality traits: the modifying effect of season of birth and sex.

    Science.gov (United States)

    Kazantseva, A; Gaysina, D; Kutlumbetova, Yu; Kanzafarova, R; Malykh, S; Lobaskova, M; Khusnutdinova, E

    2015-01-02

    Personality traits are complex phenotypes influenced by interactions of multiple genetic variants of small effect and environmental factors. It has been suggested that the brain derived neurotrophic factor gene (BDNF) is involved in personality traits. Season of birth (SOB) has also been shown to affect personality traits due to its influences on brain development during prenatal and early postnatal periods. The present study aimed to investigate the effects of BDNF on personality traits; and the modifying effects of SOB and sex on associations between BDNF and personality traits. A sample of 1018 young adults (68% women; age range 17-25years) of Caucasian origin from the Russian Federation was assessed on personality traits (Novelty Seeking, Harm Avoidance, Reward Dependence, Persistence, Self-directedness, Cooperativeness, Self-transcendence) with the Temperament and Character Inventory-125 (TCI-125). Associations between personality traits and 12 BDNF SNPs were tested using linear regression models. The present study demonstrated the effect of rs11030102 on Persistence in females only (PFDR=0.043; r(2)=1.3%). There were significant interaction effects between Val66Met (rs6265) and SOB (PFDR=0.048, r(2)=1.4%), and between rs2030323 and SOB (PFDR=0.042, r(2)=1.3%), on Harm Avoidance. Our findings provide evidence for the modifying effect of SOB on the association between BDNF and Harm Avoidance, and for the modifying effect of sex on the association between BDNF and Persistence. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Neuronal cell death, nerve growth factor and neurotrophic models: 50 years on.

    Science.gov (United States)

    Bennet, M R; Gibson, W G; Lemon, G

    2002-01-10

    Viktor Hamburger has just died at the age of 100. It is 50 years since he and Rita Levi-Montalcini laid the foundations for the study of naturally occurring cell death and of neurotrophic factors in the nervous system. In a period of less than 10 years, from 1949 to 1958, Hamburger and Levi-Montalcini made the following seminal discoveries: that neuron cell death occurs in dorsal root ganglia, sympathetic ganglia and the cervical column of motoneurons; that the predictions arising from this observation, namely that survival is dependent on the supply of a trophic factor, could be substantiated by studying the effects of a sarcoma on the proliferation of ganglionic processes both in vivo and in vitro; and that the proliferation of these processes could be used as an assay system to isolate the factor. This work provides a short review mostly of the early history of this subject in the context of the Hamburger/Levi-Montalcini paradigm. This acts as an introduction to a consideration of models that have been proposed to account for how the different sources of growth factors provide for the survival of neurons during development. It is suggested that what has been called the 'social-control' model provides the most parsimonious quantitative description of the contribution of trophic factors to neuronal survival, a concept for which we are in debt to Viktor Hamburger and Rita Levi-Montalcini.

  20. Investigating the neurobiology of music: brain-derived neurotrophic factor modulation in the hippocampus of young adult mice.

    Science.gov (United States)

    Angelucci, Francesco; Fiore, Marco; Ricci, Enzo; Padua, Luca; Sabino, Andrea; Tonali, Pietro Attilio

    2007-09-01

    It has been shown that music might be able to improve mood state in people affected by psychiatric disorders, ameliorate cognitive deficits in people with dementia and increase motor coordination in Parkinson patients. Robust experimental evidence explaining the central effects of music, however, is missing. This study was designed to investigate the effect of music on brain neurotrophin production and behavior in the mouse. We exposed young adult mice to music with a slow rhythm (6 h/day; mild sound pressure levels, between 50 and 60 db) for 21 consecutive days. At the end of the treatment, mice were tested for passive avoidance learning and then killed for analysis of brain-derived neurotrophic factor (BDNF) and nerve growth factor with enzyme-linked immunosorbent assay (ELISA) in selected brain regions. We found that music-exposed mice showed increased BDNF, but not nerve growth factor in the hippocampus. Furthermore, we observed that music exposure significantly enhanced learning performance, as measured by the passive avoidance test. Our results demonstrate that exposure to music can modulate the activity of the hippocampus by influencing BDNF production. Our findings also suggest that music exposure might be of help in several central nervous system pathologies.

  1. Edaravone Enhances Brain-Derived Neurotrophic Factor Production in the Ischemic Mouse Brain

    Directory of Open Access Journals (Sweden)

    Satoshi Okuyama

    2015-04-01

    Full Text Available Edaravone, a clinical drug used to treat strokes, protects against neuronal cell death and memory loss in the ischemic brains of animal models through its antioxidant activity. In the present study, we subcutaneously administrated edaravone to mice (3 mg/kg/day for three days immediately after bilateral common carotid artery occlusion, and revealed through an immunohistochemical analysis that edaravone (1 accelerated increases in the production of brain-derived neurotrophic factor (BDNF in the hippocampus; (2 increased the number of doublecortin-positive neuronal precursor cells in the dentate gyrus subgranular zone; and (3 suppressed the ischemia-induced inactivation of calcium-calmodulin-dependent protein kinase II in the hippocampus. We also revealed through a Western blotting analysis that edaravone (4 induced the phosphorylation of cAMP response element-binding (CREB, a transcription factor that regulates BDNF gene expression; and (5 induced the phosphorylation of extracellular signal-regulated kinases 1/2, an upstream signal factor of CREB. These results suggest that the neuroprotective effects of edaravone following brain ischemia were mediated not only by the elimination of oxidative stress, but also by the induction of BDNF production.

  2. Increased serum brain-derived neurotrophic factor (BDNF) levels in patients with narcolepsy

    DEFF Research Database (Denmark)

    Klein, Anders B; Jennum, Poul; Knudsen, Stine

    2013-01-01

    Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction in hypoc......Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness, sudden loss of muscle tone (cataplexy), fragmentation of nocturnal sleep and sleep paralysis. The symptoms of the disease strongly correlate with a reduction in hypocretin levels in CSF and a reduction...... in hypocretin neurons in hypothalamus in post-mortem tissue. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are important for activity-dependent neuronal function and synaptic modulation and it is considered that these mechanisms are important in sleep regulation. We hypothesised...... that serum levels of these factors are altered in patients with narcolepsy compared to healthy controls without sleep disturbances. Polysomnography data was obtained and serum BDNF and NGF levels measured using ELISA, while hypocretin was measured using RIA. Serum BDNF levels were significantly higher...

  3. Anxiety and depression in children and adults: influence of serotonergic and neurotrophic genes?

    Science.gov (United States)

    Middeldorp, C M; Slof-Op 't Landt, M C T; Medland, S E; van Beijsterveldt, C E M; Bartels, M; Willemsen, G; Hottenga, J-J; de Geus, E J C; Suchiman, H E D; Dolan, C V; Neale, M C; Slagboom, P E; Boomsma, D I

    2010-10-01

    There are two major hypotheses regarding the etiology of anxiety and depression: the mono-amine hypothesis and the hypothesis of an abnormal stress response acting partly via reduced neurogenesis. Association studies have focused on genes involved in these processes, but with inconclusive results. This study investigated the effect of 45 single nucleotide polymorphisms (SNPs) in genes encoding for serotonin receptors 1A, 1D, 2A, catechol-O-methyltransferase (COMT), tryptophane hydroxylase type 2 (TPH2), brain derived neurotrophic factor (BDNF), PlexinA2 and regulators of G-protein-coupled signaling (RGS) 2, 4, 16. Anxious depression (A/D) symptoms were assessed five times in 11 years in over 11 000 adults with 1504 subjects genotyped and at age 7, 10, 12 and during adolescence in over 20 000 twins with 1078 subjects genotyped. In both cohorts, a longitudinal model with one latent factor loading on all A/D measures over time was analysed. The genetic association effect modeled at the level of this latent factor was 60% and 70% heritable in the children and adults, respectively, and explained around 50% of the total phenotypic variance. Power analyses showed that the samples contained 80% power to detect an effect explaining between 1.4% and 3.6% of the variance. However, no SNP showed a consistent effect on A/D. To conclude, this longitudinal study in children and adults found no association of SNPs in the serotonergic system or core regulators of neurogenesis with A/D. Overall, there has been no convincing evidence, so far, for a role of genetic variation in these pathways in the development of anxiety and depression. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

  4. The cytokines cardiotrophin-like cytokine/cytokine-like factor-1 (CLC/CLF) and ciliary neurotrophic factor (CNTF) differ in their receptor specificities.

    Science.gov (United States)

    Tormo, Aurélie Jeanne; Letellier, Marie-Claude; Lissilaa, Rami; Batraville, Laurie-Anne; Sharma, Mukut; Ferlin, Walter; Elson, Greg; Crabé, Sandrine; Gauchat, Jean-François

    2012-12-01

    Ciliary neurotrophic factor (CNTF) and cardiotrophin-like cytokine (CLC) are two cytokines with neurotrophic and immunomodulatory activities. CNTF is a cytoplasmic factor believed to be released upon cellular damage, while CLC requires interaction with a soluble cytokine receptor, cytokine-like factor 1 (CLF), to be efficiently secreted. Both cytokines activate a receptor complex comprising the cytokine binding CNTF receptor α (CNTFRα) and two signaling chains namely, leukemia inhibitory factor receptor β (LIFRβ) and gp130. Human CNTF can recruit and activate an alternative receptor in which CNTFRα is substituted by IL-6Rα. As both CNTF and CLC have immune-regulatory activities in mice, we compared their ability to recruit mouse receptors comprising both gp130 and LIFRβ signaling chains and either IL-6Rα or IL-11Rα which, unlike CNTFRα, are expressed by immune cells. Our results indicate that 1) mouse CNTF, like its human homologue, can activate cells expressing gp130/LIFRβ with either CNTFRα or IL-6Rα and, 2) CLC/CLF is more restricted in its specificity in that it activates only the tripartite CNTFR. Several gp130 signaling cytokines influence T helper cell differentiation. We therefore investigated the effect of CNTF on CD4 T cell cytokine production. We observed that CNTF increased the number of IFN-γ producing CD4 T cells. As IFN-γ is considered a mediator of the therapeutic effect of IFN-β in multiple sclerosis, induction of IFN-γ by CNTF may contribute to the beneficial immunomodulatory effect of CNTF in mouse multiple sclerosis models. Together, our results indicate that CNTF activates the same tripartite receptors in mouse and human cells and further validate rodent models for pre-clinical investigation of CNTF and CNTF derivatives. Furthermore, CNTF and CLC/CLF differ in their receptor specificities. The receptor α chain involved in the immunomodulatory effects of CLC/CLF remains to be identified. Crown Copyright © 2012. Published by

  5. The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

    Science.gov (United States)

    Darcq, Emmanuel; Morisot, Nadege; Phamluong, Khanhky; Warnault, Vincent; Jeanblanc, Jerome; Longo, Frank M.; Massa, Stephen M.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of the p75NTR gene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders. SIGNIFICANCE STATEMENT Neuroadaptations gate or drive excessive, compulsive alcohol drinking. We previously showed that brain-derived neurotrophic factor and its receptor, TrkB, in the dorsolateral striatum (DLS), are part of an endogenous system that keeps alcohol drinking in moderation. Here, we show that a history of excessive alcohol intake produces neuroadaptations in the DLS that preclude BDNF

  6. Serum brain-derived neurotrophic factor levels and personality traits in patients with major depression.

    Science.gov (United States)

    Nomoto, Hiroshi; Baba, Hajime; Satomura, Emi; Maeshima, Hitoshi; Takebayashi, Naoko; Namekawa, Yuki; Suzuki, Toshihito; Arai, Heii

    2015-03-04

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors. Previous studies have demonstrated lower serum BDNF levels in patients with major depressive disorder (MDD) and reported an association between BDNF levels and depression-related personality traits in healthy subjects. The aim of the present study was to explore for a possible association between peripheral BDNF levels and personality traits in patients with MDD. In this cross-sectional study, a total of 123 inpatients with MDD (Diagnostic and Statistical Manual for Mental Disorders, 4th edition) at the Juntendo University Koshigaya Hospital were recruited. Serum levels of BDNF were measured. Personality traits were assessed using the 125-item short version of the Temperament and Character Inventory (TCI). Multiple regression analysis adjusted for age, sex, body mass index, dose of antidepressant, and depression severity showed that TCI Self-Directedness (SD) scores were negatively associated with serum BDNF levels (β = -0.23, p = 0.026). MDD patients who have low SD did not show the reduction in serum BDNF levels that is normally associated with depressive state. Our findings suggest that depression-related biological changes may not occur in these individuals.

  7. [Changes of the Expression of Brain Derived Neurotrophic Factors in Rats Trachea Induced by Acrolein Exposure].

    Science.gov (United States)

    Yuan, Bing; Yang, Rui-an; Zhao, Wei; Xu, Yan-yan; Dan, Qi-qin; Zhang, Yun-hui

    2015-07-01

    To investigate expressional changes of brain derived neurotrophic factor (BDNF) in the trachea of rats with acrolein inhalation. Twenty two SD rats were divided into 2 groups: the rats in experimental group were subjected to acrolein inhalation for the induce of trachea inflammatory injury, while the rats with saline (NS) inhalation were as control. All the rats were sacrificed in 1,3,6 weeks after acrolein (n = 11 at each time point) or saline inhalation (n = 11 at each time point), the samples of trachea epithelium were harvested. The immunohistochemistry and in situ hybridization was performed to detect the location of BDNF protein and mRNA in trachea. The expression of BDNF mRNA in the trachea tissues were determined by RT-PCR. There are positive cells in epithelium of trachea for BDNF protein and mRNA, with cytoplasm staining. The expression of BDNF mRNA in the trachea was increased at 1 week after acrolein inhalation (P 0.05). The inflammatory injury in trachea induced by acrolein exposure could be associated with the increased expression of BDNF. BDNF may be one of the crucial inflammatory factors in the process of inflammatory reaction in trachea with acrolein stimulation.

  8. Up-regulation of Ciliary Neurotrophic Factor in Astrocytes by Aspirin

    Science.gov (United States)

    Modi, Khushbu K.; Sendtner, Michael; Pahan, Kalipada

    2013-01-01

    Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor, and the mechanisms by which CNTF expression could be increased in the brain are poorly understood. Acetylsalicylic acid (aspirin) is one of the most widely used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA) but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP-response element-binding protein (CREB), but not NF-κB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus cAMP-response element in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of the Cntf gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not Cntf null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-α insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders. PMID:23653362

  9. Ciliary neurotrophic factor (CNTF) plus soluble CNTF receptor ? increases cyclooxygenase-2 expression, PGE2 release and interferon-?-induced CD40 in murine microglia

    OpenAIRE

    Lin, Hsiao-Wen; Jain, Mohit Raja; Li, Hong; Levison, Steven W

    2009-01-01

    Abstract Background Ciliary neurotrophic factor (CNTF) has been regarded as a potent trophic factor for motor neurons. However, recent studies have shown that CNTF exerts effects on glial cells as well as neurons. For instance, CNTF stimulates astrocytes to secrete FGF-2 and rat microglia to secrete glial cell line-derived neurotrophic factor (GDNF), which suggest that CNTF exerts effects on astrocytes and microglia to promote motor neuron survival indirectly. As CNTF is structurally related ...

  10. Dendrobium alkaloids prevent Aβ25–35-induced neuronal and synaptic loss via promoting neurotrophic factors expression in mice

    Directory of Open Access Journals (Sweden)

    Jing Nie

    2016-12-01

    Full Text Available Background Neuronal and synaptic loss is the most important risk factor for cognitive impairment. Inhibiting neuronal apoptosis and preventing synaptic loss are promising therapeutic approaches for Alzheimer’s disease (AD. In this study, we investigate the protective effects of Dendrobium alkaloids (DNLA, a Chinese medicinal herb extract, on β-amyloid peptide segment 25–35 (Aβ25-35-induced neuron and synaptic loss in mice. Method Aβ25–35(10 µg was injected into the bilateral ventricles of male mice followed by an oral administration of DNLA (40 mg/kg for 19 days. The Morris water maze was used for evaluating the ability of spatial learning and memory function of mice. The morphological changes were examined via H&E staining and Nissl staining. TUNEL staining was used to check the neuronal apoptosis. The ultrastructure changes of neurons were observed under electron microscope. Western blot was used to evaluate the protein expression levels of ciliary neurotrophic factor (CNTF, glial cell line-derived neurotrophic factor (GDNF, and brain-derived neurotrophic factor (BDNF in the hippocampus and cortex. Results DNLA significantly attenuated Aβ25–35-induced spatial learning and memory impairments in mice. DNLA prevented Aβ25–35-induced neuronal loss in the hippocampus and cortex, increased the number of Nissl bodies, improved the ultrastructural injury of neurons and increased the number of synapses in neurons. Furthermore, DNLA increased the protein expression of neurotrophic factors BDNF, CNTF and GDNF in the hippocampus and cortex. Conclusions DNLA can prevent neuronal apoptosis and synaptic loss. This effect is mediated at least in part via increasing the expression of BDNF, GDNF and CNTF in the hippocampus and cortex; improving Aβ-induced spatial learning and memory impairment in mice.

  11. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor.

    Science.gov (United States)

    Park, Hee Ra; Park, Mikyung; Choi, Jehun; Park, Kun-Young; Chung, Hae Young; Lee, Jaewon

    2010-10-04

    Obesity is a growing global health problem that contributes to diabetes, hypertension, cardiovascular diseases, dementia, and cancer. The increased consumption of saturated fats in a high-fat diet (HFD) contributes to obesity, neurodegenerative diseases, long-term memory loss, and cognitive impairment. We tested whether HFD influences adult hippocampal neurogenesis. Male C57BL/6 mice were divided into two groups and maintained on either a normal diet (ND) or HFD. Seven weeks of HFD significantly decreased the numbers of newly generated cells in the dentate gyrus of the hippocampus without neuronal loss. HFD also increased the level of malondialdehyde (MDA) and decreased the level of brain-derived neurotrophic factor (BDNF) in the hippocampus. The toxic effects of MDA were evaluated on neural progenitor cells (NPCs). MDA reduced the growth of NPCs, but BDNF treatment restored NPCs proliferation. The present data indicate that a HFD impairs hippocampal neurogenesis and NPCs proliferation through increased lipid peroxidation and decreased BDNF. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  12. Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor.

    Science.gov (United States)

    Berretta, Antonio; Tzeng, Yu-Chieh; Clarkson, Andrew N

    2014-11-01

    Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity-induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood-brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery.

  13. The effect of recombinant erythropoietin on plasma brain derived neurotrophic factor levels in patients with affective disorders

    DEFF Research Database (Denmark)

    Vinberg, Maj; Miskowiak, Kamilla; Hoejman, Pernille

    2015-01-01

    UNLABELLED: The study aims to investigate the effect of repeated infusions of recombinant erythropoietin (EPO) on plasma brain derived neurotrophic factor (BDNF) levels in patients with affective disorders. In total, 83 patients were recruited: 40 currently depressed patients with treatment......-resistant depression (TRD) (Hamilton Depression Rating Scale-17 items (HDRS-17) score >17) (study 1) and 43 patients with bipolar disorder (BD) in partial remission (HDRS-17 and Young Mania Rating Scale (YMRS) ≤ 14) (study 2). In both studies, patients were randomised to receive eight weekly EPO (Eprex; 40,000 IU...... to a role of neurotrophic factors in the potential effects of EPO seen in TRD and BD. The neurobiological mechanisms underlying these effects and the interaction between EPO and peripheral levels on BDNF need to be further elucidated in human studies including a broad range of biomarkers. TRIAL REGISTRATION...

  14. Ciliary neurotrophic factor null alleles are not a risk factor for Charcot-Marie-Tooth disease, hereditary neuropathy with pressure palsies and amyotrophic lateral sclerosis

    NARCIS (Netherlands)

    van Vught, Paul W. J.; van Wijk, Joost; Bradley, Ted E. J.; Plasmans, Dagmar; Jakobs, Marja E.; Veldink, Jan H.; de Jong, J. M. B. Vianney; van den Berg, Leonard H.; Baas, Frank

    2007-01-01

    Growth factors, such as ciliary neurotrophic factor (CNTF), have been implicated in neuronal survival and proliferation. About 2% of the human population is homozygous for a polymorphism that induces truncated and biologically inactive CNTF but does not obviously change the phenotype. In a

  15. Long noncoding nature brain-derived neurotrophic factor antisense is associated with poor prognosis and functional regulation in non-small cell lung caner.

    Science.gov (United States)

    Shen, MingJing; Xu, Zhonghua; Jiang, Kanqiu; Xu, Weihua; Chen, Yongbin; Xu, ZhongHeng

    2017-05-01

    In this study, we evaluated the prognostic potential and functional regulation of human nature antisense, brain-derived neurotrophic factor antisense, in non-small cell lung cancer. Non-small cell lung cancer carcinoma and adjacent non-carcinoma lung tissues were extracted from 151 patients. Their endogenous brain-derived neurotrophic factor antisense expression levels were compared by quantitative reverse transcription polymerase chain reaction. Clinical relevance between endogenous brain-derived neurotrophic factor antisense expression level and patients' clinicopathological variances or overall survival was analyzed. The potential of brain-derived neurotrophic factor antisense being an independent prognostic factor in non-small cell lung cancer was also evaluated. In in vitro non-small cell lung cancer cell lines, brain-derived neurotrophic factor antisense was upregulated through forced overexpression. The effects of brain-derived neurotrophic factor antisense upregulation on non-small cell lung cancer in vitro survival, proliferation, and migration were evaluated by viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, and transwell assays. Brain-derived neurotrophic factor antisense is lowly expressed in non-small cell lung cancer carcinoma tissues and further downregulated in late-stage carcinomas. Brain-derived neurotrophic factor antisense downregulation was closely associated with non-small cell lung cancer patients' advanced tumor, lymph node, metastasis stage, and positive status of lymph node metastasis, and confirmed to be an independent prognostic factor for patients' poor overall survival. In non-small cell lung cancer A549 and H226 cell lines, forced overexpression of brain-derived neurotrophic factor antisense did not alter cancer cell viability but had significantly tumor suppressive effect in inhibiting in vitro non-small cell lung cancer proliferation and migration. Endogenous brain-derived neurotrophic factor antisense in

  16. The Effect of Brain-Derived Neurotrophic Factor on Periodontal Furcation Defects

    Science.gov (United States)

    Jimbo, Ryo; Tovar, Nick; Janal, Malvin N.; Mousa, Ramy; Marin, Charles; Yoo, Daniel; Teixeira, Hellen S.; Anchieta, Rodolfo B.; Bonfante, Estevam A.; Konishi, Akihiro; Takeda, Katsuhiro; Kurihara, Hidemi; Coelho, Paulo G.

    2014-01-01

    This study aimed to observe the regenerative effect of brain-derived neurotrophic factor (BDNF) in a non-human primate furcation defect model. Class II furcation defects were created in the first and second molars of 8 non-human primates to simulate a clinical situation. The defect was filled with either, Group A: BDNF (500 µg/ml) in high-molecular weight-hyaluronic acid (HMW-HA), Group B: BDNF (50 µg/ml) in HMW-HA, Group C: HMW-HA acid only, Group D: empty defect, or Group E: BDNF (500 µg/ml) in saline. The healing status for all groups was observed at different time-points with micro computed tomography. The animals were euthanized after 11 weeks, and the tooth-bone specimens were subjected to histologic processing. The results showed that all groups seemed to successfully regenerate the alveolar buccal bone, however, only Group A regenerated the entire periodontal tissue, i.e., alveolar bone, cementum and periodontal ligament. It is suggested that the use of BDNF in combination with a scaffold such as the hyaluronic acid in periodontal furcation defects may be an effective treatment option. PMID:24454754

  17. Brain-derived neurotrophic factor Val66Met genotype modulates amygdala habituation.

    Science.gov (United States)

    Perez-Rodriguez, M Mercedes; New, Antonia S; Goldstein, Kim E; Rosell, Daniel; Yuan, Qiaoping; Zhou, Zhifeng; Hodgkinson, Colin; Goldman, David; Siever, Larry J; Hazlett, Erin A

    2017-05-30

    A deficit in amygdala habituation to repeated emotional stimuli may be an endophenotype of disorders characterized by emotion dysregulation, such as borderline personality disorder (BPD). Amygdala reactivity to emotional stimuli is genetically modulated by brain-derived neurotrophic factor (BDNF) variants. Whether amygdala habituation itself is also modulated by BDNF genotypes remains unknown. We used imaging-genetics to examine the effect of BDNF Val66Met genotypes on amygdala habituation to repeated emotional stimuli. We used functional magnetic resonance imaging (fMRI) in 57 subjects (19 BPD patients, 18 patients with schizotypal personality disorder [SPD] and 20 healthy controls [HC]) during a task involving viewing of unpleasant, neutral, and pleasant pictures, each presented twice to measure habituation. Amygdala responses across genotypes (Val66Met SNP Met allele-carriers vs. Non-Met carriers) and diagnoses (HC, BPD, SPD) were examined with ANOVA. The BDNF 66Met allele was significantly associated with a deficit in amygdala habituation, particularly for emotional pictures. The association of the 66Met allele with a deficit in habituation to unpleasant emotional pictures remained significant in the subsample of BPD patients. Using imaging-genetics, we found preliminary evidence that deficient amygdala habituation may be modulated by BDNF genotype. Copyright © 2017. Published by Elsevier B.V.

  18. Peri-Synaptic Glia Recycles Brain-Derived Neurotrophic Factor for LTP Stabilization and Memory Retention.

    Science.gov (United States)

    Vignoli, Beatrice; Battistini, Giulia; Melani, Riccardo; Blum, Robert; Santi, Spartaco; Berardi, Nicoletta; Canossa, Marco

    2016-11-23

    Glial cells respond to neuronal activation and release neuroactive molecules (termed "gliotransmitters") that can affect synaptic activity and modulate plasticity. In this study, we used molecular genetic tools, ultra-structural microscopy, and electrophysiology to assess the role of brain-derived neurotrophic factor (BDNF) on cortical gliotransmission in vivo. We find that glial cells recycle BDNF that was previously secreted by neurons as pro-neurotrophin following long-term potentiation (LTP)-inducing electrical stimulation. Upon BDNF glial recycling, we observed tight, temporal, highly localized TrkB phosphorylation on adjacent neurons, a process required to sustain LTP. Engagement of BDNF recycling by astrocytes represents a novel mechanism by which cortical synapses can expand BDNF action and provide synaptic changes that are relevant for the acquisition of new memories. Accordingly, mice deficient in BDNF glial recycling fail to recognize familiar from novel objects, indicating a physiological requirement for this process in memory consolidation. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Decreased brain-derived neurotrophic factor plasma levels in psoriasis patients

    Directory of Open Access Journals (Sweden)

    A.R. Brunoni

    2015-08-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is associated with neuroplasticity and synaptic strength, and is decreased in conditions associated with chronic stress. Nevertheless, BDNF has not yet been investigated in psoriasis, a chronic inflammatory systemic disease that is exacerbated by stress. Therefore, our aim was to determine BDNF plasma levels in psoriasis patients and healthy controls. Adult patients (n=94 presenting with psoriasis for at least 1 year were enrolled, and age- and gender-matched with healthy controls (n=307 from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil. Participants had neither a previous history of coronary artery disease nor current episode of major depression. BDNF plasma levels were determined using the Promega ELISA kit. A general linear model was used to compare BDNF levels in psoriasis patients and controls, with age, gender, systolic blood pressure, serum fasting glucose, blood lipid levels, triglycerides, smoking status, and body mass index examined. After adjusting for clinical and demographic variables, significantly decreased BNDF plasma levels were observed in psoriasis patients (P=0.01 (estimated marginal means of 3922 pg/mL; 95%CI=2660-5135 compared with controls (5788 pg/mL; 95%CI=5185-6442. Similar BDNF levels were found in both mild and severe cases of psoriasis. Our finding, that BDNF is decreased in psoriasis, supports the concept of a brain-skin connection in psoriasis. Further studies should determine if BDNF is increased after specific psoriasis treatments, and associated with different disease stages.

  20. Ciliary neurotrophic factor has intrinsic and extrinsic roles in regulating B cell differentiation and bone structure.

    Science.gov (United States)

    Askmyr, Maria; White, Kirby E; Jovic, Tanja; King, Hannah A; Quach, Julie M; Maluenda, Ana C; Baker, Emma K; Smeets, Monique F; Walkley, Carl R; Purton, Louise E

    2015-10-21

    The gp130 receptor and its binding partners play a central role in cytokine signalling. Ciliary neurotrophic factor (CNTF) is one of the cytokines that signals through the gp130 receptor complex. CNTF has previously been shown to be a negative regulator of trabecular bone remodelling and important for motor neuron development. Since haematopoietic cell maintenance and differentiation is dependent on the bone marrow (BM) microenvironment, where cells of the osteoblastic lineage are important regulators, we hypothesised that CNTF may also have important roles in regulating haematopoiesis. Analysis of haematopoietic parameters in male and female Cntf(-/-) mice at 12 and 24 weeks of age revealed altered B lymphopoiesis. Strikingly, the B lymphocyte phenotype differed based on sex, age and also the BM microenvironment in which the B cells develop. When BM cells from wildtype mice were transplanted into Cntf(-/-) mice, there were minimal effects on B lymphopoiesis or bone parameters. However, when Cntf(-/-) BM cells were transplanted into a wildtype BM microenvironment, there were changes in both haematopoiesis and bone parameters. Our data reveal that haematopoietic cell-derived CNTF has roles in regulating BM B cell lymphopoiesis and both trabecular and cortical bone, the latter in a sex-dependent manner.

  1. Ciliary neurotrophic factor controls progenitor migration during remyelination in the adult rodent brain.

    Science.gov (United States)

    Vernerey, Julien; Macchi, Magali; Magalon, Karine; Cayre, Myriam; Durbec, Pascale

    2013-02-13

    Ciliary neurotrophic factor (CNTF) has been shown to be expressed after brain lesions and in particular after demyelination. Here, we addressed the role of this cytokine in the regulation of neural progenitor migration in the adult rodent brain. Using an acute model of demyelination, we show that CNTF is strongly re-expressed after lesion and is involved in the postlesional mobilization of endogenous progenitors that participate in the myelin regenerative process. We show that CNTF controls the migration of subventricular zone (SVZ)-derived neural progenitors toward the demyelinated corpus callosum. Furthermore, an ectopic source of CNTF in adult healthy brains changes SVZ-derived neural progenitors' migratory behavior that migrate toward the source by activation of the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway. Using various in vitro assays (Boyden chambers, explants, and video time-lapse imaging), we demonstrate that CNTF controls the directed migration of SVZ-derived progenitors and oligodendrocyte precursors. Altogether, these results demonstrate that in addition to its neuroprotective activity and its role in progenitor survival and maturation, CNTF acts as a chemoattractant and participates in the recruitment of endogenous progenitors during myelin repair.

  2. Exogenous ciliary neurotrophic factor (CNTF) reduces synaptic depression during repetitive stimulation.

    Science.gov (United States)

    Garcia, Neus; Santafé, Manel M; Tomàs, Marta; Priego, Mercedes; Obis, Teresa; Lanuza, Maria A; Besalduch, Nuria; Tomàs, Josep

    2012-09-01

    It has been shown that ciliary neurotrophic factor (CNTF) has trophic and maintenance effects on several types of peripheral and central neurons, glia, and cells outside the nervous system. Both CNTF and its receptor, CNTF-Rα, are expressed in the muscle. We use confocal immunocytochemistry to show that the trophic cytokine and its receptor are present in the pre- and post-synaptic sites of the neuromuscular junctions (NMJs). Applied CNTF (7.5-200 ng/ml, 60 min-3 h) does not acutely affect spontaneous potentials (size or frequency) or quantal content of the evoked acetylcholine release from post-natal (in weak or strong axonal inputs on dually innervated end plates or in the most mature singly innervated synapses at P6) or adult (P30) NMJ of Levator auris longus muscle of the mice. However, CNTF reduces roughly 50% the depression produced by repetitive stimulation (40 Hz, 2 min) on the adult NMJs. Our findings indicate that, unlike neurotrophins, exogenous CNTF does not acutely modulate transmitter release locally at the mammalian neuromuscular synapse but can protect mature end plates from activity-induced synaptic depression. © 2012 Peripheral Nerve Society.

  3. Ciliary neurotrophic factor for macular telangiectasia type 2: results from a phase 1 safety trial.

    Science.gov (United States)

    Chew, Emily Y; Clemons, Traci E; Peto, Tunde; Sallo, Ferenc B; Ingerman, Avner; Tao, Weng; Singerman, Lawrence; Schwartz, Steven D; Peachey, Neal S; Bird, Alan C

    2015-04-01

    To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. An open-label safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. The participant's more severely affected eye (worse baseline visual acuity) received the high-dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. Published by Elsevier Inc.

  4. Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake.

    Directory of Open Access Journals (Sweden)

    Corinne Beurrier

    Full Text Available Ciliary neurotrophic factor (CNTF is a potent neuroprotective cytokine in different animal models of glutamate-induced excitotoxicity, although its action mechanisms are still poorly characterized. We tested the hypothesis that an increased function of glial glutamate transporters (GTs could underlie CNTF-mediated neuroprotection. We show that neuronal loss induced by in vivo striatal injection of the excitotoxin quinolinic acid (QA was significantly reduced (by approximately 75% in CNTF-treated animals. In striatal slices, acute QA application dramatically inhibited corticostriatal field potentials (FPs, whose recovery was significantly higher in CNTF rats compared to controls (approximately 40% vs. approximately 7%, confirming an enhanced resistance to excitotoxicity. The GT inhibitor DL-threo-beta-benzyloxyaspartate greatly reduced FP recovery in CNTF rats, supporting the role of GT in CNTF-mediated neuroprotection. Whole-cell patch-clamp recordings from striatal medium spiny neurons showed no alteration of basic properties of striatal glutamatergic transmission in CNTF animals, but the increased effect of a low-affinity competitive glutamate receptor antagonist (gamma-D-glutamylglycine also suggested an enhanced GT function. These data strongly support our hypothesis that CNTF is neuroprotective via an increased function of glial GTs, and further confirms the therapeutic potential of CNTF for the clinical treatment of progressive neurodegenerative diseases involving glutamate overflow.

  5. Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients.

    Science.gov (United States)

    Dutta, Ranjan; McDonough, Jennifer; Chang, Ansi; Swamy, Lakshman; Siu, Alan; Kidd, Grahame J; Rudick, Richard; Mirnics, Karoly; Trapp, Bruce D

    2007-10-01

    Neuronal and axonal degeneration results in irreversible neurological disability in multiple sclerosis (MS) patients. A number of adaptive or neuroprotective mechanisms are thought to repress neurodegeneration and neurological disability in MS patients. To investigate possible neuroprotective pathways in the cerebral cortex of MS patients, we compared gene transcripts in cortices of six control and six MS patients. Out of 67 transcripts increased in MS cortex nine were related to the signalling mediated by the neurotrophin ciliary neurotrophic factor (CNTF). Therefore, we quantified and localized transcriptional (RT-PCR, in situ hybridization) and translational (western, immunohistochemistry) products of CNTF-related genes. CNTF-receptor complex members, CNTFRalpha, LIFRbeta and GP130, were increased in MS cortical neurons. CNTF was increased and also expressed by neurons. Phosphorylated STAT3 and the anti-apoptotic molecule, Bcl2, known down stream products of CNTF signalling were also increased in MS cortical neurons. We hypothesize that in response to the chronic insults or stress of the pathogenesis of multiple sclerosis, cortical neurons up regulate a CNTF-mediated neuroprotective signalling pathway. Induction of CNTF signalling and the anti-apoptotic molecule, Bcl2, thus represents a compensatory response to disease pathogenesis and a potential therapeutic target in MS patients.

  6. Synergetic effects of ciliary neurotrophic factor and olfactory ensheathing cells on optic nerve reparation (complete translation

    Directory of Open Access Journals (Sweden)

    Dan-ping Yin

    2016-01-01

    Full Text Available At present, there is no effective treatment for the repair of the optic nerve after injury, or improvement of its microenvironment for regeneration. Intravitreally injected ciliary neurotrophic factor (CNTF and olfactory ensheathing cells (OECs promote the long-distance regrowth of severed optic nerve fibers after intracranial injury. Here, we examined the efficacy of these techniques alone and in combination, in a rat model of optic nerve injury. We injected condensed OEC suspension at the site of injury, or CNTF into the vitreous body, or both simultaneously. Retrograde tracing techniques showed that 4 weeks postoperatively, the number of surviving retinal ganglion cells and their axonal density in the optic nerve were greater in rats subjected to OEC injection only than in those receiving CNTF injection only. Furthermore, combined OEC + CNTF injection achieved better results than either monotherapy. These findings confirm that OECs are better than CNTF at protecting injured neurons in the eye, but that combined OEC and CNTF therapy is notably more effective than either treatment alone.

  7. Ciliary neurotrophic factor role in myelin oligodendrocyte glycoprotein expression in Cuprizone-induced multiple sclerosis mice.

    Science.gov (United States)

    Salehi, Zivar; Hadiyan, Sara Pishgah; Navidi, Reza

    2013-05-01

    Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. Myelin oligodendrocyte glycoprotein (MOG) is a minor component of the myelin sheath, but is an important autoantigen linked to the pathogenesis of MS. Ciliary neurotrophic factor (CNTF) has been shown to enhance the generation, maturation, and survival of oligodendrocytes in culture medium. The aim of this study was to demonstrate the role of CNTF on MOG expression in the cerebral cortex of Cuprizone-induced MS mice. The mice were treated by Cuprizone for five weeks in order to induce MS. The mice were then divided into 3 groups. The first group was injected subcutaneously (SC) by CNTF in the amount of 250 μg/kg BW per day. The second group (SHAM) was injected SC by normal saline and the third group was left without injection as the control group. After four weeks the mice were killed and the cerebral cortex was harvested and the expression of MOG was studied by Western blotting. The data from this study show that the MOG expression was significantly increased in the CNTF-injected group as compared to the other groups. It is concluded that CNTF increases the MOG expression and may be important in the pathophysiology of MS. It is also concluded that CNTF may play a role in the process of remyelination by inducing the MOG expression.

  8. RET-mediated glial cell line-derived neurotrophic factor signaling inhibits mouse prostate development.

    Science.gov (United States)

    Park, Hyun-Jung; Bolton, Eric C

    2017-06-15

    In humans and rodents, the prostate gland develops from the embryonic urogenital sinus (UGS). The androgen receptor (AR) is thought to control the expression of morphogenetic genes in inductive UGS mesenchyme, which promotes proliferation and cytodifferentiation of the prostatic epithelium. However, the nature of the AR-regulated morphogenetic genes and the mechanisms whereby AR controls prostate development are not understood. Glial cell line-derived neurotrophic factor (GDNF) binds GDNF family receptor α1 (GFRα1) and signals through activation of RET tyrosine kinase. Gene disruption studies in mice have revealed essential roles for GDNF signaling in development; however, its role in prostate development is unexplored. Here, we establish novel roles of GDNF signaling in mouse prostate development. Using an organ culture system for prostate development and Ret mutant mice, we demonstrate that RET-mediated GDNF signaling in UGS increases proliferation of mesenchyme cells and suppresses androgen-induced proliferation and differentiation of prostate epithelial cells, inhibiting prostate development. We also identify Ar as a GDNF-repressed gene and Gdnf and Gfrα1 as androgen-repressed genes in UGS, thus establishing reciprocal regulatory crosstalk between AR and GDNF signaling in prostate development. © 2017. Published by The Company of Biologists Ltd.

  9. A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery.

    Science.gov (United States)

    MacLellan, Crystal L; Keough, Michael B; Granter-Button, Shirley; Chernenko, Garry A; Butt, Stephanie; Corbett, Dale

    2011-10-01

    Enriched rehabilitation (ER; environmental enrichment plus skilled reaching) improves recovery after middle cerebral artery occlusion (MCAo) in rats. Fundamental issues such as whether ER is effective in other models, optimal rehabilitation intensity, and underlying recovery mechanisms have not been fully assessed. The authors tested whether the efficacy of ER varies with ischemia model and assessed the importance of rehabilitation intensity and brain-derived neurotrophic factor (BDNF) in recovery. Rats in experiment 1 received 8 weeks of ER or remained in standard housing. Functional outcome was assessed with the staircase and cylinder tasks. Surprisingly, ER provided no functional benefit in any model. In this experiment, ER was delivered during the light phase, whereas other studies delivered ER in the dark phase of the light cycle. It was hypothesized that in the light, rats engaged in less rehabilitation or alternatively that BDNF was lower. Experiment 2 tested these hypotheses. Following MCAo, rats received ER in either the light or dark phase of the light cycle. Functional outcome was assessed and BDNF levels were measured in the motor cortex and hippocampus. Recovery was accompanied by increased BDNF. This occurred only in rats that received ER in the dark and these animals reached more than those in the light condition. Data suggest that there is a critical threshold of rehabilitation, below which recovery will not occur, and that BDNF mediates functional recovery. The use of intensive rehabilitation therapies for stroke patients is strongly supported.

  10. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke.

    Science.gov (United States)

    Clarkson, Andrew N; Overman, Justine J; Zhong, Sheng; Mueller, Rudolf; Lynch, Gary; Carmichael, S Thomas

    2011-03-09

    Stroke is the leading cause of adult disability. Recovery after stroke shares similar molecular and cellular properties with learning and memory. A main component of learning-induced plasticity involves signaling through AMPA receptors (AMPARs). We systematically tested the role of AMPAR function in motor recovery in a mouse model of focal stroke. AMPAR function controls functional recovery beginning 5 d after the stroke. Positive allosteric modulators of AMPARs enhance recovery of limb control when administered after a delay from the stroke. Conversely, AMPAR antagonists impair motor recovery. The contributions of AMPARs to recovery are mediated by release of brain-derived neurotrophic factor (BDNF) in periinfarct cortex, as blocking local BDNF function in periinfarct cortex blocks AMPAR-mediated recovery and prevents the normal pattern of motor recovery. In contrast to a delayed AMPAR role in motor recovery, early administration of AMPAR agonists after stroke increases stroke damage. These findings indicate that the role of glutamate signaling through the AMPAR changes over time in stroke: early potentiation of AMPAR signaling worsens stroke damage, whereas later potentiation of the same signaling system improves functional recovery.

  11. The correlation between perceived social support, cortisol and brain derived neurotrophic factor levels in healthy women.

    Science.gov (United States)

    Ma, Doy Yung; Chang, Wei Hung; Chi, Mei Hung; Tsai, Hsin Chun; Yang, Yen Kuang; Chen, Po See

    2016-05-30

    In this study, the role of brain derived neurotrophic factor (BDNF) in stress resilience was investigated. With a focus on healthy subjects, we explored whether plasma BDNF levels are correlated with the dexamethasone suppression test (DST) and subjectively perceived social support status. Moreover, we examined the possible interacting effect of DST status and perceived social support on BDNF levels. Seventy-two healthy volunteers, 44 females and 28 males, were recruited from the community and completed the perceived routine support subscale of Measurement of Support Function (PRS_MSF) questionnaire. Plasma BDNF levels and DST suppression rate with the low dose DST were measured. There was a significant positive correlation between BDNF and DST suppression rate in the female subjects. This was also true for the plasma BDNF levels and PRS_MSF in the female subjects. The positive correlation between BDNF and PRS_MSF was significant only in female subjects with low DST suppression rates. Plasma BDNF levels were associated with stress resilience in a sex-specific manner. Subjects' belief in social support might buffer the biological stress reactions. Differences in social perception and the biological stress response between men and women merits further investigation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression

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    Hao-hao Chen

    2015-01-01

    Full Text Available Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor (BDNF. In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippocampus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.

  13. Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

    Science.gov (United States)

    Choi, Miyeon; Lee, Seung Hoon; Park, Min Hyeop; Kim, Yong-Seok; Son, Hyeon

    2017-08-05

    Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

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    De-guo Jiang

    2016-01-01

    Full Text Available Previous studies suggest that serotonin (5-HT might interact with brain-derived neurotrophic factor (BDNF during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

  15. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

    Science.gov (United States)

    Murphy, Diane D.; Cole, Nelson B.; Segal, Menahem

    1998-01-01

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons. PMID:9736750

  16. Platelet protein kinase C and brain-derived neurotrophic factor levels in borderline personality disorder patients.

    Science.gov (United States)

    Koenigsberg, Harold W; Yuan, Peixiong; Diaz, George A; Guerreri, Stephanie; Dorantes, Christine; Mayson, Sarahjo; Zamfirescu, Constantin; New, Antonia S; Goodman, Marianne; Manji, Husseini K; Siever, Larry J

    2012-09-30

    Borderline personality disorder (BPD) is a prevalent and difficult to treat psychiatric condition characterized by abrupt mood swings, intense anger and depression, unstable interpersonal relationships, impulsive self-destructive behavior and a suicide rate of approximately 10%. Possible underlying molecular dysregulations in BPD have not been well explored. Protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) have both been implicated in affective disorders, but their role in BPD has not been examined. Platelets were isolated from blood obtained from 24 medication-free BPD patients and 18 healthy control subjects. PKC-α, phosphorylated-PKC-α (p-PKCα), PKC-βII, and BDNF were measured in platelet homogenates by immunoblotting. In the males, platelet BDNF and PKC-α levels were lower in patients than controls. p-PKC-α and PKC-βII were lower at trend levels. In the entire sample, platelet p-PKCα and PKC-α activity were lower, at a trend level, in patients compared to controls. This is the first report to our knowledge of PKC and BDNF activity in BPD and calls for replication. These findings are consistent with altered PKC and BDNF activity in a range of neuropsychiatric conditions including bipolar disorder, depression and suicide. Published by Elsevier Ireland Ltd.

  17. Post-traumatic stress disorder risk and brain-derived neurotrophic factor Val66Met

    Science.gov (United States)

    Zhang, Lei; Li, Xiao-Xia; Hu, Xian-Zhang

    2016-01-01

    Brain-derived neurotrophic factor (BDNF), which regulates neuronal survival, growth differentiation, and synapse formation, is known to be associated with depression and post-traumatic stress disorder (PTSD). However, the molecular mechanism for those mental disorders remains unknown. Studies have shown that BDNF is associated with PTSD risk and exaggerated startle reaction (a major arousal manifestation of PTSD) in United States military service members who were deployed during the wars in Iraq and Afghanistan. The frequency of the Met/Met in BDNF gene was greater among those with PTSD than those without PTSD. Among individuals who experienced fewer lifetime stressful events, the Met carriers have significantly higher total and startle scores on the PTSD Checklist than the Val/Val carriers. In addition, subjects with PTSD showed higher levels of BDNF in their peripheral blood plasma than the non-probable-PTSD controls. Increased BDNF levels and startle response were observed in both blood plasma and brain hippocampus by inescapable tail shock in rats. In this paper, we reviewed these data to discuss BDNF as a potential biomarker for PTSD risk and its possible roles in the onset of PTSD. PMID:27014593

  18. Decreased brain-derived neurotrophic factor plasma levels in psoriasis patients.

    Science.gov (United States)

    Brunoni, A R; Lotufo, P A; Sabbag, C; Goulart, A C; Santos, I S; Benseñor, I M

    2015-08-01

    Brain-derived neurotrophic factor (BDNF) is associated with neuroplasticity and synaptic strength, and is decreased in conditions associated with chronic stress. Nevertheless, BDNF has not yet been investigated in psoriasis, a chronic inflammatory systemic disease that is exacerbated by stress. Therefore, our aim was to determine BDNF plasma levels in psoriasis patients and healthy controls. Adult patients (n=94) presenting with psoriasis for at least 1 year were enrolled, and age- and gender-matched with healthy controls (n=307) from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants had neither a previous history of coronary artery disease nor current episode of major depression. BDNF plasma levels were determined using the Promega ELISA kit. A general linear model was used to compare BDNF levels in psoriasis patients and controls, with age, gender, systolic blood pressure, serum fasting glucose, blood lipid levels, triglycerides, smoking status, and body mass index examined. After adjusting for clinical and demographic variables, significantly decreased BNDF plasma levels were observed in psoriasis patients (P=0.01) (estimated marginal means of 3922 pg/mL; 95%CI=2660-5135) compared with controls (5788 pg/mL; 95%CI=5185-6442). Similar BDNF levels were found in both mild and severe cases of psoriasis. Our finding, that BDNF is decreased in psoriasis, supports the concept of a brain-skin connection in psoriasis. Further studies should determine if BDNF is increased after specific psoriasis treatments, and associated with different disease stages.

  19. Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress.

    Science.gov (United States)

    Jiang, De-Guo; Jin, Shi-Li; Li, Gong-Ying; Li, Qing-Qing; Li, Zhi-Ruo; Ma, Hong-Xia; Zhuo, Chuan-Jun; Jiang, Rong-Huan; Ye, Min-Jie

    2016-09-01

    Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

  20. Brain-Derived Neurotrophic Factor Levels in Autism: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Saghazadeh, Amene; Rezaei, Nima

    2017-04-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in activity-dependent synaptic plasticity. Altered blood BDNF levels have been frequently identified in people with autism spectrum disorders (ASD). There are however wide discrepancies in the evidence. Therefore, we performed the present systematic review and meta-analysis aimed at qualitative and quantitative synthesis of studies that measured blood BDNF levels in ASD and control subjects. Observational studies were identified through electronic database searching and also hand-searching of reference lists of relevant articles. A total of 183 papers were initially identified for review and eventually twenty studies were included in the meta-analysis. A meta-analysis of blood BDNF in 887 patients with ASD and 901 control subjects demonstrated significantly higher BDNF levels in ASD compared to controls with the SMD of 0.47 (95% CI 0.07-0.86, p = 0.02). In addition subgroup meta-analyses were performed based on the BDNF specimen. The present meta-analysis study led to conclusion that BDNF might play role in autism initiation/ propagation and therefore it can be considered as a possible biomarker of ASD.

  1. Spicatoside A enhances memory consolidation through the brain-derived neurotrophic factor in mice.

    Science.gov (United States)

    Kwon, Guyoung; Lee, Hyung Eun; Lee, Dong Hwa; Woo, Hyun; Park, Se Jin; Gao, Qingtao; Ahn, Young Je; Son, Kun Ho; Ryu, Jong Hoon

    2014-06-20

    Brain-derived neurotrophic factor (BDNF) plays a pivotal role in memory consolidation. Previously, we found that the increased mature BDNF (mBDNF) levels in the hippocampal region at a specific time window after the acquisition trial are required for memory consolidation. In the present study, we investigated whether spicatoside A enhances memory consolidation, and whether its effects on memory consolidation are related to hippocampal mBDNF levels. Spicatoside A (2.5, 5, 10 or 20mg/kg) enhanced memory consolidation in a dose-dependent manner, and enhanced memory consolidation was also observed when spicatoside A was administered 1h after the acquisition trial. Concurrently, when spicatoside A was administered immediately or 1h after the acquisition trial, hippocampal mBDNF levels were similar or significantly increased at 9h after the acquisition trial compared to levels at 6h. These results suggest that increased mBDNF levels in the hippocampal region at 9h after the acquisition trial might play a pivotal role in memory consolidation and that spicatoside A might enhance memory consolidation by increasing hippocampal mBDNF levels. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Human Obesity Associated with an Intronic SNP in the Brain-Derived Neurotrophic Factor Locus

    Directory of Open Access Journals (Sweden)

    Zongyang Mou

    2015-11-01

    Full Text Available Brain-derived neurotrophic factor (BDNF plays a key role in energy balance. In population studies, SNPs of the BDNF locus have been linked to obesity, but the mechanism by which these variants cause weight gain is unknown. Here, we examined human hypothalamic BDNF expression in association with 44 BDNF SNPs. We observed that the minor C allele of rs12291063 is associated with lower human ventromedial hypothalamic BDNF expression (p < 0.001 and greater adiposity in both adult and pediatric cohorts (p values < 0.05. We further demonstrated that the major T allele for rs12291063 possesses a binding capacity for the transcriptional regulator, heterogeneous nuclear ribonucleoprotein D0B, knockdown of which disrupts transactivation by the T allele. Binding and transactivation functions are both disrupted by substituting C for T. These findings provide a rationale for BDNF augmentation as a targeted treatment for obesity in individuals who have the rs12291063 CC genotype.

  3. Peripheral brain-derived neurotrophic factor is related to cardiovascular risk factors in active and inactive elderly men

    Directory of Open Access Journals (Sweden)

    A. Zembron-Lacny

    2016-01-01

    Full Text Available Regular exercise plays an important preventive and therapeutic role in heart and vascular diseases, and beneficially affects brain function. In blood, the effects of exercise appear to be very complex and could include protection of vascular endothelial cells via neurotrophic factors and decreased oxidative stress. The purpose of this study was to identify the age-related changes in peripheral brain-derived neurotrophic factor (BDNF and its relationship to oxidative damage and conventional cardiovascular disease (CVD biomarkers, such as atherogenic index, C-reactive protein (hsCRP and oxidized LDL (oxLDL, in active and inactive men. Seventeen elderly males (61-80 years and 17 young males (20-24 years participated in this study. According to the 6-min Åstrand-Rhyming bike test, the subjects were classified into active and inactive groups. The young and elderly active men had a significantly better lipoprotein profile and antioxidant status, as well as reduced oxidative damage and inflammatory state. The active young and elderly men had significantly higher plasma BDNF levels compared to their inactive peers. BDNF was correlated with VO2max (r=0.765, P<0.001. In addition, we observed a significant inverse correlation of BDNF with atherogenic index (TC/HDL, hsCRP and oxLDL. The findings demonstrate that a high level of cardiorespiratory fitness reflected in VO2max was associated with a higher level of circulating BDNF, which in turn was related to common CVD risk factors and oxidative damage markers in young and elderly men.

  4. Altered Acoustic Startle Reflex, Prepulse Inhibition, and Peripheral Brain-Derived Neurotrophic Factor in Morphine Self-Administered Rats.

    Science.gov (United States)

    Lee, Bong Hyo; Park, Thomas Y; Lin, Erica; Li, He; Yang, Chae Ha; Choi, Kwang H

    2017-05-01

    Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine self-administration on these measures remain unclear. Adult male Sprague-Dawley rats were implanted with a catheter in the jugular vein. After 1 week of recovery, the animals were allowed to self-administer either i.v. morphine (0.5 mg/kg per infusion, 4 h/d) or saline in the operant conditioning chambers. The acoustic startle reflex and prepulse inhibition were measured at a baseline and on self-administration days 1, 3, 5, and 7 (1- and 3-hour withdrawal). Blood samples were collected on self-administration days 3, 5, and 7 from separate cohorts of animals, and the levels of brain-derived neurotrophic factor and corticosterone were assayed using the enzyme-linked immunosorbent assay method. Compared with the saline group, the morphine self-administration group showed hyper-locomotor activity and reduced defecation during the self-administration. The morphine self-administration increased acoustic startle reflex at 1-hour but not 3-hour withdrawal from morphine and disrupted prepulse inhibition at 3-hour but not 1-hour withdrawal. The blood brain-derived neurotrophic factor levels were decreased in the morphine self-administration group at self-administration days 3 and 5, while the corticosterone levels remained unchanged throughout the study. The current findings suggest that spontaneous withdrawal from i.v. morphine self-administration may have transient effects on acoustic startle, sensorimotor gating, and peripheral brain-derived neurotrophic factor levels, and these changes may contribute to the adverse effects of opiate withdrawal.

  5. Lack of association between brain-derived neurotrophic factor Val66Met polymorphism and aggressive behavior in schizophrenia.

    Science.gov (United States)

    Guan, Xuan; Dong, Zai-Quan; Tian, Yuan-Yuan; Wu, Li-Na; Gu, Yan; Hu, Ze-Qing; Zhang, Xiao

    2014-01-30

    We investigated the association of the Val66Met gene polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) gene with aggressive behavior among Southern Han Chinese schizophrenia patients. We used polymerase chain reaction-restriction fragment length polymorphism to determine the genotypes and the Modified Overt Aggression Scale (MOAS) to measure aggressive behavior. No significant differences in genotype or allele distribution of Val66Met were identified between aggressive and non-aggressive schizophrenia patients. © 2013 Published by Elsevier Ireland Ltd.

  6. ELEVATED LIPID PEROXIDATION AND DNA OXIDATION IN NERVE FROM DIABETIC RATS: EFFECTS OF ALDOSE REDUCTASE INHIBITION, INSULIN AND NEUROTROPHIC FACTORS

    OpenAIRE

    Cunha, Joice M.; Jolivalt, Corinne G.; Ramos, Khara M.; Gregory, Joshua A.; Calcutt, Nigel A.; Mizisin, Andrew P.

    2008-01-01

    We investigated the effect of treatment with an aldose reductase inhibitor, insulin or select neurotrophic factors on the generation of oxidative damage in peripheral nerve. Rats were either treated with streptozotocin (STZ) to induce insulin-deficient diabetes or fed with a diet containing 40% D-galactose to promote hexose metabolism by aldose reductase. Initial time-course studies showed that lipid peroxidation and DNA oxidation were significantly elevated in sciatic nerve after 1 week or 2...

  7. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease

    OpenAIRE

    Borba, Ericksen Mielle; Duarte, Juliana Avila; Bristot, Giovana; Scotton, Ellen; Camozzato, Ana Luiza; Chaves, M?rcia Lorena Fagundes

    2016-01-01

    Background/Aims: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Methods: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric me...

  8. Ciliary neurotrophic factor: a survival and differentiation inducer in human retinal progenitors.

    Science.gov (United States)

    Dutt, Kamla; Cao, Yang; Ezeonu, Ifeoma

    2010-07-01

    Retinitis pigmentosa, age-related macular degeneration, and Parkinson's disease remain major problems in the field of medicine. Some of the strategies being explored for treatment include replacement of damaged tissue by transplantation of healthy tissues or progenitor cells and delivery of neurotrophins to rescue degenerating tissue. One of the neurotrophins with promise is the ciliary neurotrophic factor (CNTF). In this study, we report the role played by CNTF in retinal cell differentiation and survival in retinal progenitors. We found that CNTF is a survival factor for multipotential human retinal cells and increased cell survival by 50%, over a 7-d period, under serum-free conditions, as determined by apoptotic assays (immunohistochemistry and flow cytometry). This effect is dose dependent with a maximum survival at a CNTF concentration of 20 ng/ml. We also report that CNTF might be a cell commitment factor, directing the differentiation mainly toward large multipolar cells with ganglionic and amacrine phenotype. These cells express tyrosine hydroxylase (amacrine cells) as well as, thy 1.1 and neuron-specific enolase (ganglionic cells). Additionally, there was also an increase in protein kinase C alpha, a protein expressed in rod and cone bipolars as well as cone photoreceptors and calbindin, a protein expressed in cone photoreceptors and horizontal cells. In our studies, CNTF doubled the number of cells with ganglionic phenotypes, and basic fibroblast growth factor doubled the number of cells with photoreceptor phenotype. Additionally, CNTF induced a subset of progenitors to undergo multiple rounds of cell division before acquiring the large multipolar ganglionic phenotype. Our conclusion is that CNTF could be an agent that has therapeutic potential and possibly induces differentiation of large multipolar ganglionic phenotype in a subset of progenitors.

  9. Serum levels of brain-derived neurotrophic factor in major depressive disorder : state-trait issues, clinical features and pharmacological treatment

    NARCIS (Netherlands)

    Molendijk, M. L.; Bus, B. A. A.; Spinhoven, Ph; Penninx, B. W. J. H.; Kenis, G.; Prickaerts, J.; Voshaar, R. C. Oude; Elzinga, B. M.

    2011-01-01

    Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression,

  10. Serum levels of brain-derived neurotrophic factor in major depressive disorder: state-trait issues, clinical features and pharmacological treatment

    NARCIS (Netherlands)

    Molendijk, M.L.; Bus, B.A.A.; Spinhoven, P.; Penninx, B.W.J.H.; Kenis, G.; Prickaerts, J.; Voshaar, R.C.O.; Elzinga, B.M.

    2011-01-01

    Recent evidence supports 'the neurotrophin hypothesis of depression' in its prediction that brain-derived neurotrophic factor (BDNF) is involved in depression. However, some key questions remain unanswered, including whether abnormalities in BDNF persist beyond the clinical state of depression,

  11. Glial cell line-derived neurotrophic factor up-regulates GTP-cyclohydrolase I activity and tetrahydrobiopterin levels in primary dopaminergic neurones

    DEFF Research Database (Denmark)

    Bauer, M; Suppmann, S; Meyer, M

    2002-01-01

    Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurones against toxic and physical damage. In addition, GDNF promotes differentiation and structural integrity of dopaminergic neurones. Here we show that GDNF can support the function of primary dopaminergic neurones...

  12. The effects of aerobic exercise training on oxidant–antioxidant balance, neurotrophic factor levels, and blood–brain barrier function in obese and non-obese men

    Directory of Open Access Journals (Sweden)

    Hee-Tae Roh

    2017-12-01

    Conclusion: These results suggest that obesity can reduce serum neurotrophic factor levels and can induce BBB dysfunction. On the other hand, aerobic exercise can improve an oxidant–antioxidant imbalance in obese subjects and limit BBB dysfunction.

  13. Ciliary neurotrophic factor and fibroblast growth factor increase the speed and number of regenerating axons after optic nerve injury in adult Rana pipiens.

    Science.gov (United States)

    Vega-Meléndez, Giam S; Blagburn, Jonathan M; Blanco, Rosa E

    2014-01-01

    Neurotrophins such as ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) and growth factors such as fibroblast growth factor (FGF-2) play important roles in neuronal survival and in axonal outgrowth during development. However, whether they can modulate regeneration after optic nerve injury in the adult animal is less clear. The present study investigates the effects of application of these neurotrophic factors on the speed, number, and distribution of regenerating axons in the frog Rana pipiens after optic nerve crush. Optic nerves were crushed and the factors, or phosphate-buffered saline, were applied to the stump or intraocularly. The nerves were examined at different times after axotomy, using anterograde labeling with biotin dextran amine and antibody against growth-associated protein 43. We measured the length, number, and distribution of axons projecting beyond the lesion site. Untreated regenerating axons show an increase in elongation rate over 3 weeks. CNTF more than doubles this rate, FGF-2 increases it, and BDNF has little effect. In contrast, the numbers of regenerating axons that have reached 200 μm at 2 weeks were more than doubled by FGF-2, increased by CNTF, and barely affected by BDNF. The regenerating axons were preferentially distributed in the periphery of the nerve; although the numbers of axons were increased by neurotrophic factor application, this overall distribution was substantially unaffected. Copyright © 2013 Wiley Periodicals, Inc.

  14. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants.

    Science.gov (United States)

    Sieving, Paul A; Caruso, Rafael C; Tao, Weng; Coleman, Hanna R; Thompson, Darby J S; Fullmer, Keri R; Bush, Ronald A

    2006-03-07

    Neurotrophic factors are agents with a promising ability to retard progression of neurodegenerative diseases and are effective in slowing photoreceptor degeneration in animal models of retinitis pigmentosa. Here we report a human clinical trial of a neurotrophic factor for retinal neurodegeneration. In this Phase I safety trial, human ciliary neurotrophic factor (CNTF) was delivered by cells transfected with the human CNTF gene and sequestered within capsules that were surgically implanted into the vitreous of the eye. The outer membrane of the encapsulated cell implant is semipermeable to allow CNTF to reach the retina. Ten participants received CNTF implants in one eye. When the implants were removed after 6 months, they contained viable cells with minimal cell loss and gave CNTF output at levels previously shown to be therapeutic for retinal degeneration in rcd1 dogs. Although the trial was not powered to form a judgment as to clinical efficacy, of seven eyes for which visual acuity could be tracked by conventional reading charts, three eyes reached and maintained improved acuities of 10-15 letters, equivalent to two- to three-line improvement on standard Snellen acuity charts. A surgically related choroidal detachment in one eye resulted in a transient acuity decrease that resolved with conservative management. This Phase I trial indicated that CNTF is safe for the human retina even with severely compromised photoreceptors. The approach to delivering therapeutic proteins to degenerating retinas using encapsulated cell implants may have application beyond disease caused by genetic mutations.

  15. The Impacts of Swimming Exercise on Hippocampal Expression of Neurotrophic Factors in Rats Exposed to Chronic Unpredictable Mild Stress

    Directory of Open Access Journals (Sweden)

    Pei Jiang

    2014-01-01

    Full Text Available Depression is associated with stress-induced neural atrophy in limbic brain regions, whereas exercise has antidepressant effects as well as increasing hippocampal synaptic plasticity by strengthening neurogenesis, metabolism, and vascular function. A key mechanism mediating these broad benefits of exercise on the brain is induction of neurotrophic factors, which instruct downstream structural and functional changes. To systematically evaluate the potential neurotrophic factors that were involved in the antidepressive effects of exercise, in this study, we assessed the effects of swimming exercise on hippocampal mRNA expression of several classes of the growth factors (BDNF, GDNF, NGF, NT-3, FGF2, VEGF, and IGF-1 and peptides (VGF and NPY in rats exposed to chronic unpredictable mild stress (CUMS. Our study demonstrated that the swimming training paradigm significantly induced the expression of BDNF and BDNF-regulated peptides (VGF and NPY and restored their stress-induced downregulation. Additionally, the exercise protocol also increased the antiapoptotic Bcl-xl expression and normalized the CUMS mediated induction of proapoptotic Bax mRNA level. Overall, our data suggest that swimming exercise has antidepressant effects, increasing the resistance to the neural damage caused by CUMS, and both BDNF and its downstream neurotrophic peptides may exert a major function in the exercise related adaptive processes to CUMS.

  16. Human umbilical cord blood-derived stem cells and brain-derived neurotrophic factor protect injured optic nerve: viscoelasticity characterization

    Science.gov (United States)

    Lv, Xue-man; Liu, Yan; Wu, Fei; Yuan, Yi; Luo, Min

    2016-01-01

    The optic nerve is a viscoelastic solid-like biomaterial. Its normal stress relaxation and creep properties enable the nerve to resist constant strain and protect it from injury. We hypothesized that stress relaxation and creep properties of the optic nerve change after injury. More-over, human brain-derived neurotrophic factor or umbilical cord blood-derived stem cells may restore these changes to normal. To validate this hypothesis, a rabbit model of optic nerve injury was established using a clamp approach. At 7 days after injury, the vitreous body re-ceived a one-time injection of 50 μg human brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood-derived stem cells. At 30 days after injury, stress relaxation and creep properties of the optic nerve that received treatment had recovered greatly, with patho-logical changes in the injured optic nerve also noticeably improved. These results suggest that human brain-derived neurotrophic factor or umbilical cord blood-derived stem cell intervention promotes viscoelasticity recovery of injured optic nerves, and thereby contributes to nerve recovery. PMID:27212930

  17. The effect of regular Taekwondo exercise on Brain-derived neurotrophic factor and Stroop test in undergraduate student.

    Science.gov (United States)

    Kim, Youngil

    2015-06-01

    The purpose of this study was to investigate the effect of Taekwondo exercise on Brain-derived neurotrophic factor and the Stroop test in undergraduate students. Fourteen male subjects participated in this study. They were separated into a Control group (N = 7) and an Exercise group (N = 7). Subjects participated in Taekwondo exercise training for 8 weeks. They underwent to Taekwondo exercise training for 85 minutes per day, 5 times a week at RPE of 11~15. The taekwondo exercise training comprised an aerobic exercise (20min) mode and a dynamic exercise (65min) mode. All data were analyzed by repeated measures two-way ANOVA. There were no significant differences in the physical characteristics of the subjects. Although weight and BMI showed a tendency to decreased in the exercise group (EG). Also, neurotrophic factors (BDNF, NGF, IGF-1) were not significantly different after 8 weeks in the two groups. However, BDNF and IGF-1 showed a tendency to increase in the exercise group (EG). Finally, the Stroop test (word, color) results were significantly different(p Stroop test). However the training did not statistically affect neurotrophic factors (BDNF, NGF, IGF-1) in undergraduate students.

  18. Human umbilical cord blood-derived stem cells and brain-derived neurotrophic factor protect injured optic nerve: viscoelasticity characterization

    Directory of Open Access Journals (Sweden)

    Xue-man Lv

    2016-01-01

    Full Text Available The optic nerve is a viscoelastic solid-like biomaterial. Its normal stress relaxation and creep properties enable the nerve to resist constant strain and protect it from injury. We hypothesized that stress relaxation and creep properties of the optic nerve change after injury. More-over, human brain-derived neurotrophic factor or umbilical cord blood-derived stem cells may restore these changes to normal. To validate this hypothesis, a rabbit model of optic nerve injury was established using a clamp approach. At 7 days after injury, the vitreous body re-ceived a one-time injection of 50 µg human brain-derived neurotrophic factor or 1 × 106 human umbilical cord blood-derived stem cells. At 30 days after injury, stress relaxation and creep properties of the optic nerve that received treatment had recovered greatly, with patho-logical changes in the injured optic nerve also noticeably improved. These results suggest that human brain-derived neurotrophic factor or umbilical cord blood-derived stem cell intervention promotes viscoelasticity recovery of injured optic nerves, and thereby contributes to nerve recovery.

  19. Injury-induced CRMP4 expression in adult sensory neurons; a possible target gene for ciliary neurotrophic factor.

    Science.gov (United States)

    Jang, So Young; Shin, Yoon Kyung; Jung, Junyang; Lee, Sang Hwa; Seo, Su-Yeong; Suh, Duk Joon; Park, Hwan Tae

    2010-11-12

    Neurotrophic cytokines, such as ciliary neurotrophic factor (CNTF) play an important role in the development and regeneration of the nervous system. In the present study, we screened gene expression induced by CNTF in adult dorsal root ganglion (DRG) neurons using the Illumina microarray. We found that the expression of both short and long forms of collapsin response-mediator protein 4 (CRMP4) was increased in cultured primary sensory neurons by CNTF. In addition, sciatic nerve injury induced the expression of CRMP4 mRNA and protein in DRG neurons. Finally, the increased CRMP4 protein was transported into peripheral axons following nerve injury. These findings indicate that CRMP4 may be a target gene for CNTF in the regenerative axon growth of DRG neurons after injury. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Co-administration of ciliary neurotrophic factor with its soluble receptor protects against neuronal death and enhances neurite outgrowth.

    Science.gov (United States)

    Ozog, Mark A; Modha, Geetanjalee; Church, John; Reilly, Rayne; Naus, Christian C

    2008-03-07

    Attempts to promote neuronal survival and repair with ciliary neurotrophic factor (CNTF) have met with limited success. The variability of results obtained with CNTF may, in part, reflect the fact that some of the biological actions of the cytokine are mediated by a complex formed between CNTF and its specific receptor, CNTFRalpha, which exists in both membrane-bound and soluble forms. In this study, we compared the actions of CNTF alone and CNTF complexed with soluble CNTFRalpha (hereafter termed "Complex") on neuronal survival and growth. Although CNTF alone produced limited effects, Complex protected against glutamate-mediated excitotoxicity via gap junction-dependent and -independent mechanisms. Further examination revealed that only Complex promoted neurite outgrowth. Differential gene expression analysis revealed that, compared with CNTF alone, Complex differentially regulates several neuroprotective and neurotrophic genes. Collectively, these findings indicate that CNTF exerts more robust effects on neuronal survival and growth when applied in combination with its soluble receptor.

  1. Brain-derived neurotrophic factor correlated with muscle strength in subjects undergoing stationary bicycle exercise training.

    Science.gov (United States)

    Tsai, Sen-Wei; Chan, Yin-Ching; Liang, Francois; Hsu, Chiann-Yi; Lee, I-Te

    2015-04-01

    Several central nervous disorders are associated with metabolic syndrome (MetS) and type 2 diabetes. Reduction in brain-derived neurotrophic factor (BDNF) is involved in the mechanism of central nervous dysfunction. BDNF is up-regulated after exercise, but it is not known whether increased BDNF is related to increases in muscle strength. In the present study, subjects with MetS or type 2 diabetes were enrolled in an exercise program. All participants underwent an indoor bicycle exercise program for twelve weeks. Serum BDNF was determined after overnight fasting. Muscle strength was assessed by extension of the dominant lower extremity. A total of 33 subjects were enrolled in this study. The body mass index did not change significantly (from 30.4±6.0 to 30.2±5.8kg/m(2), P=0.436), but serum BDNF increased significantly (from 17.1±9.1 to 24.2±10.7ng/mL, Pexercise-associated BDNF was significantly correlated with the increased strength in lower-extremity extension test (r=0.54, P=0.001). Using multivariate regression analysis, muscle-strength increment, but not body-weight change, was an independent factor for serum BDNF (95% CI=0.009-0.044, P=0.005). After a twelve-week program of stationary bicycle exercise, serum BDNF concentration increased, and this change was positively correlated with muscle strength of lower-extremity extension, but not body weight. ( NCT02268292, ClinicalTrials.gov). Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Glucocorticoid receptor represses brain-derived neurotrophic factor expression in neuron-like cells.

    Science.gov (United States)

    Chen, Hui; Lombès, Marc; Le Menuet, Damien

    2017-04-12

    Brain-derived neurotrophic factor (BDNF) is involved in many functions such as neuronal growth, survival, synaptic plasticity and memorization. Altered expression levels are associated with many pathological situations such as depression, epilepsy, Alzheimer's, Huntington's and Parkinson's diseases. Glucocorticoid receptor (GR) is also crucial for neuron functions, via binding of glucocorticoid hormones (GCs). GR actions largely overlap those of BDNF. It has been proposed that GR could be a regulator of BDNF expression, however the molecular mechanisms involved have not been clearly defined yet. Herein, we analyzed the effect of a GC agonist dexamethasone (DEX) on BDNF expression in mouse neuronal primary cultures and in the newly characterized, mouse hippocampal BZ cell line established by targeted oncogenesis. Mouse Bdnf gene exhibits a complex genomic structure with 8 untranslated exons (I to VIII) splicing onto one common and unique coding exon IX. We found that DEX significantly downregulated total BDNF mRNA expression by around 30%. Expression of the highly expressed exon IV and VI containing transcripts was also reduced by DEX. The GR antagonist RU486 abolished this effect, which is consistent with specific GR-mediated action. Transient transfection assays allowed us to define a short 275 bp region within exon IV promoter responsible for GR-mediated Bdnf repression. Chromatin immunoprecipitation experiments demonstrated GR recruitment onto this fragment, through unidentified transcription factor tethering. Altogether, GR downregulates Bdnf expression through direct binding to Bdnf regulatory sequences. These findings bring new insights into the crosstalk between GR and BDNF signaling pathways both playing a major role in physiology and pathology of the central nervous system.

  3. Neither cortisol nor brain-derived neurotrophic factor is associated with serotonin transporter in bipolar disorder.

    Science.gov (United States)

    Chou, Yuan-Hwa; Lirng, Jiing-Feng; Hsieh, Wen-Chi; Chiu, Yen-Chen; Tu, Yi-An; Wang, Shyh-Jen

    2016-02-01

    Converging evidence indicates the hypothalamus-pituitary-adrenal axis and serotonergic neurons exert reciprocal modulatory actions. Likewise, brain-derived neurotrophic factor (BDNF) has been implicated as a growth and differentiation factor in the development of serotonergic neurons. The aim of this study was to examine the interaction of cortisol and BDNF on serotonin transporter (SERT) in bipolar disorder (BD). Twenty-eight BD and 28 age- and gender-matched healthy controls (HCs) were recruited. (123)I-ADAM with single-photon emission computed tomography (SPECT) was applied for measurement of SERT availability in the brain, which included the midbrain, thalamus, putamen and caudate. Ten milliliters of venous blood was withdrawn, when the subject underwent SPECT, for the measurement of the plasma concentration of cortisol and BDNF. SERT availability was significantly decreased in the midbrain and caudate of BD compared with HCs, whereas plasma concentration of cortisol and BDNF did not show a significant difference. The linear mixed-effect model revealed that there was a significant interaction of group and cortisol on SERT availability of the midbrain, but not BDNF. Linear regression analyses by groups revealed that cortisol was associated with SERT availability in the midbrain in the HCs, but not in BD. Considering previous studies, which showed a significant association of cortisol with SERT availability in the HCs and major depressive disorder (MDD), our result replicated a similar finding in HCs. However, the negative finding of the association of cortisol and SERT availability in BD, which was different from MDD, suggests a different role for cortisol in the pathophysiology of mood disorder. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  4. Protecting Neural Structures and Cognitive Function During Prolonged Space Flight by Targeting the Brain Derived Neurotrophic Factor Molecular Network

    Science.gov (United States)

    Schmidt, M. A.; Goodwin, T. J.

    2014-01-01

    Brain derived neurotrophic factor (BDNF) is the main activity-dependent neurotrophin in the human nervous system. BDNF is implicated in production of new neurons from dentate gyrus stem cells (hippocampal neurogenesis), synapse formation, sprouting of new axons, growth of new axons, sprouting of new dendrites, and neuron survival. Alterations in the amount or activity of BDNF can produce significant detrimental changes to cortical function and synaptic transmission in the human brain. This can result in glial and neuronal dysfunction, which may contribute to a range of clinical conditions, spanning a number of learning, behavioral, and neurological disorders. There is an extensive body of work surrounding the BDNF molecular network, including BDNF gene polymorphisms, methylated BDNF gene promoters, multiple gene transcripts, varied BDNF functional proteins, and different BDNF receptors (whose activation differentially drive the neuron to neurogenesis or apoptosis). BDNF is also closely linked to mitochondrial biogenesis through PGC-1alpha, which can influence brain and muscle metabolic efficiency. BDNF AS A HUMAN SPACE FLIGHT COUNTERMEASURE TARGET Earth-based studies reveal that BDNF is negatively impacted by many of the conditions encountered in the space environment, including oxidative stress, radiation, psychological stressors, sleep deprivation, and many others. A growing body of work suggests that the BDNF network is responsive to a range of diet, nutrition, exercise, drug, and other types of influences. This section explores the BDNF network in the context of 1) protecting the brain and nervous system in the space environment, 2) optimizing neurobehavioral performance in space, and 3) reducing the residual effects of space flight on the nervous system on return to Earth

  5. Efficient Transduction of Feline Neural Progenitor Cells for Delivery of Glial Cell Line-Derived Neurotrophic Factor Using a Feline Immunodeficiency Virus-Based Lentiviral Construct

    Directory of Open Access Journals (Sweden)

    X. Joann You

    2011-01-01

    Full Text Available Work has shown that stem cell transplantation can rescue or replace neurons in models of retinal degenerative disease. Neural progenitor cells (NPCs modified to overexpress neurotrophic factors are one means of providing sustained delivery of therapeutic gene products in vivo. To develop a nonrodent animal model of this therapeutic strategy, we previously derived NPCs from the fetal cat brain (cNPCs. Here we use bicistronic feline lentiviral vectors to transduce cNPCs with glial cell-derived neurotrophic factor (GDNF together with a GFP reporter gene. Transduction efficacy is assessed, together with transgene expression level and stability during induction of cellular differentiation, together with the influence of GDNF transduction on growth and gene expression profile. We show that GDNF overexpressing cNPCs expand in vitro, coexpress GFP, and secrete high levels of GDNF protein—before and after differentiation—all qualities advantageous for use as a cell-based approach in feline models of neural degenerative disease.

  6. Cabergoline decreases alcohol drinking and seeking behaviors via glial cell line-derived neurotrophic factor.

    Science.gov (United States)

    Carnicella, Sebastien; Ahmadiantehrani, Somayeh; He, Dao-Yao; Nielsen, Carsten K; Bartlett, Selena E; Janak, Patricia H; Ron, Dorit

    2009-07-15

    Cabergoline is an ergotamine derivative that increases the expression of glial cell line-derived neurotrophic factor (GDNF) in vitro. We recently showed that GDNF in the ventral tegmental area (VTA) reduces the motivation to consume alcohol. We therefore set out to determine whether cabergoline administration decreases alcohol-drinking and -seeking behaviors via GDNF. Reverse transcription polymerase chain reaction (RT-PCR) and Enzyme-Linked ImmunoSorbent Assay (ELISA) were used to measure GDNF levels. Western blot analysis was used for phosphorylation experiments. Operant self-administration in rats and a two-bottle choice procedure in mice were used to assess alcohol-drinking behaviors. Instrumental performance tested during extinction was used to measure alcohol-seeking behavior. The [35S]GTPgammaS binding assay was used to assess the expression and function of the dopamine D2 receptor (D2R). We found that treatment of the dopaminergic-like cell line SH-SY5Y with cabergoline and systemic administration of cabergoline in rats resulted in an increase in GDNF level and in the activation of the GDNF pathway. Cabergoline treatment decreased alcohol-drinking and -seeking behaviors including relapse, and its action to reduce alcohol consumption was localized to the VTA. Finally, the increase in GDNF expression and the decrease in alcohol consumption by cabergoline were abolished in GDNF heterozygous knockout mice. Together, these findings suggest that cabergoline-mediated upregulation of the GDNF pathway attenuates alcohol-drinking behaviors and relapse. Alcohol abuse and addiction are devastating and costly problems worldwide. This study puts forward the possibility that cabergoline might be an effective treatment for these disorders.

  7. Use of Brevibacillus choshinensis for the production of biologically active brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Angart, Phillip A; Carlson, Rebecca J; Thorwall, Sarah; Patrick Walton, S

    2017-07-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family critical for neuronal cell survival and differentiation, with therapeutic potential for the treatment of neurological disorders and spinal cord injuries. The production of recombinant, bioactive BDNF is not practical in most traditional microbial expression systems because of the inability of the host to correctly form the characteristic cystine-knot fold of BDNF. Here, we investigated Brevibacillus choshinensis as a suitable expression host for bioactive BDNF expression, evaluating the effects of medium type (2SY and TM), temperature (25 and 30 °C), and culture time (48-120 h). Maximal BDNF bioactivity (per unit mass) was observed in cultures grown in 2SY medium at extended times (96 h at 30 °C or >72 h at 25 °C), with resulting bioactivity comparable to that of a commercially available BDNF. For cultures grown in 2SY medium at 25 °C for 72 h, the condition that led to the greatest quantity of biologically active protein in the shortest culture time, we recovered 264 μg/L of BDNF. As with other microbial expression systems, BDNF aggregates did form in all culture conditions, indicating that while we were able to recover biologically active BDNF, further optimization of the expression system could yield still greater quantities of bioactive protein. This study provides confirmation that B. choshinensis is capable of producing biologically active BDNF and that further optimization of culture conditions could prove valuable in increasing BDNF yields.

  8. Ciliary Neurotrophic Factor Protects Mice Against Streptozotocin-induced Type 1 Diabetes through SOCS3

    Science.gov (United States)

    Rezende, Luiz F.; Santos, Gustavo J.; Carneiro, Everardo M.; Boschero, Antonio C.

    2012-01-01

    Type 1 diabetes is characterized by a loss of islet β-cells. Ciliary neurotrophic factor (CNTF) protects pancreatic islets against cytokine-induced apoptosis. For this reason, we assessed whether CNTF protects mice against streptozotocin-induced diabetes (a model of type 1 diabetes) and the mechanism for this protection. WT and SOCS3 knockdown C57BL6 mice were treated for 5 days with citrate buffer or 0.1 mg/kg CNTF before receiving 80 mg/kg streptozotocin. Glycemia in non-fasted mice was measured weekly from days 0–28 after streptozotocin administration. Diabetes was defined as a blood glucose > 11.2 mmol/liter. Wild-type (WT) and SOCS3 knockdown MIN6 cells were cultured with CNTF, IL1β, or both. CNTF reduced diabetes incidence and islet apoptosis in WT but not in SOCS3kd mice. Likewise, CNTF inhibited apoptosis in WT but not in SOCS3kd MIN6 cells. CNTF increased STAT3 phosphorylation in WT and SOCS3kd mice and MIN6 cells but reduced STAT1 phosphorylation only in WT mice, in contrast to streptozotocin and IL1β. Moreover, CNTF reduced NFκB activation and required down-regulation of inducible NO synthase expression to exert its protective effects. In conclusion, CNTF protects mice against streptozotocin-induced diabetes by increasing pancreatic islet survival, and this protection depends on SOCS3. In addition, SOCS3 expression and β-cell fate are dependent on STAT1/STAT3 ratio. PMID:23038263

  9. Ciliary neurotrophic factor mediates dopamine D2 receptor-induced CNS neurogenesis in adult mice.

    Science.gov (United States)

    Yang, Peng; Arnold, Sheila A; Habas, Agata; Hetman, Michal; Hagg, Theo

    2008-02-27

    Neurogenesis continues in the adult forebrain subventricular zone (SVZ) and the dentate gyrus of the hippocampal formation. Degeneration of dopaminergic projections in Parkinson's disease and animals reduces, whereas ciliary neurotrophic factor (CNTF) promotes, neurogenesis. We tested whether the dopaminergic system promotes neurogenesis through CNTF. Astrocytes of the SVZ and dentate gyrus expressed CNTF and were close to dopaminergic terminals. Dopaminergic denervation in adult mice reduced CNTF mRNA by approximately 60%, whereas systemic treatment with the D2 agonist quinpirole increased CNTF mRNA in the SVZ and hippocampal formation, and in cultured astrocytes by 1.5-5 fold. The effect of quinpirole in vitro was blocked by the D2 antagonist eticlopride and did not cause astroglial proliferation or hypertrophy. Systemic quinpirole injections increased proliferation in wild-type mice by approximately 25-75% but not in CNTF-/- littermates or in the SVZ of mice infused with CNTF antibodies. Quinpirole increased the number of neuroblasts in wild-type but not in CNTF-/- littermates. Neurogenesis was reduced by approximately 20% in CNTF-/- mice, confirming the endogenous role of CNTF. Nigrostriatal denervation did not affect SVZ proliferation in CNTF-/- mice, suggesting that the dopaminergic innervation normally regulates neurogenesis through CNTF. Quinpirole acted on postsynaptic receptors as it reversed the reduced proliferation seen after dopaminergic denervation in wild-type mice. Thus, CNTF mediates dopaminergic innervation- and D2 receptor-induced neurogenesis in the adult forebrain. Because CNTF is predominantly expressed in the nervous system, this mechanism and the ability to pharmacologically modulate it have implications for Parkinson's disease and cell-replacement therapies for other disorders.

  10. Polymorphisms of alpha-actinin-3 and ciliary neurotrophic factor in national-level Italian athletes.

    Science.gov (United States)

    Persi, A; Maltese, P E; Bertelli, M; Cecchin, S; Ciaghi, M; Guarnieri, M C; Agnello, L; Maggioni, M A; Merati, G; Veicsteinas, A

    2013-06-01

    The R577X polymorphism of the alpha-actinin-3 (ACTN3) gene and the IVS1-6G>A polymorphism of the ciliary neurotrophic factor (CNTF) gene have been associated with a favourable muscle phenotype (more muscle fibres with high glycolytic activity), reduced predisposition for congenital dystrophy and resistance to sarcopenia in old age. The aim of this study was to look for evidence of selective pressure towards genotypes favourable for strong muscle activity in a sample of national-level Italian athletes. We analysed two stop codon polymorphisms in the DNA of 50 Italian athletes, specialised in power or endurance sports, and compared their genotypic distribution with those of a population of 50 controls. In a representative sub-group of athletes (N.=42) we then compared the genetic data with anaerobic threshold, assessed by an incremental exercise test up to exhaustion. The athlete group showed an allelic distribution of ACTN3 (R/R:64%, R/X:16%, X/X:20%) and CNTF (G/G:72%, G/A:26%, A/A:2%), significantly imbalanced towards alleles R/R and G/G, respectively, compared to controls (ACTN3=R/R:40% R/X:22% X/X:38% and CNTF=G/G:52%, G/A:24%, A/A:24%) (p=0.0024 and p=0.0001, respectively). Only the ACTN3 577X/X polymorphism showed a significant association with the anaerobic threshold of athletes (F-ratio= 4.037; p=0.025). Factorial ANOVA demonstrated a non significant interaction between favourable allelic patterns of ACTN3 and CNTF genes on aerobic performance in the athlete group. The relationship found between favourable muscle phenotype and this genetic profile may have interesting implications in sport performance and training, athlete selection and different clinical activities, such as physical rehabilitation and modifying phenotypes associated with neuromuscular diseases.

  11. [Synergetic effects of ciliary neurotrophic factor and olfactory ensheathing cells on optic nerve reparation].

    Science.gov (United States)

    Yin, Dan-ping; Liu, Lin; Cao, Li

    2013-11-01

    This study is to investigate the effect of the combination of the olfactory ensheathing cells (OEC) transplantation and intravitreous injection of ciliary neurotrophic factor (CNTF) on the retinal ganglia cells' (RGC) apoptosis and axonals' reparation and regeneration. In this study, the supraorbital margin exposure of the optic nerves was used to establish adult SD rats' optic nerve inhausted injury model as control group. Then the purified OECs were injected into the optic nerve sheaths, and CNTF was injected into the vitreous body simultaneously. The rats were divided into control group, CNTF group, OECs group, and OEC+CNTF combined group. At 4 weeks postoperatively, a cholera toxin B subunit (CTB) anterograde tracing technique and fluorescence (FG) biotinylated dextran amine (BDA) retrograde tracing technique were adopted to evaluate the survival of RGC and the regeneration of optic nerve axons. The number of survival neurons of the same vision field and the density of neurons were evaluated by analysis of variance. At the one and three quadrant distance between optic disc 2 mm spot, the number of the RGC in the control group was significantly (F = 633.38, P CNTF group, while the combined treatment with CNTF and OEC had strongest repair effect. The neuron axon density showed a statistically significant difference in the average optical density value at distance between foramen opticum 2 mm spot (OEC+CNTF: 3.18 ± 0.26, OEC: 2.96 ± 0.28, CNTF: 2.83 ± 0.37, and control: 2.75 ± 0.12, respectively, F = 17.66, P CNTF suggesting that CNTF and OEC have synergistic effect on the treatment of optic nerve injury and repair. Transplantation of OECs may genetically modify the secretion of human CNTF and promote optic nerve injury repair.

  12. Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice.

    Science.gov (United States)

    Yoneda, Mitsugu; Sugimoto, Naotoshi; Katakura, Masanori; Matsuzaki, Kentaro; Tanigami, Hayate; Yachie, Akihiro; Ohno-Shosaku, Takako; Shido, Osamu

    2017-01-01

    Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Theobromine works as a phosphodiesterase (PDE) inhibitor to increase intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the cAMP-response element-binding protein (CREB), which is involved in a large variety of brain processes, including the induction of the brain-derived neurotrophic factor (BDNF). BDNF supports cell survival and neuronal functions, including learning and memory. Thus, cAMP/CREB/BDNF pathways play an important role in learning and memory. Here, we investigated whether orally administered theobromine could act as a PDE inhibitor centrally and affect cAMP/CREB/BDNF pathways and learning behavior in mice. The mice were divided into two groups. The control group (CN) was fed a normal diet, whereas the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 30 days. We measured the levels of theobromine, phosphorylated vasodilator-stimulated phosphoprotein (p-VASP), phosphorylated CREB (p-CREB), and BDNF in the brain. p-VASP was used as an index of cAMP increases. Moreover, we analyzed the performance of the mice on a three-lever motor learning task. Theobromine was detectable in the brains of TB mice. The brain levels of p-VASP, p-CREB, and BDNF were higher in the TB mice compared with those in the CN mice. In addition, the TB mice performed better on the three-lever task than the CN mice did. These results strongly suggested that orally administered theobromine acted as a PDE inhibitor in the brain, and it augmented the cAMP/CREB/BDNF pathways and motor learning in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Concentration of Glial Cell Line-Derived Neurotrophic Factor Positively Correlates with Symptoms in Functional Dyspepsia.

    Science.gov (United States)

    Tanaka, Fumio; Tominaga, Kazunari; Fujikawa, Yoshiko; Nagami, Yasuaki; Kamata, Noriko; Yamagami, Hirokazu; Tanigawa, Tetsuya; Shiba, Masatsugu; Watanabe, Toshio; Fujiwara, Yasuhiro; Arakawa, Tetsuo

    2016-12-01

    In patients with functional dyspepsia (FD), mild duodenal inflammation correlates with increased mucosal permeability. Enteric glial cells can produce glial cell line-derived neurotrophic factor (GDNF) to repair disrupted epithelial barrier function. We examined the role of duodenal GDNF in FD pathophysiology and its association with dyspeptic symptoms. Duodenal biopsies taken from FD patients and control subjects were used for analysis. GDNF protein expression and localization were examined. Cellular infiltration of eosinophils and mast cells was measured. We also examined the intercellular space between the adjacent epithelial cells at the apical junction complex using transmission electron microscopy. In FD patients, expression of GDNF protein was significantly increased compared with controls, 107.3 (95.3-136.7) versus 49.3 (38.0-72.6) pg/mg protein (median (interquartile range), p = 0.006), respectively. GDNF was localized in enteric glial cells, eosinophils, and epithelial cells. The number of eosinophils was significantly greater in FD patients than in controls, 1039 (923-1181) versus 553 (479-598) cells/mm 2 (p = 0.021), respectively. The intercellular space was dilated at the adherent junction in FD patients compared to control patients, 32.4 (29.8-34.8) versus 22.0 (19.9-26.1) nm (p = 0.002), respectively. Intercellular distance positively correlated with the frequency of postprandial fullness and early satiation (p = 0.001, r = 0.837 and p = 0.009, r = 0.693, respectively). Expression of GDNF correlated with epigastric burning (p = 0.041, r = 0.552). Increased expression of duodenal GDNF might be involved in FD pathophysiology and symptom perception.

  14. [The neuroprotection of brain-derived neurotrophic factor in experimental retinal detachment reattached].

    Science.gov (United States)

    Zeng, Aiping; Xu, Haiyan

    2014-11-01

    To investigate the effect of exogenous brain-derived neurotrophic factor (BDNF) on the retinal repair after experimental retinal detachment (RD) reattached. Experimental study. Forty-eight normal rats were randomly divided into four groups:BDNF group, control group, RD reattached group and normal group. In order to detect the effects of BDNF on retinal degeneration caused by RD, the morphology of retina and the ultrastructure of retinal cells were observed by light microscopy and electron microscopy. The effect of BDNF on the apoptosis of retinal cells after RD reattached was detected by Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) technique. Data were analyzed using one-way analysis of variance (ANOVA) and secondary analysis for significance with independent-samples t-test. The average automatically reattached time was (31.3 ± 3.5) days. Compared with control group, there were less damage in out segment and inner segment, more retinal cells in outer nuclear layer (ONL) and inner nuclear layer (INL), thicker ONL of retina and better organizational structure of retina in BDNF group. The average thickness of ONL and INL of retina were (21.166 ± 3.087) µm, (23.508 ± 3.679) µm respectively in BDNF group, and (16.084 ± 2.928) µm, (12.885 ± 3.070) µm respectively in control group. The thickness of ONL and INL of retina showed a significant difference in BDNF group compared with control (P retina in BDNF group compared with control. This study indicates that the morphology of retina and the ultrastructure of retinal cells have changed, and the apoptosis of retinal cells are present after RD reattached. Exogenous BDNF can reduce retinal cells degeneration and inhibit the apoptosis of retinal cells and have a certain protection effects on the retinal damage caused by RD.

  15. Placental and cord blood brain derived neurotrophic factor levels are decreased in nondiabetic macrosomia.

    Science.gov (United States)

    Cai, Qian-Ying; Zhang, Heng-Xin; Wang, Chen-Chen; Sun, Hao; Sun, Shu-Qiang; Wang, Yu-Huan; Yan, Hong-Tao; Yang, Xin-Jun

    2017-08-01

    To measure levels of placental brain derived neurotrophic factor (BDNF) gene expression and umbilical cord blood BDNF in neonates with nondiabetic macrosomia and determine associations between these levels and macrosomia. This case-control study included 58 nondiabetic macrosomic and 59 normal birth weight mother-infant pairs. Data were collected from interviews and our hospital's database. BDNF gene expression was quantified in placental tissues using quantitative real-time polymerase chain reaction (n = 117). Umbilical cord blood BDNF levels were measured by enzyme-linked immunosorbent assay (n = 90). Multivariate logistic regression models were used to evaluate associations between BDNF levels and macrosomia. Placental BDNF gene expression (P = 0.026) and cord blood BDNF (P = 0.008) were lower in neonates with nondiabetic macrosomia than in normal birth weight controls. Cord blood BDNF was significantly lower in vaginally delivered macrosomic neonates than vaginally delivered controls (P = 0.014), but cord BDNF did not differ between vaginal and cesarean section delivery modes in macrosomic neonates. Cord blood BDNF was positively associated with gestational age in control neonates (r = 0.496, P macrosomia (adjusted odds ratio 0.992; 95% confidence interval 0.986-0.998). Both placental BDNF gene expression and cord blood BDNF were downregulated in neonates with nondiabetic macrosomia compared with normal birth weight neonates. Cord BDNF may partly derive from BDNF secreted by the placenta. Higher cord plasma BDNF levels protected against nondiabetic macrosomia.

  16. Acute aerobic exercise increases brain-derived neurotrophic factor levels in elderly with Alzheimer's disease.

    Science.gov (United States)

    Coelho, Flávia Gomes de Melo; Vital, Thays Martins; Stein, Angelica Miki; Arantes, Franciel José; Rueda, André Veloso; Camarini, Rosana; Teodorov, Elizabeth; Santos-Galduróz, Ruth Ferreira

    2014-01-01

    Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer's disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen healthy older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p = 0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

  17. Mechanism of hyperphagia contributing to obesity in brain-derived neurotrophic factor knockout mice.

    Science.gov (United States)

    Fox, E A; Biddinger, J E; Jones, K R; McAdams, J; Worman, A

    2013-01-15

    Global-heterozygous and brain-specific homozygous knockouts (KOs) of brain-derived neurotrophic factor (BDNF) cause late- and early-onset obesity, respectively, both involving hyperphagia. Little is known about the mechanism underlying this hyperphagia or whether BDNF loss from peripheral tissues could contribute to overeating. Since global-homozygous BDNF-KO is perinatal lethal, a BDNF-KO that spared sufficient brainstem BDNF to support normal health was utilized to begin to address these issues. Meal pattern and microstructure analyses suggested overeating of BDNF-KO mice was mediated by deficits in both satiation and satiety that resulted in increased meal size and frequency and implicated a reduction of vagal signaling from the gut to the brain. Meal-induced c-Fos activation in the nucleus of the solitary tract, a more direct measure of vagal afferent signaling, however, was not decreased in BDNF-KO mice, and thus was not consistent with a vagal afferent role. Interestingly though, meal-induced c-Fos activation was increased in the dorsal motor nucleus of the vagus nerve (DMV) of BDNF-KO mice. This could imply that augmentation of vago-vagal digestive reflexes occurred (e.g., accommodation), which would support increased meal size and possibly increased meal number by reducing the increase in intragastric pressure produced by a given amount of ingesta. Additionally, vagal sensory neuron number in BDNF-KO mice was altered in a manner consistent with the increased meal-induced activation of the DMV. These results suggest reduced BDNF causes satiety and satiation deficits that support hyperphagia, possibly involving augmentation of vago-vagal reflexes mediated by central pathways or vagal afferents regulated by BDNF levels. Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Brain-derived neurotrophic factor preserves intestinal mucosal barrier function and alters gut microbiota in mice

    Directory of Open Access Journals (Sweden)

    Chen Li

    2018-03-01

    Full Text Available The intestinal mucosal barrier (IMB enables the intestine to provide adequate containment of luminal microorganisms and molecules while preserving the ability to absorb nutrients. In this study, we explored the effect of brain-derived neurotrophic factor (BDNF on IMB function and gut microbiota in mice. BDNF gene knock-out mice (the BDNF+/− group and wild-type mice (the BDNF+/+ group were selected. The gut microbiota of these mice was analyzed by denaturing gradient gel electrophoresis (DGGE assay. The ultrastructure of the ileum and the colonic epithelium obtained from decapitated mice were observed by transmission electron microscopy. The protein expression of epithelial tight junction proteins, zonula occludens-1 (ZO-1 and occludin was detected by immunohistochemistry staining. The protein expression of claudin-1 and claudin-2 was determined by Western blotting. The DGGE band patterns of gut microbiota in the BDNF+/− group were significantly different from that in the BDNF+/+ group, which indicated that the BDNF expression alters the gut microbiota in mice. Compared with the BDNF+/+ group, the BDNF+/− group presented no significant difference in the ultrastructure of ileal epithelium; however, a significant difference was observed in the colonic epithelial barrier, manifested by decreased microvilli, widening intercellular space and bacterial invasion. Compared with the BDNF+/+ group, the expression of ZO-1 and occludin in the BDNF+/− group was significantly decreased. The expression of claudin-1 in the BDNF+/− group was significantly reduced, while the expression of claudin-2 was elevated. These findings indicate that BDNF preserves IMB function and modulates gut microbiota in mice.

  19. Complete spinal cord injury (SCI) transforms how brain derived neurotrophic factor (BDNF) affects nociceptive sensitization.

    Science.gov (United States)

    Huang, Yung-Jen; Lee, Kuan H; Grau, James W

    2017-02-01

    Noxious stimulation can induce a lasting increase in neural excitability within the spinal cord (central sensitization) that can promote pain and disrupt adaptive function (maladaptive plasticity). Brain-derived neurotrophic factor (BDNF) is known to regulate the development of plasticity and has been shown to impact the development of spinally-mediated central sensitization. The latter effect has been linked to an alteration in GABA-dependent inhibition. Prior studies have shown that, in spinally transected rats, exposure to regular (fixed spaced) stimulation can counter the development of maladaptive plasticity and have linked this effect to an up-regulation of BDNF. Here it is shown that application of the irritant capsaicin to one hind paw induces enhanced mechanical reactivity (EMR) after spinal cord injury (SCI) and that the induction of this effect is blocked by pretreatment with fixed spaced shock. This protective effect was eliminated if rats were pretreated with the BDNF sequestering antibody TrkB-IgG. Intrathecal (i.t.) application of BDNF prevented, but did not reverse, capsaicin-induced EMR. BDNF also attenuated cellular indices (ERK and pERK expression) of central sensitization after SCI. In uninjured rats, i.t. BDNF enhanced, rather than attenuated, capsaicin-induced EMR and ERK/pERK expression. These opposing effects were related to a transformation in GABA function. In uninjured rats, BDNF reduced membrane-bound KCC2 and the inhibitory effect of the GABA A agonist muscimol. After SCI, BDNF increased KCC2 expression, which would help restore GABAergic inhibition. The results suggest that SCI transforms how BDNF affects GABA function and imply that the clinical usefulness of BDNF will depend upon the extent of fiber sparing. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Fibroblast growth factor-2 counteracts the effect of ciliary neurotrophic factor on spontaneous differentiation in adult hippocampal progenitor cells.

    Science.gov (United States)

    He, Zhili; Ding, Jun; Zhang, Jianfang; Liu, Ying; Gong, Chengxin; Sun, Shenggang; Chen, Honghui

    2012-12-01

    Neural stem/progenitor cells (NSCs) can spontaneously differentiate into neurons and glial cells in the absence of mitogen fibroblast growth factor-2 (FGF-2) or epidermal growth factor (EGF) in medium and the spontaneous differentiation of NSCs is mediated partially by endogenous ciliary neurotrophic factor (CNTF). This study examined the relationship of FGF-2 and CNTF in the spontaneous differentiation of adult hippocampal progenitor cells (AHPs). AHPs were cultured in the medium containing different concentration of FGF-2 (1-100 ng/mL). Western blotting and immunofluorescence staining were applied to detect the expression of the astrocytic marker GFAP, the neuronal marker Tuj1, the oligodendrocytic marker CNPase and, Nestin, the marker of AHPs. The expression of endogenous CNTF in AHPs at early (passage 4) and late stage (passage 22) was also measured by Western blotting. The results showed that FGF-2 increased the expression of Nestin, dramatically inhibited the expression of GFAP and Tuj1 and slightly suppressed the expression of CNPase. FGF-2 down-regulated the expression of endogenous CNTF in AHPs at both early (passage 4) and late stage (passage 22). These results suggested that FGF-2 could inhibit the spontaneous differentiation of cultured AHPs by negatively regulating the expression of endogenous CNTF in AHPs.

  1. What keeps a body moving? The brain-derived neurotrophic factor val66met polymorphism and intrinsic motivation to exercise in humans.

    Science.gov (United States)

    Caldwell Hooper, Ann E; Bryan, Angela D; Hagger, Martin S

    2014-12-01

    Individuals who are intrinsically motivated to exercise are more likely to do so consistently. In previous research, those with at least one copy of the methionine (met) allele in the brain-derived neurotrophic factor gene (BDNF; rs6265) had greater increases in positive mood and lower perceived exertion during exercise. This study examined whether genotype for BDNF is also related to intrinsic motivation, measured by self-report during a treadmill exercise session and a free-choice behavioral measure (continuing to exercise given the option to stop) among 89 regular exercisers (age M = 23.58, SD = 3.95). Those with at least one copy of the met allele reported greater increases in intrinsic motivation during exercise and were more likely to continue exercising when given the option to stop (55 vs. 33%). Results suggest that underlying genetic factors may partially influence perceptions of inherent rewards associated with exercise and might inform the development of individually targeted interventions.

  2. Modulatory effects of aromatherapy massage intervention on electroencephalogram, psychological assessments, salivary cortisol and plasma brain-derived neurotrophic factor.

    Science.gov (United States)

    Wu, Jin-Ji; Cui, Yanji; Yang, Yoon-Sil; Kang, Moon-Seok; Jung, Sung-Cherl; Park, Hyeung Keun; Yeun, Hye-Young; Jang, Won Jung; Lee, Sunjoo; Kwak, Young Sook; Eun, Su-Yong

    2014-06-01

    Aromatherapy massage is commonly used for the stress management of healthy individuals, and also has been often employed as a therapeutic use for pain control and alleviating psychological distress, such as anxiety and depression, in oncological palliative care patients. However, the exact biological basis of aromatherapy massage is poorly understood. Therefore, we evaluated here the effects of aromatherapy massage interventions on multiple neurobiological indices such as quantitative psychological assessments, electroencephalogram (EEG) power spectrum pattern, salivary cortisol and plasma brain-derived neurotrophic factor (BDNF) levels. A control group without treatment (n = 12) and aromatherapy massage group (n = 13) were randomly recruited. They were all females whose children were diagnosed as attention deficit hyperactivity disorder and followed up in the Department of Psychiatry, Jeju National University Hospital. Participants were treated with aromatherapy massage for 40 min twice per week for 4 weeks (8 interventions). A 4-week-aromatherapy massage program significantly improved all psychological assessment scores in the Stat-Trait Anxiety Index, Beck Depression Inventory and Short Form of Psychosocial Well-being Index. Interestingly, plasma BDNF levels were significantly increased after a 4 week-aromatherapy massage program. Alpha-brain wave activities were significantly enhanced and delta wave activities were markedly reduced following the one-time aromatherapy massage treatment, as shown in the meditation and neurofeedback training. In addition, salivary cortisol levels were significantly reduced following the one-time aromatherapy massage treatment. These results suggest that aromatherapy massage could exert significant influences on multiple neurobiological indices such as EEG pattern, salivary cortisol and plasma BDNF levels as well as psychological assessments. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  3. Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers

    Directory of Open Access Journals (Sweden)

    McMillan Catherine R

    2004-10-01

    Full Text Available Abstract Background In order to optimize the potential benefits of neural stem cell (NSC transplantation for the treatment of neurodegenerative disorders, it is necessary to understand their biological characteristics. Although neurotrophin transduction strategies are promising, alternative approaches such as the modulation of intrinsic neurotrophin expression by NSCs, could also be beneficial. Therefore, utilizing the C17.2 neural stem cell line, we have examined the expression of selected neurotrophic factors under different in vitro conditions. In view of recent evidence suggesting a role for the pineal hormone melatonin in vertebrate development, it was also of interest to determine whether its G protein-coupled MT1 and MT2 receptors are expressed in NSCs. Results RT-PCR analysis revealed robust expression of glial cell-line derived neurotrophic factor (GDNF, brain-derived neurotrophic factor (BDNF and nerve growth factor (NGF in undifferentiated cells maintained for two days in culture. After one week, differentiating cells continued to exhibit high expression of BDNF and NGF, but GDNF expression was lower or absent, depending on the culture conditions utilized. Melatonin MT1 receptor mRNA was detected in NSCs maintained for two days in culture, but the MT2 receptor was not seen. An immature MT1 receptor of about 30 kDa was detected by western blotting in NSCs cultured for two days, whereas a mature receptor of about 40 – 45 kDa was present in cells maintained for longer periods. Immunocytochemical studies demonstrated that the MT1 receptor is expressed in both neural (β-tubulin III positive and glial (GFAP positive progenitor cells. An examination of the effects of melatonin on neurotrophin expression revealed that low physiological concentrations of this hormone caused a significant induction of GDNF mRNA expression in NSCs following treatment for 24 hours. Conclusions The phenotypic characteristics of C17.2 cells suggest that they are

  4. ROLE OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF IN THE DIAGNOSIS OF COGNTIVE DYSFUNCTION IN PATIENTS WITH TYPE 2 DIABETES

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    Irina Vladimirovna Gatskikh

    2016-02-01

    Full Text Available One of the heavy progressive vascular complications of type 2 diabetes is a central nervous system, manifesting cognitive dysfunction due to metabolic changes. Goal. Defining the role of brain-derived neurotrophic factor (BDNF in the diagnosis of cognitive dysfunction in patients with type 2 diabetes. Materials and methods. The study involved 83 patients with type 2 diabetes at the age of 40 - 70 years. Complex examination included clinical and laboratory examination, neuropsychological testing. To screen for cognitive impairment used the Montreal Cognitive Assessment Scale (MOS test. To identify early markers of cognitive impairment was determined the level of brain-derived neurotrophic factor (BDNF. Results. The study found a negative correlation between the level of BDNF and the HbA1c (r = - 0,494, p = 0.01, fasting glucose (r = - 0,499, p = 0.01, and a positive relationship between the level of BDNF and cognitive function in patients with type 2 diabetes. Conclusion. In patients with type 2 diabetes revealed cognitive dysfunction in the form of reduced memory, attention, optical-dimensional activity that correlated with chronic hyperglycemia. The role of brain-derived neurotrophic factor (BDNF in the complex diagnosis of cognitive dysfunction in patients with type 2 diabetes. With an increase in HbA1c in patients with type 2 diabetes reduces the level of BDNF in the blood plasma, and a decline in cognitive function. Recommended use of BDNF as an additional marker of cognitive dysfunction in patients with type 2 diabetes.

  5. Transplantation of ciliary neurotrophic factor-expressing adult oligodendrocyte precursor cells promotes remyelination and functional recovery after spinal cord injury.

    Science.gov (United States)

    Cao, Qilin; He, Qian; Wang, Yaping; Cheng, Xiaoxin; Howard, Russell M; Zhang, Yiping; DeVries, William H; Shields, Christopher B; Magnuson, David S K; Xu, Xiao-Ming; Kim, Dong H; Whittemore, Scott R

    2010-02-24

    Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC(+)) OLs, and CNTF significantly increased the percentage of APC(+) OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI.

  6. Intravitreal Ciliary Neurotrophic Factor Transiently Improves Cone-Mediated Function in a CNGB3-/- Mouse Model of Achromatopsia.

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    Marangoni, Dario; Vijayasarathy, Camasamudram; Bush, Ronald A; Wei, Lisa L; Wen, Rong; Sieving, Paul A

    2015-10-01

    Ciliary neurotrophic factor (CNTF) was recently shown to augment cone function in CNGB3 mutant achromat dogs. However, testing CNTF-releasing implant in human CNGB3 achromats failed to show benefit. We evaluated the effects of CNTF protein on the retinal function in an additional achromatopsia model, the CNGB3-/- mouse. Fifty-nine CNGB3-/- mice (postnatal day [PD] ± SD = 30 ± 7) received a unilateral intravitreal injection of 1 or 2 μg CNTF protein, and 15 wild-type (WT) mice (PD = 34 ± 3) received 1 μg CNTF. Retinal function was evaluated by flash ERG and photopic flicker ERG (fERG) at 7 and 14 days after treatment. Seven days post CNTF, the photopic b-wave Vmax was significantly increased in CNGB3-/- mice (P < 0.01), whereas it was reduced in WT mice (P < 0.05). Ciliary neurotrophic factor significantly increased the amplitude of photopic fERG and the photopic oscillatory potentials (OPs) in CNGB3-/- mice. Ciliary neurotrophic factor did not alter the scotopic a-wave in either CNGB3-/- or WT mice, but it increased the scotopic b-wave k (P < 0.01) in CNGB3-/- mice, indicating diminished scotopic sensitivity, and reduced the scotopic b-wave Vmax in WT mice (P < 0.05). No difference was found in ERG parameters between 1 or 2 μg CNTF. Fourteen days after CNTF injection the ERG changes in CNGB3-/- mice were lost. Intravitreal bolus CNTF protein caused a small and transient improvement of cone-mediated function in CNGB3-/- mice, whereas it reduced rod-mediated function. The increase in photopic OPs and the lack of changes in scotopic a-wave suggest a CNTF effect on the inner retina.

  7. Effects of Fluid Ingestion on Brain-Derived Neurotrophic Factor and Cognition During Exercise in the Heat

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    Roh Hee-Tae

    2017-08-01

    Full Text Available We investigated the effects of fluid ingestion during exercise in different environments on the serum brain-derived neurotrophic factor and cognition among athletes. Ten collegiate male athletes (soccer, n = 5; rugby, n = 5 were enrolled, and they completed running tests in the following four conditions (60 min each: 1 thermoneutral temperature at 18°C (group 18; 2 high ambient temperature at 32°C without fluid ingestion (group 32; 3 high ambient temperature at 32°C with water ingestion (group 32+W; and 4 high ambient temperature at 32°C with sports drink ingestion (group 32+S. Serum brain-derived neurotrophic factor levels significantly increased in group 18 immediately after exercise when compared with those at rest and were significantly higher than those in group 32 immediately and 60 min after exercise (p < 0.05. In the Stroop Color and Word Test, significantly increased Word, Color, and Color-Word scores were observed in group 18 immediately after exercise compared to those at rest (p < 0.05. However, the Color-Word score appeared to be significantly lower in group 32 immediately after exercise compared to the other groups (p < 0.05 and at 60 min post-exercise compared to group 18 (p < 0.05. We found that the exercise performed in a thermoneutral environment improved cognitive function, but the exercise performed in a hot environment did not. The differences according to the exercise environment would be largely affected by brain-derived neurotrophic factor, and fluid ingestion regardless of the type of drink (water or sports beverage was assumed to have contributed to the improvement in cognitive function caused by exercising in a hot environment.

  8. The association between brain-derived neurotrophic factor gene polymorphism and migraine: a meta-analysis.

    Science.gov (United States)

    Cai, Xiaoying; Shi, Xiaolei; Zhang, Ximeng; Zhang, Aiwu; Zheng, Minying; Fang, Yannan

    2017-12-01

    Migraine is a recurrent headache disease related to genetic variants. The brain-derived neurotrophic factor (BDNF) gene rs6265 (Val66Met) and rs2049046 polymorphism has been found to be associated with migraine. However, their roles in this disorder are not well established. Then we conduct this meta-analysis to address this issue. PubMed, Web of Science and Cochrane databases were systematically searched to identify all relevant studies. Odds ratio (OR) with corresponding 95% confidence interval (CI) was used to estimate the strength of association between BDNF gene rs6265 and rs2049046 polymorphism and migraine. Four studies with 1598 cases and 1585 controls, fulfilling the inclusion criteria were included in our meta-analysis. Overall data showed significant association between rs6265 polymorphism and migraine in allele model (OR = 0.86, 95%CI: 0.76-0.99, p = 0.03), recessive model (OR = 0.84, 95%CI: 0.72-0.98, p = 0.03) and additive model (GG vs GA: OR = 0.85, 95%CI: 0.72-1.00, p = 0.04), respectively. We also found significant association between rs2049046(A/T) polymorphism and migraine in allele model (OR = 0.88, 95%CI: 0.79-0.98, p = 0.02), recessive model (OR = 0.80, 95%CI: 0.67-0.96, p = 0.02) and additive model (AA vs TT: OR = 0.72, 95%CI: 0.57-0.92, p = 0.008; AA vs AT: OR = 0.81, 95%CI: 0.67-0.99, p = 0.03), respectively. Our meta-analysis suggested that BDNF rs6265 and rs2049046 polymorphism were associated with common migraine in Caucasian population. Further studies are awaited to update this finding in Asian population and other types of migraine.

  9. Effects of Jinmaitong Capsule () on ciliary neurotrophic factor in sciatic nerves of diabetes mellitus rats.

    Science.gov (United States)

    Shi, Yue; Liang, Xiao-Chun; Wu, Qun-Li; Sun, Lian-Qing; Qu, Ling; Zhao, Li; Wang, Pu-Yan

    2013-02-01

    To study the effects of the Chinese medicine Jinmaitong Capsule (, JMT) on the pathomorphology of sciatic nerves, ciliary neurotrophic factor (CNTF), and the mRNA expressions of CNTF in rats with streptozotocin-induced diabetes mellitus (STZ-DM). The animal model was established by one time intraperitoneal injection of streptozotocin. The rats were simply divided by random into 5 groups including model group, low-dose JMT group (JL), medium-dose JMT group (JM), high-dose JMT group (JH) and neurotropin group. For each of the above 5 groups, a group of 10 normal Wistar rats matched in body weight, age and gender were set as normal group. Intragastric administrations were started after the animal model established. The JL group were administered with five times the JMT dose recommended for a human adult; the JM group were administered with ten times the JMT dose recommended for a human adult; the JH group were administered with twenty times the JMT dose recommended for a human adult. The neurotropin group was administered with ten times the neurotropin dose recommended for a human adult. All rats were given intragastric administration for 16 weeks and then killed. In the 4th, 8th, 12th, 16th week, body weight and blood glucose level were detected before and after the intervention. The morphologic changes of the sciatic nerves were observed by optical microscope and transmission electron microscope. The CNTFmRNA expressions were detected by real-time fluorescent quantitative polymerase chain protein, and the CNTF protein expressions were detected by immunohistochemical method. The blood glucose levels of the STZ-DM rats were much higher than normal group (P0.05). Before and after the intervention in the 4th, 8th, 12th, 16th week, there were no significant differences in the body weight among all the groups (P>0.05). The sciatic nerves of STZ-DM rats might have pathomorphological changes in axons, myelin sheaths, and interstitium. The levels of CNTF and CNTF

  10. Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus.

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    Ching-Yi Tsai

    Full Text Available BACKGROUND: Status epilepticus (SE is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM, a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF via an antioxidant action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of temporal lobe SE (TLSE using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB, angiotensin AT1 receptor subtype (AT1R, nitric oxide synthase II (NOS II or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol, a specific antagonist of NADPH oxidase (apocynin or an AT1R antagonist (losartan blunted significantly the augmented superoxide anion or phosphorylated p47(phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II

  11. Combination effects of epidermal growth factor and glial cell line-derived neurotrophic factor on the in vitro developmental potential of porcine oocytes

    DEFF Research Database (Denmark)

    Valleh, Mehdi Vafaye; Rasmussen, Mikkel Aabech; Hyttel, Poul

    2016-01-01

    of improving this issue, the single and combined effects of epidermal growth factor (EGF) and glial cell line-derived neurotrophic factor (GDNF) on oocyte developmental competence were investigated. Porcine cumulus–oocyte cell complexes (COCs) were matured in serum-free medium supplemented with EGF (0, 10...... with the combination of EGF and GDNF was shown to significantly improve oocyte competence in terms of blastocyst formation, blastocyst cell number and blastocyst hatching rate (P

  12. Pumping the Brakes: Neurotrophic Factors for the Prevention of Cognitive Impairment and Dementia after Traumatic Brain Injury.

    Science.gov (United States)

    Corrigan, Frances; Arulsamy, Alina; Teng, Jason; Collins-Praino, Lyndsey E

    2017-03-01

    Traumatic brain injury (TBI) is the leading cause of disability and death worldwide, affecting as many as 54,000,000-60,000,000 people annually. TBI is associated with significant impairments in brain function, impacting cognitive, emotional, behavioral, and physical functioning. Although much previous research has focused on the impairment immediately following injury, TBI may have much longer-lasting consequences, including neuropsychiatric disorders and cognitive impairment. TBI, even mild brain injury, has also been recognized as a significant risk factor for the later development of dementia and Alzheimer's disease. Although the link between TBI and dementia is currently unknown, several proposed mechanisms have been put forward, including alterations in glucose metabolism, excitotoxicity, calcium influx, mitochondrial dysfunction, oxidative stress, and neuroinflammation. A treatment for the devastating long-term consequences of TBI is desperately needed. Unfortunately, however, no such treatment is currently available, making this a major area of unmet medical need. Increasing the level of neurotrophic factor expression in key brain areas may be one potential therapeutic strategy. Of the neurotrophic factors, granulocyte-colony stimulating factor (G-CSF) may be particularly effective for preventing the emergence of long-term complications of TBI, including dementia, because of its ability to reduce apoptosis, stimulate neurogenesis, and increase neuroplasticity.

  13. Ciliary neurotrophic factor (CNTF) promotes skeletal muscle progenitor cell (MPC) viability via the phosphatidylinositol 3-kinase-Akt pathway.

    Science.gov (United States)

    Hiatt, Kelly; Lewis, Davina; Shew, Mathew; Bijangi-Vishehsaraei, Khadijeh; Halum, Stacey

    2014-12-01

    Muscle progenitor cells (MPCs) are currently being investigated as cellular vectors to deliver neurotrophic factor (NF) for the promotion of re-innervation after axonal injury. Ideally NF delivery in such a model would enhance axonal regeneration while simultaneously promoting MPC viability. To date, insulin-like growth factor 1 (IGF-1) is one of the few NFs known to promote both re-innervation and MPC viability. We herein identify ciliary neurotrophic factor (CNTF) as a factor that promotes MPC viability in culture, and demonstrate CNTF to impart greater viability effects on MPCs than IGF-1. We demonstrate that pharmacological inhibition via LY294002 results in abrogation of CNTF-mediated viability, suggesting that the CNTF-mediated MPC viability benefit occurs via the PI3-Akt pathway. Finally, we employ a genetic model, establishing MPC cultures from mice deficient in class IA PI-3 K (p85α(-/-) ) mice, and demonstrate that the viability benefit imparted by CNTF is completely abrogated in PI-3 K-deficient MPCs compared to wild-type controls. In summary, our investigations define CNTF as a promoter of MPC viability beyond IGF-1, and reveal that the CNTF-mediated MPC viability effects occur via the PI3-Akt pathway. Copyright © 2012 John Wiley & Sons, Ltd.

  14. All-trans retinoic acid upregulates the expression of ciliary neurotrophic factor in retinal pigment epithelial cells.

    Science.gov (United States)

    Zhou, Wen-Di; Wang, Lu-Lu; Zhou, Lan-Bo; Bin, Wei; Bao, Tian-Ping; Zhang, Yi; Shu, Jin; Yang, Wei-Xia; Hui, Liang-Liang; Jin, Rui; Zhuang, Li-Li; Zhou, Guo-Ping

    2017-06-01

    Retinopathy of prematurity, a leading cause of visual impairment in low birth-weight infants, remains a crucial therapeutic challenge. Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that promotes rod and cone photoreceptor survival and cone outer segment regeneration in the degenerating retina. Ciliary neurotrophic factor expression is regulated by many factors such as all-trans retinoic acid (ATRA). In this study, we found that ATRA increased CNTF expression in mouse retinal pigment epithelial (RPE) cells in a dose- and time-dependent manner, and PKA signaling pathway is necessary for ATRA-induced CNTF upregulation. Furthermore, we showed that ATRA promoted CNTF expression through CREB binding to its promoter region. In addition, CNTF levels were decreased in serum of retinopathy of prematurity children and in retinal tissue of oxygen-induced retinopathy mice. In mouse RPE cells cultured with high oxygen, CNTF expression and secretion were decreased, but could be recovered after treatment with ATRA. In conclusion, our data suggest that ATRA administration upregulates CNTF expression in RPE cells. Copyright © 2017 John Wiley & Sons, Ltd.

  15. Autism as a disorder of deficiency of brain-derived neurotrophic factor and altered metabolism of polyunsaturated fatty acids.

    Science.gov (United States)

    Das, Undurti N

    2013-10-01

    Autism has a strong genetic and environmental basis in which inflammatory markers and factors concerned with synapse formation, nerve transmission, and information processing such as brain-derived neurotrophic factor (BDNF), polyunsaturated fatty acids (PUFAs): arachidonic (AA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) and their products and neurotransmitters: dopamine, serotonin, acetylcholine, γ-aminobutyric acid, and catecholamines and cytokines are altered. Antioxidants, vitamins, minerals, and trace elements are needed for the normal metabolism of neurotrophic factors, eicosanoids, and neurotransmitters, supporting reports of their alterations in autism. But, the exact relationship among these factors and their interaction with genes and proteins concerned with brain development and growth is not clear. It is suggested that maternal infections and inflammation and adverse events during intrauterine growth of the fetus could lead to alterations in the gene expression profile and proteomics that results in dysfunction of the neuronal function and neurotransmitters, alteration(s) in the metabolism of PUFAs and their metabolites resulting in excess production of proinflammatory eicosanoids and cytokines and a deficiency of anti-inflammatory cytokines and bioactive lipids that ultimately results in the development of autism. Based on these evidences, it is proposed that selective delivery of BDNF and methods designed to augment the production of anti-inflammatory cytokines and eicosanoids and PUFAs may prevent, arrest, or reverse the autism disease process. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Ciliary neurotrophic factor infused intracerebroventricularly shows reduced catabolic effects when linked to the TAT protein transduction domain.

    Science.gov (United States)

    Vieira, André S; Rezende, Alexandre C S; Grigoletto, Jessica; Rogério, Fabio; Velloso, Lício A; Skaper, Stephen D; Negro, Alessandro; Langone, Francesco

    2009-09-01

    Ciliary neurotrophic factor (CNTF) regulates the differentiation and survival of a wide spectrum of developing and adult neurons, including motor neuron loss after injury. We recently described a cell-penetrant recombinant human CNTF (rhCNTF) molecule, formed by fusion with the human immunodeficiency virus-1 transactivator of transcription (TAT) protein transduction domain (TAT-CNTF) that, upon subcutaneous administration, retains full neurotrophic activity without cytokine-like side-effects. Although the CNTF receptor is present in hypothalamic nuclei, which are involved in the control of energy, rhCNTF but not TAT-CNTF stimulates signal transducers and activators of transcription 3 phosphorylation in the rat hypothalamus after subcutaneous administration. This could be due limited TAT-CNTF distribution in the hypothalamus and/or altered intracellular signaling by the fusion protein. To explore these possibilities, we examined the effect of intracerebroventricular administration of TAT-CNTF in male adult rats. TAT-CNTF-induced weight loss, although the effect was smaller than that seen with either rhCNTF or leptin (which exerts CNTF-like effects via its receptor). In contrast to rhCNTF and leptin, TAT-CNTF neither induced morphological changes in adipose tissues nor increased uncoupling protein 1 expression in brown adipose tissue, a characteristic feature of rhCNTF and leptin. Acute intracerebroventricular administration of TAT-CNTF induced a less robust phosphorylation of signal transducers and activators of transcription 3 in the hypothalamus, compared with rhCNTF. The data show that fusion of a protein transduction domain may change rhCNTF CNS distribution, while further strengthening the utility of cell-penetrating peptide technology to neurotrophic factor biology beyond the neuroscience field.

  17. Brain-Derived Neurotrophic Factor and Suicide in Schizophrenia: Critical Role of Neuroprotective Mechanisms as an Emerging Hypothesis.

    Science.gov (United States)

    Shrivastava, Amresh; De Sousa, Avinash; Rao, G Prasad

    2016-01-01

    Suicide is a common occurrence in psychiatric disorders and is a cause of increased healthcare utilization worldwide. Schizophrenia is one of the most common psychiatric disorders worldwide and posited to be seen in 1% of the population worldwide. Suicide is a common occurrence in schizophrenia with 25%-30% patients with schizophrenia attempting suicide and 8%-10% completing it. There is a need for valid biological markers to help clinicians identify patients with schizophrenia that may be at a risk of suicide and thus help in them receiving better care and interventions at the earliest even before a suicide attempt occurring. There are clear neurobiological changes at a genetic, neuroimaging, and neurochemical level that occurs in patients with schizophrenia that attempt suicide. There is a new theory that postulates neuronal plasticity and neuroprotection to have a role in the biological changes that ensue when suicidal thoughts and feelings occur in patients with schizophrenia. Neurotrophic growth factors like brain-derived neurotrophic factor (BDNF) have been documented to play a role in the protection of neurons and in the prevention of neurobiological changes that may lead to suicide both in schizophrenia and depression. The present paper presents a commentary that looks at the role of BDNF as a protective factor and neurobiological marker for suicide in schizophrenia.

  18. Prevention of Memory Impairment and Neurotrophic Factors Increased by Lithium in Wistar Rats Submitted to Pneumococcal Meningitis Model

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    Lutiana R. Simões

    2017-01-01

    Full Text Available The aim of this study was to investigate the effects of lithium on brain-derived neurotrophic factor (BDNF, nerve growth factor (NGF, and glial cell line-derived neurotrophic factor (GDNF expression in the hippocampus and on memory in experimental pneumococcal meningitis. The mood-stabilizer lithium is known as a neuroprotective agent with many effects on the brain. In this study, animals received either artificial cerebrospinal fluid or Streptococcus pneumoniae suspension at a concentration of 5 × 109 CFU/mL. Eighteen hours after induction, all animals received ceftriaxone. The animals received saline or lithium (47.5 mg/kg or tamoxifen (1 mg/kg as adjuvant treatment, and they were separated into six groups: control/saline, control/lithium, control/tamoxifen, meningitis/saline, meningitis/lithium, and meningitis/tamoxifen. Ten days after meningitis induction, animals were subjected to open-field habituation and the step-down inhibitory avoidance tasks. Immediately after these tasks, the animals were killed and their hippocampus was removed to evaluate the expression of BDNF, NGF, and GDNF. In the meningitis group, treatment with lithium and tamoxifen resulted in improvement in memory. Meningitis group showed decreased expression of BDNF and GDNF in the hippocampus while lithium reestablished the neurotrophin expression. Lithium was able to prevent memory impairment and reestablishes hippocampal neurotrophin expression in experimental pneumococcal meningitis.

  19. Effects of acetylcholine and electrical stimulation on glial cell line-derived neurotrophic factor production in skeletal muscle cells.

    Science.gov (United States)

    Vianney, John-Mary; Miller, Damon A; Spitsbergen, John M

    2014-11-07

    Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor required for survival of neurons in the central and peripheral nervous system. Specifically, GDNF has been characterized as a survival factor for spinal motor neurons. GDNF is synthesized and secreted by neuronal target tissues, including skeletal muscle in the peripheral nervous system; however, the mechanisms by which GDNF is synthesized and released by skeletal muscle are not fully understood. Previous results suggested that cholinergic neurons regulate secretion of GDNF by skeletal muscle. In the current study, GDNF production by skeletal muscle myotubes following treatment with acetylcholine was examined. Acetylcholine receptors on myotubes were identified with labeled alpha-bungarotoxin and were blocked using unlabeled alpha-bungarotoxin. The question of whether electrical stimulation has a similar effect to that of acetylcholine was also investigated. Cells were stimulated with voltage pulses; at 1 and 5 Hz frequencies for times ranging from 30 min to 48 h. GDNF content in myotubes and GDNF in conditioned culture medium were quantified by enzyme-linked immunosorbant assay. Results suggest that acetylcholine and short-term electrical stimulation reduce GDNF secretion, while treatment with carbachol or long-term electrical stimulation enhances GDNF production by skeletal muscle. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults

    DEFF Research Database (Denmark)

    Hvid, L. G.; Nielsen, M. K.F.; Simonsen, C.

    2017-01-01

    Brain-derived neurotrophic factor (BDNF) is a potential important factor involved in neuroplasticity, and may be a mediator for eliciting adaptations in neuromuscular function and physical function in older individuals following physical training. As power training taxes the neural system to a very...... not appear to be a major mechanistic factor mediating neuroplasticity in mobility-limited older adults....

  1. Ciliary neurotrophic factor cell-based delivery prevents synaptic impairment and improves memory in mouse models of Alzheimer's disease.

    Science.gov (United States)

    Garcia, Pierre; Youssef, Ihsen; Utvik, Jo K; Florent-Béchard, Sabrina; Barthélémy, Vanassa; Malaplate-Armand, Catherine; Kriem, Badreddine; Stenger, Christophe; Koziel, Violette; Olivier, Jean-Luc; Escanye, Marie-Christine; Hanse, Marine; Allouche, Ahmad; Desbène, Cédric; Yen, Frances T; Bjerkvig, Rolf; Oster, Thierry; Niclou, Simone P; Pillot, Thierry

    2010-06-02

    The development of novel therapeutic strategies for Alzheimer's disease (AD) represents one of the biggest unmet medical needs today. Application of neurotrophic factors able to modulate neuronal survival and synaptic connectivity is a promising therapeutic approach for AD. We aimed to determine whether the loco-regional delivery of ciliary neurotrophic factor (CNTF) could prevent amyloid-beta (Abeta) oligomer-induced synaptic damages and associated cognitive impairments that typify AD. To ensure long-term administration of CNTF in the brain, we used recombinant cells secreting CNTF encapsulated in alginate polymers. The implantation of these bioreactors in the brain of Abeta oligomer-infused mice led to a continuous secretion of recombinant CNTF and was associated with the robust improvement of cognitive performances. Most importantly, CNTF led to full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model. In vitro as well as in vivo, CNTF activated a Janus kinase/signal transducer and activator of transcription-mediated survival pathway that prevented synaptic and neuronal degeneration. These preclinical studies suggest that CNTF and/or CNTF receptor-associated pathways may have AD-modifying activity through protection against progressive Abeta-related memory deficits. Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD.

  2. The cytokine ciliary neurotrophic factor (CNTF) activates hypothalamic urocortin-expressing neurons both in vitro and in vivo.

    Science.gov (United States)

    Purser, Matthew J; Dalvi, Prasad S; Wang, Zi C; Belsham, Denise D

    2013-01-01

    Ciliary neurotrophic factor (CNTF) induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examined its effects on urocortin-1 neurons post-exposure. Through double-label immunohistochemistry using specific antibodies against c-Fos and urocortin-1, we showed that central CNTF administration significantly activated urocortin-1 neurons in specific areas of the hypothalamus. Taken together, our studies point to a potential role for CNTF in regulating hypothalamic urocortin-1-expressing neurons to mediate its recognized effects on energy homeostasis, neuronal proliferaton/survival, and/or neurogenesis.

  3. The cytokine ciliary neurotrophic factor (CNTF activates hypothalamic urocortin-expressing neurons both in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Matthew J Purser

    Full Text Available Ciliary neurotrophic factor (CNTF induces neurogenesis, reduces feeding, and induces weight loss. However, the central mechanisms by which CNTF acts are vague. We employed the mHypoE-20/2 line that endogenously expresses the CNTF receptor to examine the direct effects of CNTF on mRNA levels of urocortin-1, urocortin-2, agouti-related peptide, brain-derived neurotrophic factor, and neurotensin. We found that treatment of 10 ng/ml CNTF significantly increased only urocortin-1 mRNA by 1.84-fold at 48 h. We then performed intracerebroventricular injections of 0.5 mg/mL CNTF into mice, and examined its effects on urocortin-1 neurons post-exposure. Through double-label immunohistochemistry using specific antibodies against c-Fos and urocortin-1, we showed that central CNTF administration significantly activated urocortin-1 neurons in specific areas of the hypothalamus. Taken together, our studies point to a potential role for CNTF in regulating hypothalamic urocortin-1-expressing neurons to mediate its recognized effects on energy homeostasis, neuronal proliferaton/survival, and/or neurogenesis.

  4. The effect of methylprednisolone intravenous infusion on the expression of ciliary neurotrophic factor in a rat spinal cord injury model.

    Science.gov (United States)

    Del Gaizo, Daniel J; Regan, Conor M; Graff, Ronald D; Mathur, Sameer

    2013-04-01

    Methylprednisolone (MP) infusion after acute spinal cord injury (SCI) remains controversial despite large randomized studies, including the National Acute Spinal Cord Injury Studies (NASCIS). To determine the effect of NASCIS protocol MP infusion on the expression of ciliary neurotrophic factor (CNTF), a neuroprotective cytokine, in a rat model after SCI. Animal laboratory study. Thirty rats were randomized into an MP infusion group (intravenous [IV]-MP) versus normal saline (NS) control group (IV-NS) after a standardized SCI. Ciliary neurotrophic factor expression was measured by reverse transcription-polymerase chain reaction at 6, 12, 24, 48, and 72 hours post-SCI. Mean CNTF expression was diminished in the MP group at 12 (p=.006) and 24 (p=.008) hours postinjury compared with the control group. Expression of CNTF was not significantly different between the groups at 6, 48, and 72 hours post-SCI. Standardized MP infusion post-SCI reduces CNTF activation in a rat SCI model. Further study is needed to determine if this effect is seen in human SCIs. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. Lipid-mediated glial cell line-derived neurotrophic factor gene transfer to cultured porcine ventral mesencephalic tissue

    DEFF Research Database (Denmark)

    Bauer, Matthias; Meyer, Morten; Brevig, Thomas

    2002-01-01

    Transplantation of dopaminergic ventral mesencephalic (VM) tissue into the basal ganglia of patients with Parkinson's disease (PD) shows at best moderate symptomatic relief in some of the treated cases. Experimental animal studies and clinical trials with allogenic and xenogenic pig-derived VM......-mediated transfer of the gene for human glial cell line-derived neurotrophic factor (GDNF) to embryonic (E27/28) porcine VM tissue kept as organotypic explant cultures. Treatment of the developing VM with two mitogens, basic fibroblast growth factor and epidermal growth factor, prior to transfection significantly...... increased transfection yields. Expression of human GDNF via an episomal vector could be detected by in situ hybridization and by the measuring of GDNF protein secreted into the culture medium. When compared to mock-transfected controls, VM tissue expressing recombinant GDNF contained significantly higher...

  6. Brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) levels in post-mortem brain tissue from patients with depression compared to healthy individuals 

    DEFF Research Database (Denmark)

    Sheldrick, A; Camara, S; Ilieva, M

    2017-01-01

    treatment and overall age 84.3±5 years versus 14 unaffected subjects at age 70.3±13.8. We detected significant elevation of BDNF (parietal cortex) and NT3 (parietal, temporal and occipital cortex, cingulate gyrus, thalamus, putamen and nucleus caudatus regions) in MDD patients who received antidepressant...... suggests that antidepressant treatment may improve or normalise cerebral concentrations of neurotrophic factors. Therefore, we examined the concentration of brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3) in different brain regions (cortex, cingulate gyrus, thalamus, hippocampus, putamen...

  7. A putative model of overeating and obesity based on brain-derived neurotrophic factor: direct and indirect effects.

    Science.gov (United States)

    Ooi, Cara L; Kennedy, James L; Levitan, Robert D

    2012-08-01

    Increased food intake is a major contributor to the obesity epidemic in all age groups. Elucidating brain systems that drive overeating and that might serve as targets for novel prevention and treatment interventions is thus a high priority for obesity research. The authors consider 2 major pathways by which decreased activity of brain-derived neurotrophic factor (BDNF) may confer vulnerability to overeating and weight gain in an obesogenic environment. The first "direct" pathway focuses on the specific role of BDNF as a mediator of food intake control at brain areas rich in BDNF receptors, including the hypothalamus and hindbrain. It is proposed that low BDNF activity limited to this direct pathway may best explain overeating and obesity outside the context of major neuropsychiatric disturbance. A second "indirect" pathway considers the broad neurotrophic effects of BDNF on key monoamine systems that mediate mood dysregulation, impulsivity, and executive dysfunction as well as feeding behavior per se. Disruption in this pathway may best explain overeating and obesity in the context of various neuropsychiatric disturbances including mood disorders, attention-deficit disorder, and/or binge eating disorders. An integrative model that considers these potential roles of BDNF in promoting obesity is presented. The implications of this model for the early prevention and treatment of obesity are also considered.

  8. Activation of transcription factors STAT1 and STAT5 in the mouse median eminence after systemic ciliary neurotrophic factor administration.

    Science.gov (United States)

    Severi, Ilenia; Senzacqua, Martina; Mondini, Eleonora; Fazioli, Francesca; Cinti, Saverio; Giordano, Antonio

    2015-10-05

    Exogenously administered ciliary neurotrophic factor (CNTF) causes weight loss in obese rodents and humans through leptin-like activation of the Jak-STAT3 signaling pathway in hypothalamic arcuate neurons. Here we report for the first time that 40min after acute systemic treatment, rat recombinant CNTF (intraperitoneal injection of 0.3mg/kg of body weight) induced nuclear translocation of the tyrosine-phosphorylated forms of STAT1 and STAT5 in the mouse median eminence and other circumventricular organs, including the vascular organ of the lamina terminalis and the subfornical organ. In the tuberal hypothalamus of treated mice, specific nuclear immunostaining for phospo-STAT1 and phospho-STAT5 was detected in ependymal cells bordering the third ventricle floor and lateral recesses, and in median eminence cells. Co-localization studies documented STAT1 and STAT5 activation in median eminence β-tanycytes and underlying radial glia-like cells. A few astrocytes in the arcuate nucleus responded to CNTF by STAT5 activation. The vast majority of median eminence tanycytes and radial glia-like cells showing phospho-STAT1 and phospho-STAT5 immunoreactivity were also positive for phospho-STAT3. In contrast, STAT3 was the sole STAT isoform activated by CNTF in arcuate nucleus and median eminence neurons. Finally, immunohistochemical evaluation of STAT activation 20, 40, 80, and 120min from the injection demonstrated that cell activation was accompanied by c-Fos expression. Collectively, our findings show that CNTF activates STAT3, STAT1, and STAT5 in vivo. The distinctive activation pattern of these STAT isoforms in the median eminence may disclose novel targets and pathways through which CNTF regulates food intake. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Gray Matter Volume in Adolescent Anxiety: An Impact of the Brain-Derived Neurotrophic Factor Val[superscript 66]Met Polymorphism?

    Science.gov (United States)

    Mueller, Sven C.; Aouidad, Aveline; Gorodetsky, Elena; Goldman, David; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Minimal research links anxiety disorders in adolescents to regional gray matter volume (GMV) abnormalities and their modulation by genetic factors. Prior research suggests that a brain-derived neurotrophic factor (BNDF) Val[superscript 66]Met polymorphism may modulate such brain morphometry profiles. Method: Using voxel-based…

  10. Plasma brain-derived neurotrophic factor and reverse dipping pattern of nocturnal blood pressure in patients with cardiovascular risk factors.

    Directory of Open Access Journals (Sweden)

    Manabu Kadoya

    Full Text Available Basic studies have shown that brain-derived neurotrophic factor (BDNF has critical roles in the survival, growth, maintenance, and death of central and peripheral neurons, while it is also involved in regulation of the autonomic nervous system. Furthermore, recent clinical studies have suggested potential role of plasma BDNF in the circulatory system.We investigated the mutual relationships among plasma BDNF, patterns of nocturnal blood pressure changes (dippers, non-dippers, extra-dippers, and reverse-dippers, and cardiac autonomic function as determined by heart rate variability (HRV.This was a cross-sectional study of patients registered in the Hyogo Sleep Cardio-Autonomic Atherosclerosis (HSCAA Study from October 2010 to November 2012.Two-hundred fifty patients with 1 or more cardiovascular risk factor(s (obesity, smoking, presence of cardiovascular event history, hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease were enrolled.Plasma BDNF levels (natural logarithm transformed were significantly (p = 0.001 lower in reverse-dipper patients (7.18±0.69 pg/ml, mean ± SD, n = 36 as compared to dippers (7.86±0.86 pg/ml, n = 100. Multiple logistic regression analysis showed that BDNF (odds ratios: 0.417, 95% confidence interval: 0.228-0.762, P = 0.004 was the sole factor significantly and independently associated with the reverse-dippers as compared with dippers. Furthermore, plasma BDNF level was significantly and positively correlated with the time-domain (SDNN, SDANN5, CVRR and frequency-domain (LF of HRV parameters. Finally, multiple logistic regression analyses showed that the relationship between plasma BDNF and the reverse-dippers was weakened, yet remained significant or borderline significant even after adjusting for HRV parameters.Low plasma BDNF was independently associated with patients showing a reverse-dipper pattern of nocturnal blood pressure, in which an imbalance of cardiac autonomic function

  11. Electroacupuncture enhances motor recovery performance with brain-derived neurotrophic factor expression in rats with cerebral infarction.

    Science.gov (United States)

    Kim, Min-Wook; Chung, You Chul; Jung, Hee Chan; Park, Moon-Seo; Han, Young-Min; Chung, Yong-An; Maeng, Lee-So; Park, Sang-In; Lim, Jiyeon; Im, Woo-Seok; Chung, Jin Young; Kim, Minky; Mook, Inhee; Kim, Manho

    2012-09-01

    Electroacupuncture (EA) is a traditional medicine in patients with post-stroke rehabilitation. Brain-derived neurotrophic factor (BDNF) is a potent growth factor involved in recovery following cerebral injury. The aim of the present study was to investigate whether EA increases BDNF levels and facilitates functional recovery. Occlusion of the middle cerebral artery was performed in rats (N=12) followed by reperfusion. EA was applied at the GV20 (Baihui) acupoint. Motor and sensory functions were monitored on the Garcia scale for 2 weeks. Expressions of BDNF and receptor tyrosine kinase B (trkB) were determined by immunoblotting and immunohistochemistry. Improvement of Garcia scores, particularly in motor performance, were noted in the group with EA stimulation (precovery and stimulates BDNF/trkB expression in rats with cerebral ischaemia.

  12. The aryl hydrocarbon receptor AhR links atopic dermatitis and air pollution via induction of the neurotrophic factor artemin.

    Science.gov (United States)

    Hidaka, Takanori; Ogawa, Eisaku; Kobayashi, Eri H; Suzuki, Takafumi; Funayama, Ryo; Nagashima, Takeshi; Fujimura, Taku; Aiba, Setsuya; Nakayama, Keiko; Okuyama, Ryuhei; Yamamoto, Masayuki

    2017-01-01

    Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus. The activation of AhR via air pollutants induced expression of artemin, alloknesis, epidermal hyper-innervation and inflammation. AhR activation and ARTN expression were positively correlated in the epidermis of patients with atopic dermatitis. Thus, AhR in keratinocytes senses environmental stimuli and elicits an atopic-dermatitis pathology. We propose a mechanism of air-pollution-induced atopic dermatitis via activation of AhR.

  13. Cross-sex hormone treatment in male-to-female transsexual persons reduces serum brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Fuss, Johannes; Hellweg, Rainer; Van Caenegem, Eva; Briken, Peer; Stalla, Günter K; T'Sjoen, Guy; Auer, Matthias K

    2015-01-01

    Serum levels of brain-derived neurotrophic factor (BDNF) are reduced in male-to-female transsexual persons (MtF) compared to male controls. It was hypothesized before that this might reflect either an involvement of BDNF in a biomechanism of transsexualism or to be the result of persistent social stress due to the condition. Here, we demonstrate that 12 month of cross-sex hormone treatment reduces serum BDNF levels in male-to-female transsexual persons independent of anthropometric measures. Participants were acquired through the European Network for the Investigation of Gender Incongruence (ENIGI). Reduced serum BDNF in MtF thus seems to be a result of hormonal treatment rather than a consequence or risk factor of transsexualism. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  14. Effect of Exercise Intensity on Neurotrophic Factors and Blood-Brain Barrier Permeability Induced by Oxidative-Nitrosative Stress in Male College Students.

    Science.gov (United States)

    Roh, Hee-Tae; Cho, Su-Youn; Yoon, Hyung-Gi; So, Wi-Young

    2017-06-01

    We investigated the effects of aerobic exercise intensity on oxidative-nitrosative stress, neurotrophic factor expression, and blood-brain barrier (BBB) permeability. Fifteen healthy men performed treadmill running under low-intensity (LI), moderate-intensity (MI), and high-intensity (HI) conditions. Blood samples were collected immediately before exercise (IBE), immediately after exercise (IAE), and 60 min after exercise (60MAE) to examine oxidative-nitrosative stress (reactive oxygen species [ROS]; nitric oxide [NO]), neurotrophic factors (brain-derived neurotrophic factor [BDNF]; nerve growth factor [NGF]), and blood-brain barrier (BBB) permeability (S-100β; neuron-specific enolase). ROS concentration significantly increased IAE and following HI (4.9 ± 1.7 mM) compared with that after LI (2.8 ± 1.4 mM) exercise (p exercise (p exercise (p exercise (p exercise (p .05). Moderate- and/or high-intensity exercise may induce higher oxidative-nitrosative stress than may low-intensity exercise, which can increase peripheral neurotrophic factor levels by increasing BBB permeability.

  15. Protective and reversal effects of conserved dopamine neurotrophic factor on PC12 cells following 6-hydroxydopamine administration.

    Science.gov (United States)

    Mei, Jiaming; Niu, Chaoshi

    2015-07-01

    Conserved dopamine neurotrophic factor (CDNF), a member of the mammalian mesencephalic astrocyte-derived neurotrophic factor family of conserved secreted factors, has been reported to protect and rescue dopaminergic neurons in vivo. PC12 pheochromocytoma cells are widely used as a cell model for Parkinson's disease (PD) for experimental studies. In the present study, PC12 cells were induced using 6-hydroxydopamine (6-OHDA) to mimic PD, which was used to investigate the protective and reversal effects of CDNF against PD in vitro. Cell growth was assessed using an MTT assay, the rate of cell apoptosis was detected using flow cytometry and the apoptotic morphology of cells was observed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining. Pre-treatment of PC12 cells with CDNF (50, 100 and 200 nM) prior to exposure to 100 µM 6-OHDA for 24 h, resulted in a significant increase in cell viability compared with that of 6-OHDA only-treated cells, with cell survival rates of 46.6, 54.7 and 69.6%, respectively. In addition, PC12 cells were treated with CDNF (50, 100 and 200 nM) following 6-OHDA administration, which resulted in cell survival rates of 47.7, 57.6 and 57.5%, respectively. Flow cytometric and TUNEL staining analyses revealed that CDNF exhibited significant dose-dependent protective and reversal effects on the apoptotic rate of PC12 cells following 6-OHDA treatment. In conclusion, the results of the present study showed that CDNF exhibited neuroprotective and reversal effects on the 6-OHDA-induced apoptosis of PC12 cells in a dose-dependent manner.

  16. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

    Directory of Open Access Journals (Sweden)

    Karina Soares de Oliveira

    Full Text Available ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF. Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

  17. Reg-2, a downstream signaling protein in the ciliary neurotrophic factor survival pathway, alleviates experimental autoimmune encephalomyelitis

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    Hong eJiang

    2016-05-01

    Full Text Available Ciliary neurotrophic factor (CNTF, originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE. However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2. Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis.

  18. Antidiabetic Effect of Brain-Derived Neurotrophic Factor and Its Association with Inflammation in Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Ceren Eyileten

    2017-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF is a neurotrophin, which plays an important role in the central nervous system, and systemic or peripheral inflammatory conditions, such as acute coronary syndrome and type 2 diabetes mellitus (T2DM. BDNF is also expressed in several nonneuronal tissues, and platelets are the major source of peripheral BDNF. Here, we reviewed the potential role of BDNF in platelet reactivity in T2DM and its association with selected inflammatory and platelet activation mediators. Besides that, we focused on adipocytokines such as leptin, resistin, and adiponectin which are considered to take part in inflammation and both lipid and glucose metabolism in diabetic patients as previous studies showed the relation between adipocytokines and BDNF. We also reviewed the evidences of the antidiabetic effect of BDNF and the association with circulating inflammatory cytokines in T2DM.

  19. Cross-sectional associations of objectively measured physical activity with brain-derived neurotrophic factor in adolescents

    DEFF Research Database (Denmark)

    Huang, Tao; Gejl, Anne Kær; Tarp, Jakob

    2017-01-01

    OBJECTIVE: The purpose of this study was to examine the associations between objectively measured physical activity and serum brain-derived neurotrophic factor (BDNF) in adolescents. METHODS: Cross-sectional analyses were performed using data from 415 adolescents who participated in the 2015 follow......-up of the Childhood Health Activity and Motor Performance School Study Denmark (the CHAMPS-study DK). Physical activity was objectively measured by accelerometry monitors. Serum BDNF levels were analyzed using the Enzyme-linked immunosorbent assay (ELISA). Anthropometrics and pubertal status were measured using.......035). In girls, mean physical activity and MVPA were not associated with serum BDNF. Without adjustment for wear time, sedentary time was not associated with serum BDNF in either sex. CONCLUSION: These findings indicate that higher physical activity is associated with lower serum BDNF in boys, but not in girls....

  20. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease

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    Ericksen Mielle Borba

    2016-12-01

    Full Text Available Background/Aims: Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD pathology. Serum brain-derived neurotrophic factor (BDNF reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]. Methods: Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. Results: MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. Discussion: The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.

  1. Brain-Derived Neurotrophic Factor Serum Levels and Hippocampal Volume in Mild Cognitive Impairment and Dementia due to Alzheimer Disease.

    Science.gov (United States)

    Borba, Ericksen Mielle; Duarte, Juliana Avila; Bristot, Giovana; Scotton, Ellen; Camozzato, Ana Luiza; Chaves, Márcia Lorena Fagundes

    2016-01-01

    Hippocampal atrophy is a recognized biomarker of Alzheimer disease (AD) pathology. Serum brain-derived neurotrophic factor (BDNF) reduction has been associated with neurodegeneration. We aimed to evaluate BDNF serum levels and hippocampal volume in clinical AD (dementia and mild cognitive impairment [MCI]). Participants were 10 patients with MCI and 13 with dementia due to AD as well as 10 healthy controls. BDNF serum levels were determined by ELISA and volumetric measures with NeuroQuant®. MCI and dementia patients presented lower BDNF serum levels than healthy participants; dementia patients presented a smaller hippocampal volume than MCI patients and healthy participants. The findings support that the decrease in BDNF might start before the establishment of neuronal injury expressed by the hippocampal reduction.

  2. Intraspinal Rewiring of the Corticospinal Tract Requires Target-Derived Brain-Derived Neurotrophic Factor and Compensates Lost Function after Brain Injury

    Science.gov (United States)

    Ueno, Masaki; Hayano, Yasufumi; Nakagawa, Hiroshi; Yamashita, Toshihide

    2012-01-01

    Brain injury that results in an initial behavioural deficit is frequently followed by spontaneous recovery. The intrinsic mechanism of this functional recovery has never been fully understood. Here, we show that reorganization of the corticospinal tract induced by target-derived brain-derived neurotrophic factor is crucial for spontaneous recovery…

  3. Interaction Between Childhood Adversity, Brain-Derived Neurotrophic Factor val/met and Serotonin Transporter Promoter Polymorphism on Depression : The TRAILS Study

    NARCIS (Netherlands)

    Nederhof, E; Bouma, Esther; Oldehinkel, A.J.; Ormel, J.

    2010-01-01

    Background: The three-way interaction between the functional polymorphism in the serotonin transporter gene linked promoter region, the val66met polymorphism in the brain-derived neurotrophic factor gene, and childhood adversity in the prediction of depression in children, reported by Kaufman and

  4. Effect of brain-derived neurotrophic factor on activity-regulated cytoskeleton-associated protein gene expression in primary frontal cortical neurons. Comparison with NMDA and AMPA

    DEFF Research Database (Denmark)

    El-Sayed, Mona; Hofman-Bang, Jacob; Mikkelsen, Jens D

    2011-01-01

    The effect of brain-derived neurotrophic factor (BDNF) on activity-regulated cytoskeleton-associated protein (Arc) mRNA levels in primary neuronal cultures of rat frontal cortex was characterized pharmacologically and compared to the effect on expression of c-fos, bdnf, neuritin, cox-2 as examples...

  5. Long-term Follow-up of Patients With Retinitis Pigmentosa Receiving Intraocular Ciliary Neurotrophic Factor Implants.

    Science.gov (United States)

    Birch, David G; Bennett, Lea D; Duncan, Jacque L; Weleber, Richard G; Pennesi, Mark E

    2016-10-01

    To evaluate the long-term efficacy of ciliary neurotrophic factor delivered via an intraocular encapsulated cell implant for the treatment of retinitis pigmentosa. Long-term follow-up of a multicenter, sham-controlled study. Thirty-six patients at 3 CNTF4 sites were randomly assigned to receive a high- or low-dose implant in 1 eye and sham surgery in the fellow eye. The primary endpoint (change in visual field sensitivity at 12 months) had been reported previously. Here we measure long-term visual acuity, visual field, and optical coherence tomography (OCT) outcomes in 24 patients either retaining or explanting the device at 24 months relative to sham-treated eyes. Eyes retaining the implant showed significantly greater visual field loss from baseline than either explanted eyes or sham eyes through 42 months. By 60 months and continuing through 96 months, visual field loss was comparable among sham-treated eyes, eyes retaining the implant, and explanted eyes, as was visual acuity and OCT macular volume. Over the short term, ciliary neurotrophic factor released continuously from an intravitreal implant led to loss of total visual field sensitivity that was greater than the natural progression in the sham-treated eye. This additional loss of sensitivity related to the active implant was reversible when the implant was removed. Over the long term (60-96 months), there was no evidence of efficacy for visual acuity, visual field sensitivity, or OCT measures of retinal structure. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Evidence of associations between brain-derived neurotrophic factor (BDNF serum levels and gene polymorphisms with tinnitus

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    Aysun Coskunoglu

    2017-01-01

    Full Text Available Background: Brain-derived neurotrophic factor (BDNF gene polymorphisms are associated with abnormalities in regulation of BDNF secretion. Studies also linked BDNF polymorphisms with changes in brainstem auditory-evoked response test results. Furthermore, BDNF levels are reduced in tinnitus, psychiatric disorders, depression, dysthymic disorder that may be associated with stress, conversion disorder, and suicide attempts due to crises of life. For this purpose, we investigated whether there is any role of BDNF changes in the pathophysiology of tinnitus. Materials and Methods: In this study, we examined the possible effects of BDNF variants in individuals diagnosed with tinnitus for more than 3 months. Fifty-two tinnitus subjects between the ages of 18 and 55, and 42 years healthy control subjects in the same age group, who were free of any otorhinolaryngology and systemic disease, were selected for examination. The intensity of tinnitus and depression was measured using the tinnitus handicap inventory, and the differential diagnosis of psychiatric diagnoses made using the Structured Clinical Interview for Fourth Edition of Mental Disorders. BDNF gene polymorphism was analyzed in the genomic deoxyribonucleic acid (DNA samples extracted from the venous blood, and the serum levels of BDNF were measured. One-way analysis of variance and Chi-squared tests were applied. Results: Serum BDNF level was found lower in the tinnitus patients than controls, and it appeared that there is no correlation between BDNF gene polymorphism and tinnitus. Conclusions: This study suggests neurotrophic factors such as BDNF may have a role in tinnitus etiology. Future studies with larger sample size may be required to further confirm our results.

  7. Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson's Disease-Lessons from Transgenic Mice.

    Science.gov (United States)

    Machado, Venissa; Zöller, Tanja; Attaai, Abdelraheim; Spittau, Björn

    2016-01-26

    Parkinson's disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors.

  8. Effect of budesonide and cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL22 in patients with allergic rhinitis

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    Xiang Xu

    2017-11-01

    Full Text Available Objective: To investigate the effect of budesonide combined with cetirizine hydrochloride on neurotrophic factor, airway function and chemokines CCL17 and CCL12 in patients with allergic rhinitis. Methods: A total of 123 patients with Allergic Rhinitis were randomly divided into three groups, A group treated with budesonide nasal spray, B group treated with cetirizine hydrochloride, C group treated with budesonide combined with cetirizine hydrochloride, then the Neurotrophic factors, airway function indexes and chemokines CCL17 and CCL12 levels in three groups were compared. Results: Before the treatments, the three groups of patients in neurotrophic factor, airway function index and chemokines CCL17, CCL22 have no differences, Compared with before the treatments, after receiving different treatments, the three groups of patients in all indicators were Showed significant differences. In the indexes of neurotrophic factor (NGF, BDNF, NT-3mRNA expression, there was no significant difference between group A and group B, and group C was lower than group A and B. In airway function indexes (FVC, FEV1 and PEF, A group was significantly higher than B group, C group was significantly higher than A group; In the chemokines CCL17 and CCL22 indicators, C group was lower than A group, A group was lower than B group, the difference was significant. Conclusions: Budesonide combined with cetirizine hydrochloride in the treatment of Allergic Rhinitis, can effectively control the patients' neurotrophic factor, pulmonary ventilation and chemokine CC17, CCL22 indicators, the effect is better than Budesonide alone or Cetirizine hydrochloride.

  9. Brain-derived neurotrophic factor improves proliferation of endometrial epithelial cells by inhibition of endoplasmic reticulum stress during early pregnancy.

    Science.gov (United States)

    Lim, Whasun; Bae, Hyocheol; Bazer, Fuller W; Song, Gwonhwa

    2017-12-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family binds to two transmembrane receptors; neurotrophic receptor tyrosine kinase 2 (NTRK2) with high affinity and p75 with low affinity. Although BDNF-NTRK2 signaling in the central nervous system is known, signaling in the female reproductive system is unknown. Therefore, we determined effects of BDNF on porcine endometrial luminal epithelial (pLE) cells isolated from Day 12 of pregnancy, as well as expression of BDNF and NTRK2 in endometria of cyclic and pregnant pigs. BDNF-NTRK2 genes were expressed in uterine glandular (GE) and luminal (LE) epithelia during early pregnancy. In addition, their expression in uterine GE and LE decreased with increasing parity of sows. Recombinant BDNF increased proliferation in pLE cells in a dose-dependent, as well as expression of PCNA and Cyclin D1 in nuclei of pLE cells. BDNF also activated phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38 proteins in pLE cells. In addition, cell death resulting from tunicamycin-induced ER stress was prevented when pLE cells were treated with the combination of tunicamycin and BDNF which also decreased cells in the Sub-G 1 phase of the cell cycle. Furthermore, tunicamycin-induced unfolded protein response genes were mostly down-regulated to the basal levels as compared to non-treated pLE cells. Our finding suggests that BDNF acts via NTRK2 to induce development of pLE cells for maintenance of implantation and pregnancy by activating cell signaling via the PI3K and MAPK pathways and by inhibiting ER stress. © 2017 Wiley Periodicals, Inc.

  10. Gene therapy with brain-derived neurotrophic factor as a protection: retinal ganglion cells in a rat glaucoma model.

    Science.gov (United States)

    Martin, Keith R G; Quigley, Harry A; Zack, Donald J; Levkovitch-Verbin, Hana; Kielczewski, Jennifer; Valenta, Danielle; Baumrind, Lisa; Pease, Mary Ellen; Klein, Ronald L; Hauswirth, William W

    2003-10-01

    To develop a modified adenoassociated viral (AAV) vector capable of efficient transfection of retinal ganglion cells (RGCs) and to test the hypothesis that use of this vector to express brain-derived neurotrophic factor (BDNF) could be protective in experimental glaucoma. Ninety-three rats received one unilateral, intravitreal injection of either normal saline (n = 30), AAV-BDNF-woodchuck hepatitis posttranscriptional regulatory element (WPRE; n = 30), or AAV-green fluorescent protein (GFP)-WPRE (n = 33). Two weeks later, experimental glaucoma was induced in the injected eye by laser application to the trabecular meshwork. Survival of RGCs was estimated by counting axons in optic nerve cross sections after 4 weeks of glaucoma. Transgene expression was assessed by immunohistochemistry, Western blot analysis, and direct visualization of GFP. The density of GFP-positive cells in retinal wholemounts was 1,828 +/- 299 cells/mm(2) (72,273 +/- 11,814 cells/retina). Exposure to elevated intraocular pressure was similar in all groups. Four weeks after initial laser treatment, axon loss was 52.3% +/- 27.1% in the saline-treated group (n = 25) and 52.3% +/- 24.2% in the AAV-GFP-WPRE group (n = 30), but only 32.3% +/- 23.0% in the AAV-BDNF-WPRE group (n = 27). Survival in AAV-BDNF-WPRE animals increased markedly and the difference was significant compared with those receiving either AAV-GFP-WPRE (P = 0.002, t-test) or saline (P = 0.006, t-test). Overexpression of the BDNF gene protects RGC as estimated by axon counts in a rat glaucoma model, further supporting the potential feasibility of neurotrophic therapy as a complement to the lowering of IOP in the treatment of glaucoma.

  11. Glial cell line-derived neurotrophic factor promotes the development of adrenergic neurons in mouse neural crest cultures

    Science.gov (United States)

    Maxwell, Gerald D.; Reid, Kate; Elefanty, Andrew; Bartlett, Perry F.; Murphy, Mark

    1996-01-01

    Growth of mouse neural crest cultures in the presence of glial cell line-derived neurotrophic factor (GDNF) resulted in a dramatic dose-dependent increase in the number of tyrosine hydroxylase (TH)-positive cells that developed when 5% chicken embryo extract was present in the medium. In contrast, growth in the presence of bone morphogenetic protein (BMP)-2, BMP-4, BMP-6, transforming growth factor (TGF) β1, TGF-β2, and TGF-β3 elicited no increase in the number of TH-positive cells. The TH-positive cells that developed in the presence of GDNF had neuronal morphology and contained the middle and low molecular weight neurofilament proteins. Numerous TH-negative cells with the morphology of neurons also were observed in GDNF-treated cultures. Analysis revealed that the period from 6 to 12 days in vitro was the critical time for exposure to GDNF to generate the increase in TH-positive cell number. The growth factors neurotrophin-3 and fibroblast growth factor-2 elicited increases in the number of TH-positive cells similar to that seen in response to GDNF. In contrast, nerve growth factor was unable to substitute for GDNF. These findings extend the previously reported biological activities of GDNF by showing that it can act on mouse neural crest cultures to promote the development of neurons. PMID:8917581

  12. The brain-derived neurotrophic factor (BDNF) val66met polymorphism differentially affects performance on subscales of the Wechsler Memory Scale – Third Edition (WMS-III)

    Science.gov (United States)

    Lamb, Yvette N.; Thompson, Christopher S.; McKay, Nicole S.; Waldie, Karen E.; Kirk, Ian J.

    2015-01-01

    Single nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the catechol-O-methyltransferase (COMT) gene influence brain structure and function, as well as cognitive abilities. They are most influential in the hippocampus and prefrontal cortex (PFC), respectively. Recall and recognition are forms of memory proposed to have different neural substrates, with recall having a greater dependence on the PFC and hippocampus. This study aimed to determine whether the BDNF val66met or COMT val158met polymorphisms differentially affect recall and recognition, and whether these polymorphisms interact. A sample of 100 healthy adults was assessed on recall and familiarity-based recognition using the Faces and Family Pictures subscales of the Wechsler Memory Scale – Third Edition (WMS-III). COMT genotype did not affect performance on either task. The BDNF polymorphism (i.e., met carriers relative to val homozygotes) was associated with poorer recall ability, while not influencing recognition. Combining subscale scores in memory tests such as the WMS might obscure gene effects. Our results demonstrate the importance of distinguishing between recall and familiarity-based recognition in neurogenetics research. PMID:26347681

  13. The brain-derived neurotrophic factor (BDNF) val66met polymorphism differentially affects performance on subscales of the Wechsler Memory Scale - Third Edition (WMS-III).

    Science.gov (United States)

    Lamb, Yvette N; Thompson, Christopher S; McKay, Nicole S; Waldie, Karen E; Kirk, Ian J

    2015-01-01

    Single nucleotide polymorphisms in the brain-derived neurotrophic factor (BDNF) gene and the catechol-O-methyltransferase (COMT) gene influence brain structure and function, as well as cognitive abilities. They are most influential in the hippocampus and prefrontal cortex (PFC), respectively. Recall and recognition are forms of memory proposed to have different neural substrates, with recall having a greater dependence on the PFC and hippocampus. This study aimed to determine whether the BDNF val(66)met or COMT val(158)met polymorphisms differentially affect recall and recognition, and whether these polymorphisms interact. A sample of 100 healthy adults was assessed on recall and familiarity-based recognition using the Faces and Family Pictures subscales of the Wechsler Memory Scale - Third Edition (WMS-III). COMT genotype did not affect performance on either task. The BDNF polymorphism (i.e., met carriers relative to val homozygotes) was associated with poorer recall ability, while not influencing recognition. Combining subscale scores in memory tests such as the WMS might obscure gene effects. Our results demonstrate the importance of distinguishing between recall and familiarity-based recognition in neurogenetics research.

  14. In vivo visualisation of murine corneal nerve fibre regeneration in response to ciliary neurotrophic factor.

    Science.gov (United States)

    Reichard, Maria; Hovakimyan, Marina; Guthoff, Rudolf F; Stachs, Oliver

    2014-03-01

    The aim of this study was to examine the murine subbasal nerve fibre plexus (SNP) regeneration altered by surgical dissection. Investigations in the mouse model addressed the regeneration capabilities of the SNP, and the influence of local ciliary neurotrophic factor (CNTF) application on the regeneration process. In preliminary experiments, the healthy mouse cornea was monitored using in vivo confocal laser-scanning microscopy (CLSM) from the age of 8-52 weeks, to reveal and rule out the age-dependent changes in SNP. Nerve fibre density (NFD) was determined with the semi-automatic nerve tracing program NeuronJ. No quantitative or qualitative changes in NFD were detected in untreated animals over time; mean NFD in mice aged 8 weeks (28.30 ± 9.12 mm/mm2), 16 weeks (29.23 ± 7.28 mm/mm2), 30 weeks (26.31 ± 8.58 mm/mm2) and 52 weeks (26.34 ± 6.04 mm/mm2) showed no statistically significant differences between time points (p > 0.05). For regeneration studies a circular incision through corneal epithelium and anterior stroma of minimum 60 μm depth was generated with a custom-made guided trephine system to cut the subbasal corneal nerves in adult mice. The corneal nerve pattern was monitored and NFD was measured before and up to 8 weeks after surgery. Animals were divided in three groups each comprising 6 mice. The CNTF group received eye drops containing CNTF (25 ng/ml) 3 times daily for 3 weeks, whereas the control group received no further medication. In the sham group the same treatment schedule was applied as in CNTF group, using vehicle. The regenerating subbasal nerve fibres sprouted out of stromal nerves within the cut and additionally regrew over the scar rim from outside. They showed parallel orientation but were thinner than before incision. Whorl patterning was observed after 4 weeks. All three groups revealed a marked NFD reduction starting at one week after incision, followed by continuous recovery. After 8 weeks the NFD reached 23.5 ± 2.4 mm/mm2 (78

  15. Ciliary neurotrophic factor-treated astrocyte-conditioned medium increases the intracellular free calcium concentration in rat cortical neurons.

    Science.gov (United States)

    Sun, Meiqun; Liu, Hongli; Min, Shengping; Wang, Hongtao; Wang, Xiaojing

    2016-04-01

    Ciliary neurotrophic factor (CNTF) is involved in the activation of astrocytes. A previous study showed that CNTF-treated astrocyte-conditioned medium (CNTF-ACM) contributed to the increase of the calcium current and the elevation of corresponding ion channels in cortical neurons. On this basis, it is reasonable to assume that CNTF-ACM may increase the intracellular free calcium concentration ([Ca 2+ ] i ) in neurons. In the present study, the effects of CNTF-ACM on [Ca 2+ ] i in rat cortical neurons were determined, and on this basis, the aim was to investigate the potential active ingredients in ACM that are responsible for this biological process. As expected, the data indicated that CNTF-ACM resulted in a clear elevation of [Ca 2+ ] i in neurons. Additionally, the fibroblast growth factor-2 (FGF-2) contained in the CNTF-ACM was found to participate in the upregulation of [Ca 2+ ] i . Taken together, CNTF induces the production of active factors (at least including FGF-2) released from astrocytes, which finally potentiate the increase of [Ca 2+ ] i in cortical neurons.

  16. A lack of correlation between brain-derived neurotrophic factor serum level and verbal memory performance in healthy Polish population

    Directory of Open Access Journals (Sweden)

    Monika eWilkosc

    2016-05-01

    Full Text Available Brain derived neurotrophic factor is considered to be connected with memory and learning through the processes of long term synaptic potentiation and synaptic plasticity. The aim of the study was to examine the relationship between precursor BDNF (proBNDF and mature BDNF (mBDNF serum levels and performance on Rey Auditory-Verbal Learning Test (RAVLT in 150 healthy volunteers. In addition, we have verified the relationships between serum concentration of both forms of BDNF and RAVLT with sociodemographic and lifestyle factors. We found no strong evidence for the correlation of proBDNF and mBDNF serum levels with performance on RAVLT in healthy Polish population in early and middle adulthood. We observed the mBDNF serum concentration to be higher in women compared with men. Moreover, we revealed higher mBDNF level to be connected with lower Body Mass Index (BMI. In turn, the results of RAVLT correlated with sociodemographic and lifestyle factors, such as: age, education, gender, BMI and smoking.

  17. The Actin Cytoskeleton Is Involved in Glial Cell Line-Derived Neurotrophic Factor (GDNF)-Induced Ret Translocation into Lipid Rafts in Dopaminergic Neuronal Cells.

    Science.gov (United States)

    Li, Li; Song, Haijing; Mu, Peipei; Xu, Ming; Liu, Chaoxia; Wang, Ying; Qin, Yingsong; Sun, Shen; Gao, Jin; Wang, Ting; Gao, Dianshuai

    2017-09-07

    Glial cell line-derived neurotrophic factor (GDNF), a potential therapeutic factor for Parkinson's disease (PD), exerts its biological effects through the Ret receptor tyrosine kinase. The redistribution of Ret into lipid rafts substantially influences Ret signaling, but the mechanisms underlying Ret translocation remain unclear. The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF-induced Ret translocation into lipid rafts. In MN9D dopaminergic neuronal cells, we used density gradient centrifugation and immunofluorescence confocal microscopy to separate and visualize lipid rafts, co-immunoprecipitation to analyze protein-protein interactions, and latrunculin B (Lat B) and jasplakinolide (Jas) to disrupt and enhance the polymerization of the actin cytoskeleton, respectively. The results showed that Ret translocated into lipid rafts and coimmunoprecipitated with actin in response to GDNF treatment. After Lat B or Jas treatment, the Ret-F-actin association induced by GDNF was impaired or enhanced respectively and then the levels of Ret translocated into lipid rafts were correspondingly inhibited or promoted. These data indicate that actin polymerization and cytoskeletal remodeling are integral to GDNF-induced cell signaling in dopaminergic cells and define a new role of the actin cytoskeleton in promoting Ret redistribution into lipid rafts.

  18. The Actin Cytoskeleton Is Involved in Glial Cell Line-Derived Neurotrophic Factor (GDNF-Induced Ret Translocation into Lipid Rafts in Dopaminergic Neuronal Cells

    Directory of Open Access Journals (Sweden)

    Li Li

    2017-09-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF, a potential therapeutic factor for Parkinson’s disease (PD, exerts its biological effects through the Ret receptor tyrosine kinase. The redistribution of Ret into lipid rafts substantially influences Ret signaling, but the mechanisms underlying Ret translocation remain unclear. The purpose of our study was to further explore the signaling mechanisms of GDNF and to determine whether the actin cytoskeleton is involved in the GDNF-induced Ret translocation into lipid rafts. In MN9D dopaminergic neuronal cells, we used density gradient centrifugation and immunofluorescence confocal microscopy to separate and visualize lipid rafts, co-immunoprecipitation to analyze protein-protein interactions, and latrunculin B (Lat B and jasplakinolide (Jas to disrupt and enhance the polymerization of the actin cytoskeleton, respectively. The results showed that Ret translocated into lipid rafts and coimmunoprecipitated with actin in response to GDNF treatment. After Lat B or Jas treatment, the Ret–F-actin association induced by GDNF was impaired or enhanced respectively and then the levels of Ret translocated into lipid rafts were correspondingly inhibited or promoted. These data indicate that actin polymerization and cytoskeletal remodeling are integral to GDNF-induced cell signaling in dopaminergic cells and define a new role of the actin cytoskeleton in promoting Ret redistribution into lipid rafts.

  19. Neuroprotection via maintenance or increase of antioxidants and neurotrophic factors in ischemic gerbil hippocampus treated with tanshinone I.

    Science.gov (United States)

    Park, Joon Ha; Park, Ok Kyu; Yan, Bingchun; Ahn, Ji Hyeon; Kim, In Hye; Lee, Jae-Chul; Kwon, Seung-Hae; Yoo, Ki-Yeon; Lee, Choong Hyun; Hwang, In Koo; Choi, Jung Hoon; Won, Moo-Ho; Kim, Jong-Dai

    2014-01-01

    Danshen (Radix Salvia miltiorrhizae) has been used as a traditional medicine in Asia for treatment of various microcirculatory disturbance related diseases. Tanshinones are mainly hydrophobic active components, which have been isolated from Danshen and show various biological functions. In this study, we observed the neuroprotective effect of tanshinone I (TsI) against ischemic damage in the gerbil hippocampal CA1 region (CA1) after transient cerebral ischemia and examined its neuroprotective mechanism. The gerbils were divided into vehicle-treated-sham-group, vehicle-treated-ischemia-group, TsI-treated-sham-group, and TsI-treated-ischemia-group. TsI was administrated intraperitoneally three times (once a day for three days) before ischemia-reperfusion. The neuroprotective effect of TsI was examined using H&E staining, neuronal nuclei (NeuN) immunohistochemistry and Fluoro-Jade B staining. To investigate the neuroprotective mechanism of TsI after ischemia-reperfusion, immunohistochemical (IHC) and Western blotting analyses for Cu, Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-I (IGF-I) were performed. Treatment with TsI protected pyramidal neurons from ischemia-induced neuronal death in the CA1 after ischemia-reperfusion. In addition, treatment with TsI maintained the levels of SOD1 and SOD2 as determined by IHC and Western blotting in the CA1 after ischemia-reperfusion compared with the vehicle-ischemia-group. In addition, treatment with TsI increased the levels of BDNF and IGF-I determined by IHC and Western blotting in the TsI-treated-sham-group compared with the vehicle-treated-sham-group, and their levels were maintained in the stratum pyramidale of the ischemic CA1 in the TsI-treated-ischemia-group. Treatment with TsI protects pyramidal neurons of the CA1 from ischemic damage induced by transient cerebral ischemia via the maintenance of antioxidants and the increase of

  20. Ciliary neurotrophic factor promotes motor reinnervation of the musculocutaneous nerve in an experimental model of end-to-side neurorrhaphy.

    Science.gov (United States)

    Dubový, Petr; Raška, Otakar; Klusáková, Ilona; Stejskal, Lubomír; Celakovský, Pavel; Haninec, Pavel

    2011-06-22

    It is difficult to repair nerve if proximal stump is unavailable or autogenous nerve grafts are insufficient for reconstructing extensive nerve damage. Therefore, alternative methods have been developed, including lateral anastomosis based on axons' ability to send out collateral sprouts into denervated nerve. The different capacity of a sensory or motor axon to send a sprout is controversial and may be controlled by cytokines and/or neurotrophic factors like ciliary neurotrophic factor (CNTF). The aim of the present study was to quantitatively assess collateral sprouts sent out by intact motor and sensory axons in the end-to-side neurorrhaphy model following intrathecal administration of CNTF in comparison with phosphate buffered saline (vehiculum) and Cerebrolysin. The distal stump of rat transected musculocutaneous nerve (MCN) was attached in an end-to-side fashion with ulnar nerve. CNTF, Cerebrolysin and vehiculum were administered intrathecally for 2 weeks, and all animals were allowed to survive for 2 months from operation. Numbers of spinal motor and dorsal root ganglia neurons were estimated following their retrograde labeling by Fluoro-Ruby and Fluoro-Emerald applied to ulnar and musculocutaneous nerve, respectively. Reinnervation of biceps brachii muscles was assessed by electromyography, behavioral test, and diameter and myelin sheath thickness of regenerated axons. Vehiculum or Cerebrolysin administration resulted in significantly higher numbers of myelinated axons regenerated into the MCN stumps compared with CNTF treatment. By contrast, the mean diameter of the myelinated axons and their myelin sheath thickness in the cases of Cerebrolysin- or CNTF-treated animals were larger than were those for rats treated with vehiculum. CNTF treatment significantly increased the percentage of motoneurons contributing to reinnervation of the MCN stumps (to 17.1%) when compared with vehiculum or Cerebrolysin treatments (at 9.9 or 9.6%, respectively). Reduced numbers

  1. Ciliary neurotrophic factor promotes motor reinnervation of the musculocutaneous nerve in an experimental model of end-to-side neurorrhaphy

    Directory of Open Access Journals (Sweden)

    Čelakovský Pavel

    2011-06-01

    Full Text Available Abstract Background It is difficult to repair nerve if proximal stump is unavailable or autogenous nerve grafts are insufficient for reconstructing extensive nerve damage. Therefore, alternative methods have been developed, including lateral anastomosis based on axons' ability to send out collateral sprouts into denervated nerve. The different capacity of a sensory or motor axon to send a sprout is controversial and may be controlled by cytokines and/or neurotrophic factors like ciliary neurotrophic factor (CNTF. The aim of the present study was to quantitatively assess collateral sprouts sent out by intact motor and sensory axons in the end-to-side neurorrhaphy model following intrathecal administration of CNTF in comparison with phosphate buffered saline (vehiculum and Cerebrolysin. The distal stump of rat transected musculocutaneous nerve (MCN was attached in an end-to-side fashion with ulnar nerve. CNTF, Cerebrolysin and vehiculum were administered intrathecally for 2 weeks, and all animals were allowed to survive for 2 months from operation. Numbers of spinal motor and dorsal root ganglia neurons were estimated following their retrograde labeling by Fluoro-Ruby and Fluoro-Emerald applied to ulnar and musculocutaneous nerve, respectively. Reinnervation of biceps brachii muscles was assessed by electromyography, behavioral test, and diameter and myelin sheath thickness of regenerated axons. Results Vehiculum or Cerebrolysin administration resulted in significantly higher numbers of myelinated axons regenerated into the MCN stumps compared with CNTF treatment. By contrast, the mean diameter of the myelinated axons and their myelin sheath thickness in the cases of Cerebrolysin- or CNTF-treated animals were larger than were those for rats treated with vehiculum. CNTF treatment significantly increased the percentage of motoneurons contributing to reinnervation of the MCN stumps (to 17.1% when compared with vehiculum or Cerebrolysin treatments (at

  2. The role of brain-derived neurotrophic factor in bone marrow stromal cell-mediated spinal cord repair.

    Science.gov (United States)

    Ritfeld, Gaby J; Patel, Ajay; Chou, Alexander; Novosat, Tabitha L; Castillo, Deborah G; Roos, Raymund A C; Oudega, Martin

    2015-01-01

    The ability of intraspinal bone marrow stromal cell (BMSC) transplants to elicit repair is thought to result from paracrine effects by secreted trophic factors including brain-derived neurotrophic factor (BDNF). Here we used gene therapy to increase or silence BDNF production in BMSCs to investigate the role of BDNF in BMSC-mediated neuroprotection. In a spinal cord organotypic culture, BMSC-conditioned medium significantly enhanced spinal motoneuron survival by 64% compared with culture medium only. Only conditioned medium of BDNF-hypersecreting BMSCs sustained this neuroprotective effect. In a rat model of spinal cord contusion, a BDNF-dependent neuroprotective effect was confirmed; only with a subacute transplant of BDNF-hypersecreting BMSCs were significantly more spared motoneurons found at 4 weeks postinjury compared with vehicle controls. Spared nervous tissue volume was improved by 68% with both control BMSCs and BDNF-hypersecreting BMSCs. In addition, blood vessel density in the contusion with BDNF-hypersecreting BMSCs was 35% higher compared with BMSC controls and sixfold higher compared with vehicle controls. BDNF-silenced BMSCs did not survive the first week of transplantation, and no neuroprotective effect was found at 4 weeks after transplantation. Together, our data broaden our understanding of the role of BDNF in BMSC-mediated neuroprotection and successfully exploit BDNF dependency to enhance anatomical spinal cord repair.

  3. The role of brain-derived neurotrophic factor (BDNF in comorbid depression: possible linkage with steroid hormones, cytokines, and nutrition

    Directory of Open Access Journals (Sweden)

    Tadahiro eNumakawa

    2014-09-01

    Full Text Available Increasing evidence demonstrates a connection between growth factor function (including brain-derived neurotrophic factor, BDNF, glucocorticoid levels (one of the steroid hormones, and the pathophysiology of depressive disorders. Because both BDNF and glucocorticoids regulate synaptic function in the central nervous system, their functional interaction is of major concern. Interestingly, alterations in levels of estrogen, another steroid hormone, may play a role in depressive-like behavior in postpartum females with fluctuations of BDNF-related molecules in the brain. BDNF and cytokines, which are protein regulators of inflammation, stimulate multiple intracellular signaling cascades involved in neuropsychiatric illness. Pro-inflammatory cytokines may increase vulnerability to depressive symptoms, such as the increased risk observed in patients with cancer and/or autoimmune diseases. In this review, we discuss the possible relationship between inflammation and depression, in addition to the crosstalk among cytokines, BDNF and steroids. Further, since nutritional status has been shown to affect critical pathways involved in depression through both BDNF function and the monoamine system, we also review current evidence surrounding diet and supplementation (e.g., flavonoids on BDNF-mediated brain functions.

  4. Up-regulation of ciliary neurotrophic factor in astrocytes by aspirin: implications for remyelination in multiple sclerosis.

    Science.gov (United States)

    Modi, Khushbu K; Sendtner, Michael; Pahan, Kalipada

    2013-06-21

    Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor, and the mechanisms by which CNTF expression could be increased in the brain are poorly understood. Acetylsalicylic acid (aspirin) is one of the most widely used analgesics. Interestingly, aspirin increased mRNA and protein expression of CNTF in primary mouse and human astrocytes in a dose- and time-dependent manner. Aspirin induced the activation of protein kinase A (PKA) but not protein kinase C (PKC). H-89, an inhibitor of PKA, abrogated aspirin-induced expression of CNTF. The activation of cAMP-response element-binding protein (CREB), but not NF-κB, by aspirin, the abrogation of aspirin-induced expression of CNTF by siRNA knockdown of CREB, the presence of a consensus cAMP-response element in the promoter of CNTF, and the recruitment of CREB and CREB-binding protein to the CNTF promoter by aspirin suggest that aspirin increases the expression of the Cntf gene via the activation of CREB. Furthermore, we demonstrate that aspirin-induced astroglial CNTF was also functionally active and that supernatants of aspirin-treated astrocytes of wild type, but not Cntf null, mice increased myelin-associated proteins in oligodendrocytes and protected oligodendrocytes from TNF-α insult. These results highlight a new and novel myelinogenic property of aspirin, which may be of benefit for multiple sclerosis and other demyelinating disorders.

  5. Expression of ciliary neurotrophic factor (CNTF), CNTF receptor alpha (CNTFR-alpha) following experimental intracerebral hemorrhage in rats.

    Science.gov (United States)

    Yokota, Hiroshi; Yoshikawa, Masahide; Hirabayashi, Hidehiro; Nakase, Hiroyuki; Uranishi, Ryunosuke; Nishimura, Fumihiko; Sugie, Yuko; Ishizaka, Shigeaki; Sakaki, Toshisuke

    2005-04-04

    Ciliary neurotrophic factor (CNTF) is known as a neuro-survival factor in the developing and developed CNS, as well as in the CNS following injury. However, little is known about the expression of CNTF or that of its receptor (CNTFR-alpha) in cases of intracerebral hemorrhage (ICH). We investigated the temporal and spatial profiles of CNTF and CNTFR-alpha expression using a collagenase-induced ICH rat model. CNTF expression was up-regulated from the day following ICH induction and reached a peak level at 5 to 14 days, with increased expression observed in brain tissue surrounding the hematoma lesion and white matter structures in association with astroglial proliferation. Further, CNTFR-alpha was transiently expressed in the cerebral cortex surrounding the hematoma, with a peak at 5 days. Administration of exogenous CNTF into the lesion following initiation of ICH resulted in a prolonged expression of CNTFR-alpha on cortical neurons neighboring the hematoma. Our findings suggest differential regulation of CNTF and CNTFR-alpha, and the possibility of a therapeutic strategy using CNTF administration for ICH.

  6. Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling.

    Science.gov (United States)

    McGregor, Narelle E; Poulton, Ingrid J; Walker, Emma C; Pompolo, Sueli; Quinn, Julian M W; Martin, T John; Sims, Natalie A

    2010-03-01

    Ciliary neurotrophic factor (CNTF) receptor (CNTFR) expression has been described in osteoblast-like cells, suggesting a role for CNTF in bone metabolism. When bound to CNTF, neuropoietin (NP), or cardiotrophin-like-cytokine (CLC), CNTFR forms a signaling complex with gp130 and the leukemia inhibitory factor receptor, which both play critical roles in bone cell biology. This study aimed to determine the role of CNTFR-signaling cytokines in bone. Immunohistochemistry detected CNTF in osteoblasts, osteocytes, osteoclasts, and proliferating chondrocytes. CNTFR mRNA was detected in primary calvarial osteoblasts and was upregulated during osteoblast differentiation. Treatment of osteoblasts with CNTF or CLC, but not NP, significantly inhibited mineralization and osterix mRNA levels. Twelve-week-old male CNTF ( -/- ) mice demonstrated reduced femoral length, cortical thickness, and periosteal circumference; but femoral trabecular bone mineral density (Tb.BMD) and tibial trabecular bone volume (BV/TV) were not significantly different from wild-type, indicating a unique role for CNTF in bone growth in male mice. In contrast, female CNTF ( -/- ) femora were of normal width, but femoral Tb.BMD, tibial BV/TV, trabecular number, and trabecular thickness were all increased. Female CNTF ( -/- ) tibiae also demonstrated high osteoblast number and mineral apposition rate compared to wild-type littermates, and this was intrinsic to the osteoblast lineage. CNTF is expressed locally in bone and plays a unique role in female mice as an inhibitor of trabecular bone formation and in male mice as a stimulus of cortical growth.

  7. Genomic organization and chromosomal localization of the human and mouse genes encoding the {alpha} receptor component for ciliary neurotrophic factor

    Energy Technology Data Exchange (ETDEWEB)

    Valenzuela, D.M.; Rojas, E.; McClain, J. [Regeneron Pharmaceuticals, Inc., Tarrytown, NY (United States)] [and others

    1995-01-01

    Ciliary neurotrophic factor (CNTF) has recently been found to share receptor components with, and to be structurally related to, a family of broadly acting cytokines, including interleukin-6, leukemia inhibitory factor, and oncostatin M. However, the CNTF receptor complex also includes a CNTF-specific component known as CNTF receptor {alpha} (CNTFR{alpha}). Here we describe the molecular cloning of the human and mouse genes encoding CNTFR. We report that the human and mouse genes have an identical intron-exon structure that correlates well with the domain structure of CNTFR{alpha}. That is, the signal peptide and the immunoglobulin-like domain are each encoded by single exons, the cytokine receptor-like domain is distributed among 4 exons, and the C-terminal glycosyl phosphatidylinositol recognition domain in encoded by the final coding exon. The position of the introns within the cytokine receptor-like domain corresponds to those found in other members of the cytokine receptor superfamily. Confirming a recent study using radiation hybrids, we have also mapped the human CNTFR gene to chromosome band 9p13 and the mouse gene to a syntenic region of chromosome 4. 24 refs., 4 figs.

  8. Epigenetic and epistatic interactions between serotonin transporter and brain-derived neurotrophic factor genetic polymorphism: insights in depression.

    Science.gov (United States)

    Ignácio, Z M; Réus, G Z; Abelaira, H M; Quevedo, J

    2014-09-05

    Epidemiological studies have shown significant results in the interaction between the functions of brain-derived neurotrophic factor (BDNF) and 5-HT in mood disorders, such as major depressive disorder (MDD). The latest research has provided convincing evidence that gene transcription of these molecules is a target for epigenetic changes, triggered by stressful stimuli that starts in early childhood and continues throughout life, which are subsequently translated into structural and functional phenotypes culminating in depressive disorders. The short variants of 5-HTTLPR and BDNF-Met are seen as forms which are predisposed to epigenetic aberrations, which leads individuals to a susceptibility to environmental adversities, especially when subjected to stress in early life. Moreover, the polymorphic variants also feature epistatic interactions in directing the functional mechanisms elicited by stress and underlying the onset of depressive disorders. Also emphasized are works which show some mediators between stress and epigenetic changes of the 5-HTT and BDNF genes, such as the hypothalamic-pituitary-adrenal (HPA) axis and the cAMP response element-binding protein (CREB), which is a cellular transcription factor. Both the HPA axis and CREB are also involved in epistatic interactions between polymorphic variants of 5-HTTLPR and Val66Met. This review highlights some research studying changes in the epigenetic patterns intrinsic to genes of 5-HTT and BDNF, which are related to lifelong environmental adversities, which in turn increases the risks of developing MDD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  9. Effect of cigarette smoke on monocyte procoagulant activity: Focus on platelet-derived brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Amadio, Patrizia; Baldassarre, Damiano; Sandrini, Leonardo; Weksler, Babette B; Tremoli, Elena; Barbieri, Silvia S

    2017-01-01

    Cigarette smoke (CS) activates platelets, promotes vascular dysfunction, and enhances Tissue Factor (TF) expression in blood monocytes favoring pro-thrombotic states. Brain-derived neurotrophic factor (BDNF), a member of the family of neurotrophins involved in survival, growth, and maturation of neurons, is released by activated platelets (APLTs) and plays a role in the cardiovascular system. The effect of CS on circulating levels of BDNF is controversial and the function of circulating BDNF in atherothrombosis is not fully understood. Here, we have shown that human platelets, treated with an aqueous extract of CS (CSE), released BDNF in a dose-dependent manner. In addition, incubation of human monocytes with BDNF or with the supernatant of platelets activated with CSE increased TF activity by a Tropomyosin receptor kinase B (TrkB)-dependent mechanism. Finally, comparing serum and plasma samples of 12 male never smokers (NS) and 29 male active smokers (AS) we observed a significant increase in microparticle-associated TF activity (MP-TF) as well as BDNF in AS, while in serum, BDNF behaved oppositely. Taken together these findings suggest that platelet-derived BDNF is involved in the regulation of TF activity and that CS plays a role in this pathway by favoring a pro-atherothrombotic state.

  10. Precursor N-cadherin mediates glial cell line-derived neurotrophic factor-promoted human malignant glioma.

    Science.gov (United States)

    Xiong, Ye; Liu, Liyun; Zhu, Shuang; Zhang, Baole; Qin, Yuxia; Yao, Ruiqin; Zhou, Hao; Gao, Dian Shuai

    2017-04-11

    As the most prevalent primary brain tumor, gliomas are highly metastatic, invasive and are characteristic of high levels of glial cell-line derived neurotrophic factor (GDNF). GDNF is an important factor for invasive glioma cell growth; however, the underlying mechanism involved is unclear. In this study, we affirm a significantly higher expression of the precursor of N-cadherin (proN-cadherin) in most gliomas compared with normal brain tissues. Our findings reveal that GDNF interacts with the extracellular domain of proN-cadherin, which suggests that proN-cadherin mediates GDNF-induced glioma cell migration and invasion. We hypothesize that proN-cadherin might cause homotypic adhesion loss within neighboring cells and at the same time promote heterotypic adhesion within the extracellular matrix (ECM) through a certain mechanism. This study also demonstrates that the interaction between GDNF and proN-cadherin activates specific intracellular signaling pathways; furthermore, GDNF promoted the secretion of matrix metalloproteinase-9 (MMP-9), which degrades the ECM via proN-cadherin. To reach the future goal of developing novel therapies of glioma, this study, reveals a unique mechanism of glioma cell migration and invasion.

  11. Expression of gp120 in mice evokes anxiety behavior: co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala

    Science.gov (United States)

    Bachis, Alessia; Forcelli, Patrick; Masliah, Eliezer; Campbell, Lee; Mocchetti, Italo

    2016-01-01

    Human immunodeficiency virus type 1 (HIV) infection of the brain produces cognitive and motor disorders. In addition, HIV positive individuals exhibit behavioral alterations, such as apathy, and a decrease in spontaneity or emotional responses, typically seen in anxiety disorders. Anxiety can lead to psychological stress, which has been shown to influence HIV disease progression. These considerations underscore the importance of determining if anxiety in HIV is purely psychosocial, or if by contrast, there are the molecular cascades associated directly with HIV infection that may mediate anxiety. The present study had two goals: 1) to determine if chronic exposure to viral proteins would induce anxiety-like behavior in an animal model and 2) to determine if this exposure results in anatomical abnormalities that could explain increased anxiety. We have used gp120 transgenic mice, which display behavior and molecular deficiencies similar to HIV positive subjects with cognitive and motor impairments. In comparison to wild type mice, 6 months old gp120 transgenic mice demonstrated an anxiety like behavior measured by open field, light/dark transition task, and prepulse inhibition tests. Moreover, gp120 transgenic mice have an increased number of spines in the amygdala, as well as higher levels of brain-derived neurotrophic factor and tissue plasminogen activator when compared to age-matched wild type. Our data support the hypothesis that HIV, through gp120, may cause structural changes in the amygdala that lead to maladaptive responses to anxiety. PMID:26845379

  12. Brain Derived Neurotrophic Factor (BDNF) levels as a possible predictor of psychopathology in healthy twins at high and low risk for affective disorder

    DEFF Research Database (Denmark)

    Vinberg, Maj; Miskowiak, Kamilla; Kessing, Lars Vedel

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction with the B......Brain Derived Neurotrophic Factor (BDNF) is a potential biomarker of affective disorder. However, longitudinal studies evaluating a potential predictive role of BDNF on subsequent psychopathology are lacking. The aim of this study was to investigate whether BDNF alone or in interaction...... with the BDNF Val66Met polymorphism predict onset of affective disorder in healthy individuals at heritable risk for affective disorder. In a high-risk study, we assessed whole blood levels of BDNF in 234 healthy monozygotic and dizygotic twins with or without a co-twin history of affective disorder (high...

  13. High-Mobility Group Box-1 Induces Decreased Brain-Derived Neurotrophic Factor-Mediated Neuroprotection in the Diabetic Retina

    Directory of Open Access Journals (Sweden)

    Ahmed M. Abu El-Asrar

    2013-01-01

    Full Text Available To test the hypothesis that brain-derived neurotrophic factor-(BDNF- mediated neuroprotection is reduced by high-mobility group box-1 (HMGB1 in diabetic retina, paired vitreous and serum samples from 46 proliferative diabetic retinopathy and 34 nondiabetic patients were assayed for BDNF, HMGB1, soluble receptor for advanced glycation end products (sRAGE, soluble intercellular adhesion molecule-1 (sICAM-1, monocyte chemoattractant protein-1 (MCP-1, and TBARS. We also examined retinas of diabetic and HMGB1 intravitreally injected rats. The effect of the HMGB1 inhibitor glycyrrhizin on diabetes-induced changes in retinal BDNF expressions was studied. Western blot, ELISA, and TBARS assays were used. BDNF was not detected in vitreous samples. BDNF levels were significantly lower in serum samples from diabetic patients compared with nondiabetics, whereas HMGB1, sRAGE, sICAM-1, and TBARS levels were significantly higher in diabetic serum samples. MCP-1 levels did not differ significantly. There was significant inverse correlation between serum levels of BDNF and HMGB1. Diabetes and intravitreal administration of HMGB1 induced significant upregulation of the expression of HMGB1, TBARS, and cleaved caspase-3, whereas the expression of BDNF and synaptophysin was significantly downregulated in rat retinas. Glycyrrhizin significantly attenuated diabetes-induced downregulation of BDNF. Our results suggest that HMGB1-induced downregulation of BDNF might be involved in pathogenesis of diabetic retinal neurodegeneration.

  14. No effect of escitalopram versus placebo on brain-derived neurotrophic factor in healthy individuals: a randomised trial.

    Science.gov (United States)

    Knorr, Ulla; Koefoed, Pernille; Soendergaard, Mia H Greisen; Vinberg, Maj; Gether, Ulrik; Gluud, Christian; Wetterslev, Jørn; Winkel, Per; Kessing, Lars V

    2016-04-01

    Brain-derived neurotrophic factor (BDNF) seems to play an important role in the course of depression including the response to antidepressants in patients with depression. We aimed to study the effect of an antidepressant intervention on peripheral BDNF in healthy individuals with a family history of depression. We measured changes in BDNF messenger RNA (mRNA) expression and whole-blood BDNF levels in 80 healthy first-degree relatives of patients with depression randomly allocated to receive daily tablets of escitalopram 10 mg versus placebo for 4 weeks. We found no statistically significant difference between the escitalopram and the placebo group in the change in BDNF mRNA expression and whole-blood BDNF levels. Post hoc analyses showed a statistically significant negative correlation between plasma escitalopram concentration and change in whole-blood BDNF levels in the escitalopram-treated group. The results of this randomised trial suggest that escitalopram 10 mg has no effect on peripheral BDNF levels in healthy individuals.

  15. Correlation between hedgehog (hh) protein family and brain-derived neurotrophic factor (bdnf) in autism spectrum disorder (asd)

    International Nuclear Information System (INIS)

    Halepoto, D.M.; Bashir, S.

    2015-01-01

    To determine the correlation of Sonic Hedgehog (SHH), Indian Hedgehog (IHH), and Brain-Derived Neurotrophic Factor (BDNF) in children with Autism Spectrum Disorder (ASD). Study Design: An observational, comparative study. Place and Duration of Study: Autism Research and Treatment Center, Al-Amodi Autism Research Chair, Department of Physiology, Faculty of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia, from October 2011 to May 2012. Methodology: Serum levels of SHH, IHH and BDNF were determined in recently diagnosed autistic patients and age matched healthy children (n=25), using the Enzyme-Linked Immunosorbent Assay (ELISA). Childhood Autism Rating Scale (CARS) was used for the assessment of autistic severity. Spearman correlation co-efficient-r was determined. Results: The serum levels of IHH and SHH were significantly higher in autistic subjects than those of control subjects. There was significant correlation between age and IHH (r = 0.176, p = 0.03), BDNF and severe IHH (r = 0.1763, p = 0.003), and severe BDNF and severe SHH (r = 0.143, p < 0.001). However, there were no significant relationships among the serum levels of SHH, IHH and BDNF and the CARS score, age or gender. Conclusion: The findings support a correlation between SHH, IHH and BDNF in autistic children, suggesting their pathological role in autism. (author)

  16. Serum levels of brain-derived neurotrophic factor correlate with the number of T2 MRI lesions in multiple sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Comini-Frota, E.R. [Unidade de Neurologia, Hospital Universitário, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, D.H. [Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Miranda, E.C. [Ecoar Diagnostic Center, Belo Horizonte, MG (Brazil); Brum, D.G. [Hospital das Clínicas,Faculdade de Medicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Kaimen-Maciel, D.R. [Unidade de Neurologia, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR (Brazil); Donadi, E.A. [Hospital das Clínicas,Faculdade de Medicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Teixeira, A.L. [Unidade de Neurologia, Hospital Universitário, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2011-11-23

    The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.

  17. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

    Science.gov (United States)

    Rendeiro, Catarina; Vauzour, David; Rattray, Marcus; Waffo-Téguo, Pierre; Mérillon, Jean Michel; Butler, Laurie T; Williams, Claire M; Spencer, Jeremy P E

    2013-01-01

    Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, pmemory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.

  18. Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder

    Directory of Open Access Journals (Sweden)

    Tatiana Lauxen Peruzzolo

    2015-01-01

    Full Text Available Pediatric bipolar disorder (PBD is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder. We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm3, respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD.

  19. Serum brain-derived neurotrophic factor and interleukin-6 response to high-volume mechanically demanding exercise.

    Science.gov (United States)

    Verbickas, Vaidas; Kamandulis, Sigitas; Snieckus, Audrius; Venckunas, Tomas; Baranauskiene, Neringa; Brazaitis, Marius; Satkunskiene, Danguole; Unikauskas, Alvydas; Skurvydas, Albertas

    2018-01-01

    The aim of this study was to follow circulating brain-derived neurotrophic factor (BDNF) and interleukin-6 (IL-6) levels in response to severe muscle-damaging exercise. Young healthy men (N = 10) performed a bout of mechanically demanding stretch-shortening cycle exercise consisting of 200 drop jumps. Voluntary and electrically induced knee extension torque, serum BDNF levels, and IL-6 levels were measured before and for up to 7 days after exercise. Muscle force decreased by up to 40% and did not recover by 24 hours after exercise. Serum BDNF was decreased 1 hour and 24 hours after exercise, whereas IL-6 increased immediately and 1 hour after but recovered to baseline by 24 hours after exercise. IL-6 and 100-Hz stimulation torque were correlated (r = -0.64, P exercise. In response to acute, severe muscle-damaging exercise, serum BDNF levels decrease, whereas IL-6 levels increase and are associated with peripheral fatigue. Muscle Nerve 57: E46-E51, 2018. © 2017 Wiley Periodicals, Inc.

  20. Ciliary Neurotrophic Factor (CNTF) for Macular Telangiectasia Type 2 (MacTel): Results from a phase I safety trial

    Science.gov (United States)

    Chew, Emily Y.; Clemons, Traci E.; Peto, Tunde; Sallo, Ferenc B.; Ingerman, Avner; Tao, Weng; Singerman, Lawrence; Schwartz, Steven D.; Peachey, Neal S.; Bird, Alan C.

    2015-01-01

    PURPOSE To evaluate the safety and tolerability of intraocular delivery of ciliary neurotrophic factor (CNTF) using an encapsulated cell implant for the treatment of macular telangiectasia type 2. DESIGN An open-labeled safety trial conducted in 2 centers enrolling 7 participants with macular telangiectasia type 2. METHODS The participant’s more severely affected eye (worse baseline visual acuity) received the high dose implant of CNTF. Patients were followed for a period of 36 months. The primary safety outcome was a change in the parameters of the electroretinogram (ERG). Secondary efficacy outcomes were changes in visual acuity, en face measurements of the optical coherence tomography of the disruption in the ellipsoid zone, and microperimetry when compared with baseline. RESULTS The ERG findings demonstrated a reduction in the amplitude of the scotopic b-wave in 4 participants 3 months after implantation (month 3). All parameters returned to baseline values by month 12 and remained so at month 36 with no clinical impact on dark adaptation. There was no change in visual acuity compared with baseline. The area of the defect as measured functionally by microperimetry and structurally by the en face OCT imaging of the ellipsoid zone loss appeared unchanged from baseline. CONCLUSIONS The intraocular delivery of CNTF in the encapsulated cell implant appeared to be safe and well tolerated in eyes with macular telangiectasia type 2. Further evaluation in a randomized controlled clinical trial is warranted to test for efficacy. PMID:25528956

  1. Muscle and motor neuron ciliary neurotrophic factor receptor α together maintain adult motor neuron axons in vivo.

    Science.gov (United States)

    Lee, Nancy; Serbinski, Carolyn R; Braunlin, Makayla R; Rasch, Matthew S; Rydyznski, Carolyn E; MacLennan, A John

    2016-12-01

    The molecular mechanisms maintaining adult motor innervation are comparatively unexplored relative to those involved during development. In addition to the fundamental neuroscience question, this area has important clinical ramifications given that loss of neuromuscular contact is thought to underlie several adult onset human neuromuscular diseases including amyotrophic lateral sclerosis. Indirect evidence suggests that ciliary neurotrophic factor (CNTF) receptors may contribute to adult motor neuron axon maintenance. To directly address this in vivo, we used adult onset mouse genetic disruption techniques to deplete motor neuron and muscle CNTF receptor α (CNTFRα), the essential ligand binding subunit of the receptor, and incorporated reporters labelling affected motor neuron axons and terminals. The combined depletion of motor neuron and muscle CNTFRα produced a large loss of motor neuron terminals and retrograde labelling of motor neurons with FluoroGold indicated axon die-back well beyond muscle, together revealing an essential role for CNTFRα in adult motor axon maintenance. In contrast, selective depletion of motor neuron CNTFRα did not affect motor innervation. These data, along with our previous work indicating no effect of muscle specific CNTFRα depletion on motor innervation, suggest that motor neuron and muscle CNTFRα function in concert to maintain motor neuron axons. The data also raise the possibility of motor neuron and/or muscle CNTFRα as therapeutic targets for adult neuromuscular denervating diseases. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  2. The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons.

    Science.gov (United States)

    Couvreur, Odile; Aubourg, Alain; Crépin, Delphine; Degrouard, Jéril; Gertler, Arieh; Taouis, Mohammed; Vacher, Claire-Marie

    2012-02-15

    Ciliary neurotrophic factor (CNTF) is a neural cytokine that reduces appetite and body weight when administrated to rodents or humans. We have demonstrated recently that the level of CNTF in the arcuate nucleus (ARC), a key hypothalamic region involved in food intake regulation, is positively correlated with protection against diet-induced obesity. However, the comprehension of the physiological significance of neural CNTF action was still incomplete because CNTF lacks a signal peptide and thus may not be secreted by the classical exocytosis pathways. Knowing that CNTF distribution shares similarities with that of its receptor subunits in the rat ARC, we hypothesized that CNTF could exert a direct intracrine effect in ARC cells. Here, we demonstrate that CNTF, together with its receptor subunits, translocates to the cell nucleus of anorexigenic POMC neurons in the rat ARC. Furthermore, the stimulation of hypothalamic nuclear fractions with CNTF induces the phosphorylation of several signaling proteins, including Akt, as well as the transcription of the POMC gene. These data strongly suggest that intracellular CNTF may directly modulate POMC gene expression via the activation of receptors localized in the cell nucleus, providing a novel plausible mechanism of CNTF action in regulating energy homeostasis.

  3. Neuroprotective properties of ciliary neurotrophic factor on retinoic acid (RA)-predifferentiated SH-SY5Y neuroblastoma cells.

    Science.gov (United States)

    Wang, Ke; Zhou, Fanfan; Zhu, Xue; Zhang, Kai; Huang, Biao; Zhu, Lan; Zhu, Ling

    2014-01-01

    Ciliary neurotrophic factor (CNTF) is a neurocytokine, which could promote survival and/or differentiation in many cell types. In this study, the biological effects of CNTF on retinoic acid (RA)-predifferentiated SH-SY5Y neuroblastoma cells and the underlying molecular mechanism of this effect were investigated for the first time. The results showed that RA was able to increase cells susceptibility to CNTF via regulating the expression levels of CNTF receptors. A further study revealed that CNTF could induce phosphorylation of STAT3, Akt and ERK1/2 in RA-predifferentiated SH-SY5Y neuroblastoma cells, while the promoting activity of CNTF on survival and neurite growth of cells was attenuated by co-treatment with JAK2 inhibitor AG490 (25 μM), STAT3 inhibitor Curcumin (50 μM), PI3K inhibitor LY-294002 (50 µM), but not by co-treatment with MEK inhibitor PD98059 (50 μM). These findings suggested that JAK2/STAT3, as well as PI3K/Akt, play important roles in mediating the survival and neurite growth response of RA-predifferentiated cells to CNTF. Our study may be useful to further understand the functional role of CNTF and offer a convenient model to explore the therapeutic potential of CNTF in neurodegenerative diseases.

  4. [Evaluation of the concentration of cerebrospinal fluid ciliary neurotrophic factor (CNTF) in patients with purulent, bacterial meningitis--own observations].

    Science.gov (United States)

    Kepa, Lucjan

    2012-01-01

    THE AIM of the study was evaluation of usefulness of cerebrospinal fluid (CSF) ciliary neurotrophic factor (CNTF) concentration assessment in adults with purulent, bacterial meningoencephalitis. The investigation was performed in 14 subjects hospitalized at the Department of Infectious Diseases of Medical University of Silesia in Bytom from 2007 - 2009 due to purulent, bacterial meningoencephalitis. All patients were divided into to groups according to the severity of their clinical condition: I group - very severe course of the disease, II group - moderate and mild course of the disease. In all individuals CSF CNTF concentration was evaluated during the first 24 hours of hospitalization. Mean CSF CNTF concentration in patients in very severe clinical condition (group I) was 14,73 pg/ mL compared to 6,79 pg/mL in subjects of group II with moderate and mild course of disease. The difference between CSF mean concentration of this cytokine was statistically significant (p CNTF concentrations and other CSF inflammatory parameters. Control assays performed in 4 patients from group I revealed evident decrease of CSF CNTF level in fatal course of the disease. In survivals with recovery CSF concentration of this cytokine was only slightly decreased compared to initial level. CONCLUSIONS. The obtained results indicate the usefulness of CSF CNTF concentration assessment in estimation of severity of the patient's clinical condition. The level of this cytokine concentration also seems to be helpful as prognostic marker in purulent, bacterial meningoencephalitis.

  5. Ciliary neurotrophic factor (CNTF): New facets of an old molecule for treating neurodegenerative and metabolic syndrome pathologies.

    Science.gov (United States)

    Pasquin, Sarah; Sharma, Mukut; Gauchat, Jean-François

    2015-10-01

    Ciliary neurotrophic factor (CNTF) is the most extensively studied member of the cytokine family that signal through intracellular chains of the gp130/LIFRβ receptor. The severe phenotype in patients suffering from mutations inactivating LIFRβ indicates that members of this cytokine family play key, non-redundant roles during development. Accordingly, three decades of research has revealed potent and promising trophic and regulatory activities of CNTF in neurons, oligodendrocytes, muscle cells, bone cells, adipocytes and retinal cells. These findings led to clinical trials to test the therapeutic potential of CNTF and CNTF derivatives for treating neurodegenerative and metabolic diseases. Promising results have encouraged continuation of studies for treating retinal degenerative diseases. Results of some clinical trials showed that side-effects may limit the systemically administrated doses of CNTF. Therefore, therapies being currently tested rely on local delivery of CNTF using encapsulated cytokine-secreting implants. Since the side effects of CNTF might be linked to its ability to activate the alternative IL6Rα-LIFRβ-gp130 receptor, CNTFR-specific mutants of CNTF have been developed that bind to the CNTFRα-LIFRβ-gp130 receptor. These developments may prove to be a breakthrough for therapeutic applications of systemically administered CNTF in pathologies such as multiple sclerosis or Alzheimer's disease. The "designer cytokine approach" offers future opportunities to further enhance specificity by conjugating mutant CNTF with modified soluble CNTFRα to target therapeutically relevant cells that express gp130-LIFRβ and a specific cell surface marker. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Expression of a fusion protein of human ciliary neurotrophic factor and soluble CNTF-receptor and identification of its activity.

    Science.gov (United States)

    Sun, Yi; Pia, März; Uwe, Otten; Ge, Ji-Guang; Stefan, Rose-John

    2003-01-01

    Ciliary neurotrophic factor (CNTF) has pleiotropic actions on many neuronal populations as well as on glia. Signal transduction by CNTF requires that it bind first to CNTF-R, permitting the recruitment of gp130 and LIF-R, forming a tripartite receptor complex. Cells that only express gp130 and LIF-R, but not CNTF-R are refractory to stimulation by CNTF. On many target cells CNTF only acts in the presence of its specific agonistic soluble receptors. We engineered a soluble fusion protein by linking the COOH-terminus of sCNTF-R to the NH2-terminus of CNTF. Recombinant CNTF/sCNTF-R fusion protein (Hyper-CNTF) was successfully expressed in COS-7 cells. The apparent molecular mass of the Hyper-CNTF protein was estimated from western blots to be 75 kDa. Proliferation assays of transfected BAF/3 cells in response to CNTF and Hyper-CNTF were used to verify the activity of the cytokines. The proliferative results confirmed that CNTF required homodimerization of the gp130, CNTF-R and LIF-R receptor subunit whereas Hyper-CNTF required heterodimerization of the gp130 and LIF-R receptor subunit. We concluded that the fusion protein Hyper-CNTF had superagonistic activity on target cells expressing gp130 and LIF-R, but lacking membrane-bound CNTF-R.

  7. Effect of Locally Administered Ciliary Neurotrophic Factor on the Survival of Transected and Repaired Adult Sheep Facial Nerve

    Directory of Open Access Journals (Sweden)

    Rashid Al Abri

    2014-05-01

    Full Text Available Objective: to determine whether the administration of Ciliary Neurotrophic Factor (CNTF at the site of repaired facial nerve enhances regeneration in the adult sheep model. Methods: Ten adult sheep were divided into 2 groups: control and study group (CNTF group. In the CNTF group, the buccal branch of the facial nerve was transected and then repaired by epineural sutures. CNTF was injected over the left depressor labii maxillaris muscle in the vicinity of the transected and repaired nerve for 28 days under local anesthesia. In the CNTF group, the sheep were again anesthetized after nine months and the site of facial nerve repair was exposed. Detailed electrophysiological, tension experiments and morphometric studies were carried out and then analyzed statistically. Results: The skin CV min, refractory period, Jitter and tension parameters were marginally raised in the CNTF group than the control but the difference was statistically insignificant between the two groups. Morphometric indices also did not show any significant changes in the CNTF group. Conclusion: CNTF has no profound effect on neuronal regeneration of adult sheep animal model.

  8. Expression of ciliary neurotrophic factor (CNTF) and its tripartite receptor complex by cells of the human optic nerve head.

    Science.gov (United States)

    Liu, Xiaochun; Clark, Abbot F; Wordinger, Robert J

    2007-05-23

    Ciliary neurotrophic factor (CNTF) promotes gene expression, cell survival and differentiation in various types of peripheral and central neurons, glia and nonneural cells. The level of CNTF rises rapidly upon injury to neural tissue, suggesting that CNTF exerts its cytoprotective effects after release from cells via mechanisms induced by cell injury. The purpose of this study was to determine if cells in the optic nerve head express CNTF and its tripartite receptor complex. Well-established optic nerve head astrocytes (ONHA) and lamina cribrosa (LC) cell cultures were derived from normal human donors. Total RNA was reverse transcribed and polymerase chain reaction (PCR) amplified for mRNA detection. Cytoplasmic protein expression was determined by immunocytochemistry and Western blot analysis of the cellular lysates. Serum free medium was concentrated and used for detecting extracellular proteins. CNTF complexed with CNTFR-alpha was assayed by immunoprecipitation. Cells isolated from the human optic nerve head express CNTF and its tripartite receptor complex members (CNTFR-alpha, gp130, LIFR-beta). Taken together, these data suggest a possible neuroprotective role of CNTF in the optic nerve head.

  9. Collagen scaffolds combined with collagen-binding ciliary neurotrophic factor facilitate facial nerve repair in mini-pigs.

    Science.gov (United States)

    Lu, Chao; Meng, Danqing; Cao, Jiani; Xiao, Zhifeng; Cui, Yi; Fan, Jingya; Cui, Xiaolong; Chen, Bing; Yao, Yao; Zhang, Zhen; Ma, Jinling; Pan, Juli; Dai, Jianwu

    2015-05-01

    The preclinical studies using animal models play a very important role in the evaluation of facial nerve regeneration. Good models need to recapitulate the distance and time for axons to regenerate in humans. Compared with the most used rodent animals, the structure of facial nerve in mini-pigs shares more similarities with humans in microanatomy. To evaluate the feasibility of repairing facial nerve defects by collagen scaffolds combined with ciliary neurotrophic factor (CNTF), 10-mm-long gaps were made in the buccal branch of mini-pigs' facial nerve. Three months after surgery, electrophysiological assessment and histological examination were performed to evaluate facial nerve regeneration. Immunohistochemistry and transmission electron microscope observation showed that collagen scaffolds with collagen binding (CBD)-CNTF could promote better axon regeneration, Schwann cell migration, and remyelination at the site of implant device than using scaffolds alone. Electrophysiological assessment also showed higher recovery rate in the CNTF group. In summary, combination of collagen scaffolds and CBD-CNTF showed promising effects on facial nerve regeneration in mini-pig models. © 2014 Wiley Periodicals, Inc.

  10. CCK-4-induced anxiety but not panic is associated with serum brain-derived neurotrophic factor in healthy subjects.

    Science.gov (United States)

    Maron, E; Tõru, I; Mäemets, K; Sepp, S; Vasar, V; Shlik, J; Zharkovsky, A

    2009-06-01

    Recent animal studies consistently confirm the involvement of brain-derived neurotrophic factor (BDNF) in the regulation of anxiety-related behaviours. The role of BDNF in human anxiety has been less investigated. The aim of our study was to examine the association between serum BDNF levels and panic/anxiety responses to cholecystokinin-tetrapeptide (CCK-4) challenge in healthy subjects. BDNF concentrations were detected in serum samples of 37 male and female volunteers before and 120 min after CCK-4 injection. The baseline levels of serum BDNF did not predict the occurrence of CCK-4-induced panic attacks or intensity of panic symptoms and did not significantly change 2 h after the challenge. BDNF serum concentrations 120 min after provocation did not differentiate panickers from non-panickers; however, the subjects reporting stronger anxiety response showed higher levels of BDNF than those with mild anxiety. The anxiety net increase on the Visual Analogue Scale, but not severity of panic symptoms, significantly and positively correlated with the change in BDNF concentration from baseline values. This is the first challenge study to demonstrate a possible impact of BDNF on human anxiety. Our findings suggest a general involvement of BDNF in the regulation of anxiety rather than a specific role of BDNF in disposition to panic attacks.

  11. Dietary levels of pure flavonoids improve spatial memory performance and increase hippocampal brain-derived neurotrophic factor.

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    Catarina Rendeiro

    Full Text Available Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w, results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively, to a similar extent to that following blueberry supplementation (p = 0.002. These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, p<0.01, suggesting a common mechanism for the enhancement of memory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods.

  12. Antidepressant-Like Effects of Acupuncture-Insights From DNA Methylation and Histone Modifications of Brain-Derived Neurotrophic Factor

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    Huili Jiang

    2018-03-01

    Full Text Available Sensitive and stable biomarkers that facilitate depression detection and monitor the antidepressant efficiency are currently unavailable. Thus, the objective is to investigate the potential of DNA methylation and histone modifications of brain-derived neurotrophic factor (BDNF in monitoring severity and antidepressive effects of acupuncture. The depression rat model was imitated by social isolation and chronic unpredicted mild stress (CUMS. The expression of serum BDNF was detected by enzyme-linked immunosorbent assay (ELISA, the hippocampal BDNF, acetylation levels in histone H3 lysine 9 (acH3K9, and HDAC2 by Western blot, the hippocampal mRNA of BDNF by RT-polymerase chain reaction (PCR. The DNA methylation patterns of the promoter I of BDNF was detected by MS-PCR. We investigated that the expression of BDNF in serum and hippocampus were significantly downregulated compared with controls. The same trend was found in mRNA of BDNF. Notably, acupuncture reversed the downregulation of BDNF in serum and hippocampus and mRNA of BDNF compared with model group. Acupuncture reversed the CUMS-induced downregulation of hippocampal acH3K9. On the contrary, the CUMS-induced upregulation of hippocampal HDAC2 in model group was significantly reversed by acupuncture. Collectively, the antidepressant effect of acupuncture might be mediated by regulating the DNA methylation and histone modifications of BDNF, which may represent novel biomaker for detection of depression and monitoring severity and antidepressive effects.

  13. Cross-sectional associations of objectively measured physical activity with brain-derived neurotrophic factor in adolescents.

    Science.gov (United States)

    Huang, Tao; Gejl, Anne Kær; Tarp, Jakob; Andersen, Lars Bo; Peijs, Lone; Bugge, Anna

    2017-03-15

    The purpose of this study was to examine the associations between objectively measured physical activity and serum brain-derived neurotrophic factor (BDNF) in adolescents. Cross-sectional analyses were performed using data from 415 adolescents who participated in the 2015 follow-up of the Childhood Health Activity and Motor Performance School Study Denmark (the CHAMPS-study DK). Physical activity was objectively measured by accelerometry monitors. Serum BDNF levels were analyzed using the Enzyme-linked immunosorbent assay (ELISA). Anthropometrics and pubertal status were measured using standardized procedures. With adjustment for age, pubertal status and body mass index, mean physical activity (counts per minute) was negatively associated with serum BDNF in boys (P=0.013). Similarly, moderate-to-vigorous physical activity (MVPA) was negatively associated with serum BDNF in boys (P=0.035). In girls, mean physical activity and MVPA were not associated with serum BDNF. Without adjustment for wear time, sedentary time was not associated with serum BDNF in either sex. These findings indicate that higher physical activity is associated with lower serum BDNF in boys, but not in girls. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Exercise in the Early Stage after Stroke Enhances Hippocampal Brain-Derived Neurotrophic Factor Expression and Memory Function Recovery.

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    Himi, Naoyuki; Takahashi, Hisashi; Okabe, Naohiko; Nakamura, Emi; Shiromoto, Takashi; Narita, Kazuhiko; Koga, Tomoshige; Miyamoto, Osamu

    2016-12-01

    Exercise in the early stage after stroke onset has been shown to facilitate the recovery from physical dysfunction. However, the mechanism of recovery has not been clarified. In this study, the effect of exercise on spatial memory function recovery in the early stage was shown, and the mechanism of recovery was discussed using a rat model of brain embolism. Intra-arterial microsphere (MS) injection induced small emboli in the rat brain. Treadmill exercise was started at 24 hours (early group) or 8 days (late group) after MS injection. The non-exercise (NE) and sham-operated groups were included as controls. Memory function was evaluated by the Morris water maze test, and hippocampal levels of brain-derived neurotrophic factor (BDNF) were measured by enzyme-linked immunosorbent assays. To further investigate the effect of BDNF on memory function, BDNF was continuously infused into the hippocampus via implantable osmotic pumps in the early or late stage after stroke. Memory function significantly improved only in the early group compared with the late and the NE groups, although hippocampal BDNF concentrations were temporarily elevated after exercise in both the early and the late groups. Rats infused with BDNF in the early stage exhibited significant memory function recovery; however, rats that received BDNF infusion in the late stage showed no improvement. Exercise elevates hippocampal BDNF levels in the early stage after cerebral embolism, and this event facilitates memory function recovery. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Sympathetic Innervation Induced in Engrafted Engineered Cardiomyocyte Sheets by Glial Cell Line Derived Neurotrophic Factor In Vivo

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    Xian-ming Fu

    2013-01-01

    Full Text Available The aim of myocardial tissue engineering is to repair or regenerate damaged myocardium with engineered cardiac tissue. However, this strategy has been hampered by lack of functional integration of grafts with native myocardium. Autonomic innervation may be crucial for grafts to function properly with host myocardium. In this study, we explored the feasibility of in vivo induction of autonomic innervation to engineered myocardial tissue using genetic modulation by adenovirus encoding glial cell line derived neurotrophic factor (GDNF. GFP-transgene (control group or GDNF overexpressing (GDNF group engineered cardiomyocyte sheets were transplanted on cryoinjured hearts in rats. Nerve fibers in the grafts were examined by immunohistochemistry at 1, 2, and 4 weeks postoperatively. Growth associated protein-43 positive growing nerves and tyrosine hydroxylase positive sympathetic nerves were first detected in the grafts at 2 weeks postoperatively in control group and 1 week in GDNF group. The densities of growing nerve and sympathetic nerve in grafts were significantly increased in GDNF group. No choline acetyltransferase immunopositive parasympathetic nerves were observed in grafts. In conclusion, sympathetic innervation could be effectively induced into engrafted engineered cardiomyocyte sheets using GDNF.

  16. Brain-Derived Neurotrophic Factor Expression in Individuals With Schizophrenia and Healthy Aging: Testing the Accelerated Aging Hypothesis of Schizophrenia.

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    Islam, Farhana; Mulsant, Benoit H; Voineskos, Aristotle N; Rajji, Tarek K

    2017-07-01

    Schizophrenia has been hypothesized to be a syndrome of accelerated aging. Brain plasticity is vulnerable to the normal aging process and affected in schizophrenia: brain-derived neurotrophic factor (BDNF) is an important neuroplasticity molecule. The present review explores the accelerated aging hypothesis of schizophrenia by comparing changes in BDNF expression in schizophrenia with aging-associated changes. Individuals with schizophrenia show patterns of increased overall mortality, metabolic abnormalities, and cognitive decline normally observed later in life in the healthy population. An overall decrease is observed in BDNF expression in schizophrenia compared to healthy controls and in older individuals compared to a younger cohort. There is a marked decrease in BDNF levels in the frontal regions and in the periphery among older individuals and those with schizophrenia; however, data for BDNF expression in the occipital, parietal, and temporal cortices and the hippocampus is inconclusive. Accelerated aging hypothesis is supported based on frontal regions and peripheral studies; however, further studies are needed in other brain regions.

  17. Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.

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    Yukiko Doi

    Full Text Available The neurodegenerative processes that underlie Alzheimer's disease are mediated, in part, by soluble oligomeric amyloid β, a neurotoxic protein that inhibits hippocampal long-term potentiation, disrupts synaptic plasticity, and induces the production of reactive oxygen species. Here we show that the sphingosine-1-phosphate (S1P receptor (S1PR agonist fingolimod phosphate (FTY720-P-a new oral drug for multiple sclerosis-protects neurons against oligomeric amyloid β-induced neurotoxicity. We confirmed that primary mouse cortical neurons express all of the S1P receptor subtypes and FTY720-P directly affects the neurons. Treatment with FTY720-P enhanced the expression of brain-derived neurotrophic factor (BDNF in neurons. Moreover, blocking BDNF-TrkB signaling with a BDNF scavenger, TrkB inhibitor, or ERK1/2 inhibitor almost completely ablated these neuroprotective effects. These results suggested that the neuroprotective effects of FTY720-P are mediated by upregulated neuronal BDNF levels. Therefore, FTY720-P may be a promising therapeutic agent for neurodegenerative diseases, such as Alzheimer's disease.

  18. Serum concentrations of brain-derived neurotrophic factor in patients diagnosed with gender dysphoria undergoing sex reassignment surgery

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    Maiko A. Schneider

    Full Text Available Abstract Introduction: Transsexualism (ICD-10 is a condition characterized by a strong and persistent dissociation with one's assigned gender. Sex reassignment surgery (SRS and hormone therapy provide a means of allowing transsexual individuals to feel more congruent with their gender and have played a major role in treatment over the past 70 years. Brain-derived neurotrophic factor (BDNF appears to play a key role in recovery from acute surgical trauma and environmentally mediated vulnerability to psychopathology. We hypothesize that BDNF may be a biomarker of alleviation of gender incongruence suffering. Objectives: To measure preoperative and postoperative serum BDNF levels in transsexual individuals as a biomarker of alleviation of stress related to gender incongruence after SRS. Methods: Thirty-two male-to-female transsexual people who underwent both surgery and hormonal treatment were selected from our initial sample. BDNF serum levels were assessed before and after SRS with sandwich enzyme linked immunosorbent assay (ELISA. The time elapsed between the pre-SRS and post-SRS blood collections was also measured. Results: No significant difference was found in pre-SRS or post-SRS BDNF levels or with relation to the time elapsed after SRS when BDNF levels were measured. Conclusion: Alleviation of the suffering related to gender incongruence after SRS cannot be assessed by BDNF alone. Surgical solutions may not provide a quick fix for psychological distress associated with transsexualism and SRS may serve as one step toward, rather than as the conclusion of, construction of a person's gender identity.

  19. Serum concentrations of brain-derived neurotrophic factor in patients diagnosed with gender dysphoria undergoing sex reassignment surgery.

    Science.gov (United States)

    Schneider, Maiko A; Andreazza, Tahiana; Fontanari, Anna Martha V; Costa, Angelo B; Silva, Dhiordan C da; Aguiar, Bianca W de; Massuda, Raffael; Pedrini, Mariana; Gama, Clarissa S; Schwarz, Karine; Kauer-Sant'Anna, Marcia; Lobato, Maria Ines R

    2017-01-01

    Transsexualism (ICD-10) is a condition characterized by a strong and persistent dissociation with one's assigned gender. Sex reassignment surgery (SRS) and hormone therapy provide a means of allowing transsexual individuals to feel more congruent with their gender and have played a major role in treatment over the past 70 years. Brain-derived neurotrophic factor (BDNF) appears to play a key role in recovery from acute surgical trauma and environmentally mediated vulnerability to psychopathology. We hypothesize that BDNF may be a biomarker of alleviation of gender incongruence suffering. To measure preoperative and postoperative serum BDNF levels in transsexual individuals as a biomarker of alleviation of stress related to gender incongruence after SRS. Thirty-two male-to-female transsexual people who underwent both surgery and hormonal treatment were selected from our initial sample. BDNF serum levels were assessed before and after SRS with sandwich enzyme linked immunosorbent assay (ELISA). The time elapsed between the pre-SRS and post-SRS blood collections was also measured. No significant difference was found in pre-SRS or post-SRS BDNF levels or with relation to the time elapsed after SRS when BDNF levels were measured. Alleviation of the suffering related to gender incongruence after SRS cannot be assessed by BDNF alone. Surgical solutions may not provide a quick fix for psychological distress associated with transsexualism and SRS may serve as one step toward, rather than as the conclusion of, construction of a person's gender identity.

  20. The associations between serum brain-derived neurotrophic factor, potential confounders, and cognitive decline: a longitudinal study.

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    Jasmine Nettiksimmons

    Full Text Available Brain-derived neurotrophic factor (BDNF plays a role in the maintenance and function of neurons. Although persons with Alzheimer's disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression, suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline.

  1. Plasma brain-derived neurotrophic factor levels, learning capacity and cognition in patients with first episode psychosis

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    de Azua Sonia Ruiz

    2013-01-01

    Full Text Available Abstract Background Cognitive impairments are seen in first psychotic episode (FEP patients. The neurobiological underpinnings that might underlie these changes remain unknown. The aim of this study is to investigate whether Brain Derived Neurotrophic Factor (BDNF levels are associated with cognitive impairment in FEP patients compared with healthy controls. Methods 45 FEP patients and 45 healthy controls matched by age, gender and educational level were selected from the Basque Country area of Spain. Plasma BDNF levels were assessed in healthy controls and in patients. A battery of cognitive tests was applied to both groups, with the patients being assessed at 6 months after the acute episode and only in those with a clinical response to treatment. Results Plasma BDNF levels were altered in patients compared with the control group. In FEP patients, we observed a positive association between BDNF levels at six months and five cognitive domains (learning ability, immediate and delayed memory, abstract thinking and processing speed which persisted after controlling for medications prescribed, drug use, intelligence quotient (IQ and negative symptoms. In the healthy control group, BDNF levels were not associated with cognitive test scores. Conclusion Our results suggest that BDNF is associated with the cognitive impairment seen after a FEP. Further investigations of the role of this neurotrophin in the symptoms associated with psychosis onset are warranted.

  2. Correlations of recognition memory performance with expression and methylation of brain-derived neurotrophic factor in rats

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    Pablo C Muñoz

    2010-01-01

    Full Text Available Object recognition memory allows discrimination between novel and familiar objects. This kind of memory consists of two components: recollection, which depends on the hippocampus, and familiarity, which depends on the perirhinal cortex (Pcx. The importance of brain-derived neurotrophic factor (BDNF for recognition memory has already been recognized. Recent evidence suggests that DNA methylation regulates the expression of BDNF and memory. Behavioral and molecular approaches were used to understand the potential contribution of DNA methylation to recognition memory. To that end, rats were tested for their ability to distinguish novel from familiar objects by using a spontaneous object recognition task. Furthermore, the level of DNA methylation was estimated after trials with a methyl-sensitive PCR. We found a signifcant correlation between performance on the novel object task and the expression of BDNF, negatively in hippocampal slices and positively in perirhinal cortical slices. By contrast, methylation of DNA in CpG island 1 in the promoter of exon 1 in BDNF only correlated in hippocampal slices, but not in the Pxc cortical slices from trained animals. These results suggest that DNA methylation may be involved in the regulation of the BDNF gene during recognition memory, at least in the hippocampus.

  3. Delivery of Brain-Derived Neurotrophic Factor by 3D Biocompatible Polymeric Scaffolds for Neural Tissue Engineering and Neuronal Regeneration

    KAUST Repository

    Limongi, Tania

    2018-04-04

    Biopolymers are increasingly employed for neuroscience applications as scaffolds to drive and promote neural regrowth, thanks to their ability to mediate the upload and subsequent release of active molecules and drugs. Synthetic degradable polymers are characterized by different responses ranging from tunable distension or shrinkage to total dissolution, depending on the function they are designed for. In this paper we present a biocompatible microfabricated poly-ε-caprolactone (PCL) scaffold for primary neuron growth and maturation that has been optimized for the in vitro controlled release of brain-derived neurotrophic factor (BDNF). We demonstrate that the designed morphology confers to these devices an enhanced drug delivery capability with respect to monolithic unstructured supports. After incubation with BDNF, micropillared PCL devices progressively release the neurotrophin over 21 days in vitro. Moreover, the bioactivity of released BDNF is confirmed using primary neuronal cultures, where it mediates a consistent activation of BDNF signaling cascades, increased synaptic density, and neuronal survival. These results provide the proof-of-principle on the fabrication process of micropatterned PCL devices, which represent a promising therapeutic option to enhance neuronal regeneration after lesion and for neural tissue engineering and prosthetics.

  4. Acute high-intensity exercise-induced cognitive enhancement and brain-derived neurotrophic factor in young, healthy adults.

    Science.gov (United States)

    Hwang, Jungyun; Brothers, R Matthew; Castelli, Darla M; Glowacki, Elizabeth M; Chen, Yen T; Salinas, Mandy M; Kim, Jihoon; Jung, Yeonhak; Calvert, Hannah G

    2016-09-06

    Acute exercise can positively impact cognition. The present study examined the effect of acute high-intensity aerobic exercise on prefrontal-dependent cognitive performance and brain-derived neurotrophic factor (BDNF). Fifty-eight young adults were randomly assigned to one of two experimental groups: (a) an acute bout of high-intensity exercise (n=29) or (b) a non-exercise control (n=29). Participants in the exercise group improved performance on inhibitory control in Stroop interference and on cognitive flexibility in Trail Making Test (TMT) Part-B compared with participants in the control group and increased BDNF immediately after exercise. There was a significant relationship between BDNF and TMT Part-B on the pre-post change following exercise. These findings provide support for the association between improved prefrontal-dependent cognitive performance and increased BDNF in response to acute exercise. We conclude that the changes in BDNF concentration may be partially responsible for prefrontal-dependent cognitive functioning following an acute bout of exercise. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Role of two sequence motifs of mesencephalic astrocyte-derived neurotrophic factor in its survival-promoting activity.

    Science.gov (United States)

    Mätlik, K; Yu, Li-ying; Eesmaa, A; Hellman, M; Lindholm, P; Peränen, J; Galli, E; Anttila, J; Saarma, M; Permi, P; Airavaara, M; Arumäe, U

    2015-12-31

    Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a prosurvival protein that protects the cells when applied intracellularly in vitro or extracellularly in vivo. Its protective mechanisms are poorly known. Here we studied the role of two short sequence motifs within the carboxy-(C) terminal domain of MANF in its neuroprotective activity: the CKGC sequence (a CXXC motif) that could be involved in redox reactions, and the C-terminal RTDL sequence, an endoplasmic reticulum (ER) retention signal. We mutated these motifs and analyzed the antiapoptotic effect and intracellular localization of these mutants of MANF when overexpressed in cultured sympathetic or sensory neurons. As an in vivo model for studying the effect of these mutants after their extracellular application, we used the rat model of cerebral ischemia. Even though we found no evidence for oxidoreductase activity of MANF, the mutation of CXXC motif completely abolished its protective effect, showing that this motif is crucial for both MANF's intracellular and extracellular activity. The RTDL motif was not needed for the neuroprotective activity of MANF after its extracellular application in the stroke model in vivo. However, in vitro the deletion of RTDL motif inactivated MANF in the sympathetic neurons where the mutant protein localized to Golgi, but not in the sensory neurons where the mutant localized to the ER, showing that intracellular MANF protects these peripheral neurons in vitro only when localized to the ER.

  6. Preservation of general intelligence following traumatic brain injury: contributions of the Met66 brain-derived neurotrophic factor.

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    Aron K Barbey

    Full Text Available Brain-derived neurotrophic factor (BDNF promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI. In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156 consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points, verbal comprehension (6 IQ points, perceptual organization (6 IQ points, working memory (8 IQ points, and processing speed (8 IQ points after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI.

  7. Dietary Levels of Pure Flavonoids Improve Spatial Memory Performance and Increase Hippocampal Brain-Derived Neurotrophic Factor

    Science.gov (United States)

    Rendeiro, Catarina; Vauzour, David; Rattray, Marcus; Waffo-Téguo, Pierre; Mérillon, Jean Michel; Butler, Laurie T.; Williams, Claire M.; Spencer, Jeremy P. E.

    2013-01-01

    Evidence suggests that flavonoid-rich foods are capable of inducing improvements in memory and cognition in animals and humans. However, there is a lack of clarity concerning whether flavonoids are the causal agents in inducing such behavioral responses. Here we show that supplementation with pure anthocyanins or pure flavanols for 6 weeks, at levels similar to that found in blueberry (2% w/w), results in an enhancement of spatial memory in 18 month old rats. Pure flavanols and pure anthocyanins were observed to induce significant improvements in spatial working memory (p = 0.002 and p = 0.006 respectively), to a similar extent to that following blueberry supplementation (p = 0.002). These behavioral changes were paralleled by increases in hippocampal brain-derived neurotrophic factor (R = 0.46, pmemory. However, unlike protein levels of BDNF, the regional enhancement of BDNF mRNA expression in the hippocampus appeared to be predominantly enhanced by anthocyanins. Our data support the claim that flavonoids are likely causal agents in mediating the cognitive effects of flavonoid-rich foods. PMID:23723987

  8. Histone deacetylase activity and brain-derived neurotrophic factor (BDNF levels in a pharmacological model of mania

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    Laura Stertz

    2014-03-01

    Full Text Available Objective: In the present study, we aimed to examine the effects of repeated D-amphetamine (AMPH exposure, a well-accepted animal model of acute mania in bipolar disorder (BD, and histone deacetylase (HDAC inhibitors on locomotor behavior and HDAC activity in the prefrontal cortex (PFC and peripheral blood mononuclear cells (PBMCs of rats. Moreover, we aimed to assess brain-derived neurotrophic factor (BDNF protein and mRNA levels in these samples. Methods: We treated adult male Wistar rats with 2 mg/kg AMPH or saline intraperitoneally for 14 days. Between the 8th and 14th days, rats also received 47.5 mg/kg lithium (Li, 200 mg/kg sodium valproate (VPT, 2 mg/kg sodium butyrate (SB, or saline. We evaluated locomotor activity in the open-field task and assessed HDAC activity in the PFC and PBMCs, and BDNF levels in the PFC and plasma. Results: AMPH significantly increased locomotor activity, which was reversed by all drugs. This hyperactivity was associated with increased HDAC activity in the PFC, which was partially reversed by Li, VPT, and SB. No differences were found in BDNF levels. Conclusion: Repeated AMPH administration increases HDAC activity in the PFC without altering BDNF levels. The partial reversal of HDAC increase by Li, VPT, and SB may account for their ability to reverse AMPH-induced hyperactivity.

  9. Zirconium oxide ceramic foam: a promising supporting biomaterial for massive production of glial cell line-derived neurotrophic factor.

    Science.gov (United States)

    Liu, Zhong-wei; Li, Wen-qiang; Wang, Jun-kui; Ma, Xian-cang; Liang, Chen; Liu, Peng; Chu, Zheng; Dang, Yong-hui

    2014-12-01

    This study investigated the potential application of a zirconium oxide (ZrO2) ceramic foam culturing system to the production of glial cell line-derived neurotrophic factor (GDNF). Three sets of ZrO2 ceramic foams with different pore densities of 10, 20, and 30 pores per linear inch (PPI) were prepared to support a 3D culturing system. After primary astrocytes were cultured in these systems, production yields of GDNF were evaluated. The biomaterial biocompatibility, cell proliferation and activation of cellular signaling pathways in GDNF synthesis and secretion in the culturing systems were also assessed and compared with a conventional culturing system. In this study, we found that the ZrO2 ceramic foam culturing system was biocompatible, using which the GDNF yields were elevated and sustained by stimulated cell proliferation and activation of signaling pathways in astrocytes cultured in the system. In conclusion, the ZrO2 ceramic foam is promising for the development of a GDNF mass production device for Parkinson's disease treatment.

  10. DNA methylation profiles of the brain-derived neurotrophic factor (BDNF gene as a potent diagnostic biomarker in major depression.

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    Manabu Fuchikami

    Full Text Available Major depression, because of its recurring and life-threatening nature, is one of the top 10 diseases for global disease burden. Major depression is still diagnosed on the basis of clinical symptoms in patients. The search for specific biological markers is of great importance to advance the method of diagnosis for depression. We examined the methylation profile of 2 CpG islands (I and IV at the promoters of the brain-derived neurotrophic factor (BDNF gene, which is well known to be involved in the pathophysiology of depression. We analyzed genomic DNA from peripheral blood of 20 Japanese patients with major depression and 18 healthy controls to identify an appropriate epigenetic biomarker to aid in the establishment of an objective system for the diagnosis of depression. Methylation rates at each CpG unit was measured using a MassArray® system (SEQUENOM, and 2-dimensional hierarchical clustering analyses were undertaken to determine the validity of these methylation profiles as a diagnostic biomarker. Analyses of the dendrogram from methylation profiles of CpG I, but not IV, demonstrated that classification of healthy controls and patients at the first branch completely matched the clinical diagnosis. Despite the small number of subjects, our results indicate that classification based on the DNA methylation profiles of CpG I of the BDNF gene may be a valuable diagnostic biomarker for major depression.

  11. The Effect of Exercise Training on Resting Concentrations of Peripheral Brain-Derived Neurotrophic Factor (BDNF: A Meta-Analysis.

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    Adam Dinoff

    Full Text Available The mechanisms through which physical activity supports healthy brain function remain to be elucidated. One hypothesis suggests that increased brain-derived neurotrophic factor (BDNF mediates some cognitive and mood benefits. This meta-analysis sought to determine the effect of exercise training on resting concentrations of BDNF in peripheral blood.MEDLINE, Embase, PsycINFO, SPORTDiscus, Rehabilitation & Sports Medicine Source, and CINAHL databases were searched for original, peer-reviewed reports of peripheral blood BDNF concentrations before and after exercise interventions ≥ 2 weeks. Risk of bias was assessed using standardized criteria. Standardized mean differences (SMDs were generated from random effects models. Risk of publication bias was assessed using funnel plots and Egger's test. Potential sources of heterogeneity were explored in subgroup analyses.In 29 studies that met inclusion criteria, resting concentrations of peripheral blood BDNF were higher after intervention (SMD = 0.39, 95% CI: 0.17-0.60, p < 0.001. Subgroup analyses suggested a significant effect in aerobic (SMD = 0.66, 95% CI: 0.33-0.99, p < 0.001 but not resistance training (SMD = 0.07, 95% CI: -0.15-0.30, p = 0.52 interventions. No significant difference in effect was observed between males and females, nor in serum vs plasma.Aerobic but not resistance training interventions increased resting BDNF concentrations in peripheral blood.

  12. Brain-Derived Neurotrophic Factor Attenuates Septic Myocardial Dysfunction via eNOS/NO Pathway in Rats

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    Ni Zeng

    2017-01-01

    Full Text Available Sepsis-induced myocardial dysfunction increases mortality in sepsis, yet the underlying mechanism is unclear. Brain-derived neurotrophic factor (BDNF has been found to enhance cardiomyocyte function, but whether BDNF has a beneficial effect against septic myocardial dysfunction is unknown. Septic shock was induced by cecal ligation and puncture (CLP. BDNF was expressed in primary cardiomyocytes, and its expression was significantly reduced after sepsis. In rats with sepsis, a sharp decline in survival was observed after CLP, with significantly reduced cardiac BDNF expression, enhanced myocardial fibrosis, elevated oxidative stress, increased myocardial apoptosis, and decreased endothelial nitric oxide (NO synthase (eNOS and NO. Supplementation with recombined BDNF protein (rhBDNF enhanced myocardial BDNF and increased survival rate with improved cardiac function, reduced oxidative stress, and myocardial apoptosis, which were associated with increased eNOS expression, NO production, and Trk-B, a BDNF receptor. Pretreatment with NOS inhibitor, N (omega-nitro-L-arginine methyl ester, abolished the abovementioned BDNF cardioprotective effects without affecting BDNF and Trk-B. It is concluded that BDNF protects the heart against septic cardiac dysfunction by reducing oxidative stress and apoptosis via Trk-B, and it does so through activation of eNOS/NO pathway. These findings provide a new treatment strategy for sepsis-induced myocardial dysfunction.

  13. Impaired glyoxalase activity is associated with reduced expression of neurotrophic factors and pro-inflammatory processes in diabetic skin cells.

    Science.gov (United States)

    Reichert, Olga; Fleming, Thomas; Neufang, Gitta; Schmelz, Martin; Genth, Harald; Kaever, Volkhard; Wenck, Horst; Stäb, Franz; Terstegen, Lara; Kolbe, Ludger; Roggenkamp, Dennis

    2017-01-01

    Patients suffering from type II diabetes develop several skin manifestations including cutaneous infections, diabetic dermopathy, diabetic bullae and acanthosis nigricans. Diabetic micro- and macroangiopathy as well as diabetic neuropathy are believed to play a crucial role in the development of diabetic skin disorders. A reduced cutaneous nerve fibre density was reported in diabetic subjects, which subsequently leads to impaired sensory nerve functions. Using an innervated skin model, we investigated the impact of human diabetic dermal fibroblasts and keratinocytes on porcine sensory neurons. Diabetic skin cells showed a reduced capacity to induce neurite outgrowth due to a decreased support with neurotrophic factors, such as NGF. Furthermore, diabetic keratinocytes displayed insulin resistance and increased expression of pro-inflammatory cytokines demonstrating the persistent effect of diabetes mellitus on human skin cells. Dysregulations were related to a significantly reduced glyoxalase enzyme activity in diabetic keratinocytes as experimentally reduced glyoxalase activity mimicked the increase in pro-inflammatory cytokine expression and reduction in NGF. Our results demonstrate an impaired crosstalk of diabetic skin cells and sensory neurons favouring hypo-innervation. We suggest that reduced methylglyoxal detoxification contributes to an impaired neurocutaneous interaction in diabetic skin. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Prefrontal cortex modulates the correlations between brain-derived neurotrophic factor level, serotonin, and the autonomic nervous system.

    Science.gov (United States)

    Chang, Wei Hung; Lee, I Hui; Chi, Mei Hung; Lin, Shih-Hsien; Chen, Kao Chin; Chen, Po See; Chiu, Nan Tsing; Yao, Wei Jen; Yang, Yen Kuang

    2018-02-07

    Top-down regulation in the human brain and anatomical connections between the prefrontal cortex (PFC) and specific catecholamine-related regions have been well-studied. However, the way in which the PFC modulates downstream neuro-networks in terms of serotonin and the autonomic nervous system (ANS) by variation in the level of brain-derived neurotrophic factor (BDNF) is still unclear. We recruited sixty-seven healthy subjects. Serotonin transporter (SERT) availability was examined by SPECT with [ 123 I]ADAM analysis; heart rate variability (HRV) testing was performed, and the BDNF level was measured. The Wisconsin card-sorting test (WCST), which assesses PFC activation, was also conducted. The interactions of BDNF level and SERT availability were significant in relation to the HRV indexes of low frequency, high frequency, total power, and mean heart rate range. Moderate to significant positive correlations between SERT availability and the above-mentioned HRV indexes existed only in subjects with a low BDNF level. Furthermore, in the low BDNF level group, only those with high WCST perseveration errors or low category completions exhibited significant positive correlations between SERT availability and HRV indexes. A lower BDNF level and poorer PFC function might modulate the synergistic effects of serotonergic and ANS systems in order to maintain brain physiological and psychological homeostasis.

  15. Effect of brain-derived neurotrophic factor on sperm function, oxidative stress and membrane integrity in human.

    Science.gov (United States)

    Najafi, A; Amidi, F; Sedighi Gilani, M A; Moawad, A R; Asadi, E; Khanlarkhni, N; Fallah, P; Rezaiian, Z; Sobhani, A

    2017-03-01

    Oxidative stress has negative impacts on the clinical outcomes of assisted reproduction techniques. The brain-derived neurotrophic factor (BDNF) promotes the viability of nerve cells and is known to decrease oxidative stress and apoptosis in different cells. The aim of this study was to evaluate the effect of BDNF treatment on human sperm functions that are known to be essential for fertilisation. Our findings showed that treatment of human spermatozoa with 0.133 nM BDNF significantly increased the percentages of both total (P = 0.001) and progressive (P sperm cells compared to those observed in the nontreated (control) group. We also showed that the mean fluorescence intensity of DCFH-DA, as an indicator of intracellular reactive oxygen species, was significantly lower (P sperm cells (P sperm cells compared to the control (P = 0.001). In conclusion, BDNF has protective effects against oxidative stress in spermatozoa and could improve sperm functions that are essential for sperm-egg fusion and subsequent fertilisation. © 2016 Blackwell Verlag GmbH.

  16. Clinical correlates of plasma brain-derived neurotrophic factor in post-traumatic stress disorder spectrum after a natural disaster.

    Science.gov (United States)

    Stratta, Paolo; Sanità, Patrizia; Bonanni, Roberto L; de Cataldo, Stefano; Angelucci, Adriano; Rossi, Rodolfo; Origlia, Nicola; Domenici, Luciano; Carmassi, Claudia; Piccinni, Armando; Dell'Osso, Liliana; Rossi, Alessandro

    2016-10-30

    Clinical correlates of plasma Brain-Derived Neurotrophic Factor (BDNF) have been investigated in a clinical population with Post Traumatic Stress Disorder (PTSD) symptoms and healthy control subjects who survived to the L'Aquila 2009 earthquake. Twenty-six outpatients and 14 control subjects were recruited. Assessments included: Structured Clinical Interview for DSM-IV Axis-I disorders Patient Version, Trauma and Loss Spectrum-Self Report (TALS-SR) for post-traumatic spectrum symptoms. Thirteen patients were diagnosed as Full PTSD and 13 as Partial PTSD. The subjects with full-blown PTSD showed lower BDNF level than subjects with partial PTSD and controls. Different relationship patterns of BDNF with post-traumatic stress spectrum symptoms have been reported in the three samples. Our findings add more insight on the mechanisms regulating BDNF levels in response to stress and further proofs of the utility of the distinction of PTSD into full and partial categories. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. Serum level of brain-derived neurotrophic factor in fibromyalgia syndrome correlates with depression but not anxiety.

    Science.gov (United States)

    Nugraha, Boya; Korallus, Christoph; Gutenbrunner, Christoph

    2013-02-01

    Brain-derived neurotrophic factor (BDNF) has been known to play a role in fibromyalgia syndrome (FMS) patients. Depression and anxiety are quite common additional symptoms in FMS. However the role of BDNF in these symptoms still needs to be elucidated. Although BDNF has been shown to be relevant in major depression, however studies could not show such differences between FMS patients with and without major depression. As mood-related symptom occurs frequently and differs in its intensity in FMS patients, BDNF level should be measured in subgroup regarding depression and anxiety scale. Therefore the aim of this study was to evaluate the correlation of BDNF in serum of FMS with intensity of depression and anxiety. Additionally, interleukin (IL)-6 was measured. This study showed that serum level of BDNF was age-dependent in HCs. FMS patients had higher level of serum BDNF as compared to HC. Additionally, serum level of BDNF showed correlation with depression, but not with anxiety. Serum level of BDNF increased with depression score in FMS. However, serum level of IL-6 was not correlated with both depression and anxiety scores. Taken together, BDNF is involved in the pathophysiology of FMS. Additionally, it seems to be correlated with intensity of depressive symptoms in FMS. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus)

    International Nuclear Information System (INIS)

    Yuan, Lilai; Li, Jiasu; Zha, Jinmiao; Wang, Zijian

    2016-01-01

    Organophosphate flame retardants (OPFRs) have been detected at high concentrations in various environmental and biotic samples, but little is known about their toxicity. In this study, the potential neurotoxicity of three OPFRs (TCEP, TDCPP, and TPP) and Chlorpyrifos (CPF, an organophosphate pesticide) were compared in Chinese rare minnow using an acute toxicity test and a 21-day fish assay. The acute test demonstrated significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by CPF. Although significant AChE inhibition at high concentration of TPP was also observed, none of the OPFRs had effects similar to CPF on these enzymes, indicating that their acute toxicities to Chinese rare minnow may be unrelated to cholinesterase inhibition. In addition, the 21-day fish assay with TDCPP demonstrated no significant effects on cholinesterase activities or neurotransmitter levels. Nonetheless, this OPFR exhibited widespread effects on the neurotrophic factors and their receptors (e.g., ntf3, ntrk1, ntrk2, ngfr, and fgf2, fgf11, fgf22, fgfr4), indicating that TDCPP or other OPFRs may elicit neurological effects by targeting neurotrophic factors and their receptors in Chinese rare minnow. - Highlights: • Significant inhibition of AChE and BChE activities by CPF was observed. • None of the OPFRs had similar effects on the cholinesterase like the CPF. • TDCPP showed significant effects on the neurotrophic factor genes in rare minnow. - Although none of the tested OPFRs showed any significant effects on cholinesterase activities and neurotransmitter levels, TDCPP did elicit widespread effects on neurotrophic factor genes.

  19. Effect of Mirtazapine Treatment on Serum Levels of Brain-Derived Neurotrophic Factor and Tumor Necrosis Factor-α in Patients of Major Depressive Disorder with Severe Depression.

    Science.gov (United States)

    Gupta, Rachna; Gupta, Keshav; Tripathi, A K; Bhatia, M S; Gupta, Lalit K

    2016-01-01

    This study evaluated the clinical efficacy of mirtazapine and its effect on serum brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-α (TNF-α) levels in patients of major-depressive disorder (MDD) with severe depression. Patients (aged 18-60) with MDD diagnosed by DSM-IV criteria, and Hamilton Rating Scale for Depression (HAM-D) score ≥25 were included (n = 30). Mirtazapine was given in the doses of 30 mg/day. All patients were followed up for 12 weeks for the evaluation of clinical efficacy, safety along with serum BDNF and TNF-α levels. HAM-D score at the start of treatment was 30.1 ± 1.92, which significantly (p depressed patients and treatment response is associated with an increase in serum BDNF and a decrease in serum TNF-α levels. © 2016 S. Karger AG, Basel.

  20. Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: developing and demonstrating "clinical proof-of-concept" for AAV-neurturin (CERE-120) in Parkinson's disease.

    Science.gov (United States)

    Bartus, Raymond T; Baumann, Tiffany L; Brown, Lamar; Kruegel, Brian R; Ostrove, Jeffrey M; Herzog, Christopher D

    2013-01-01

    Neurotrophic factors have long shown promise as potential therapies for age-related neurodegenerative diseases. However, 20 years of largely disappointing clinical results have underscored the difficulties involved with safely and effectively delivering these proteins to targeted sites within the central nervous system. Recent progress establishes that gene transfer can now likely overcome the delivery issues plaguing the translation of neurotrophic factors. This may be best exemplified by adeno-associated virus serotype-2-neurturin (CERE-120), a viral-vector construct designed to deliver the neurotrophic factor, neurturin to degenerating nigrostriatal neurons in Parkinson's disease. Eighty Parkinson's subjects have been dosed with CERE-120 (some 7+ years ago), with long-term, targeted neurturin expression confirmed and no serious safety issues identified. A double-blind, controlled Phase 2a trial established clinical "proof-of-concept" via 19 of the 24 prescribed efficacy end points favoring CERE-120 at the 12-month protocol-prescribed time point and all but one favoring CERE-120 at the 18-month secondary time point (p = 0.007 and 0.001, respectively). Moreover, clinically meaningful benefit was seen with CERE-120 on several specific protocol-prescribed, pairwise, blinded, motor, and quality-of-life end points at 12 months, and an even greater number of end points at 18 months. Because the trial failed to meet the primary end point (Unified Parkinson's Disease Rating Scale motor-off, measured at 12 months), a revised multicenter Phase 1/2b protocol was designed to enhance the neurotrophic effects of CERE-120, using insight gained from the Phase 2a trial. This review summarizes the development of CERE-120 from its inception through establishing "clinical proof-of-concept" and beyond. The translational obstacles and issues confronted, and the strategies applied, are reviewed. This information should be informative to investigators interested in translational

  1. Epigenetic Manipulation of Brain-derived Neurotrophic Factor Improves Memory Deficiency Induced by Neonatal Anesthesia in Rats.

    Science.gov (United States)

    Wu, Jiang; Bie, Bihua; Naguib, Mohamed

    2016-03-01

    Although neonatal exposure to anesthetic drugs is associated with memory deficiency in rodent models and possibly in pediatric patients, the underlying mechanisms remain elusive. The authors tested their hypothesis that exposure of the developing brain to anesthesia triggers epigenetic modification, involving the enhanced interaction among transcription factors (histone deacetylase 2, methyl-cytosine-phosphate-guanine-binding protein 2, and DNA methyltransferase 1) in Bdnf promoter region(s) that inhibit brain-derived neurotrophic factor (BDNF) expression, resulting in insufficient drive for local translation of synaptic mRNAs. The authors further hypothesized that noninvasive environmental enrichment (EE) will attenuate anesthesia-induced epigenetic inhibition of BDNF signaling and memory loss in rodent models. Seven days after birth (P7), neonatal rats were randomly assigned to receive either isoflurane anesthesia for 6 h or sham anesthesia. On P21, pups were weaned, and animals were randomly assigned to EE or a standard cage environment (no EE). Behavioral, molecular, and electrophysiological studies were performed on rats on P65. The authors found a substantial reduction of hippocampal BDNF (n = 6 to 7) resulting from the transcriptional factors-mediated epigenetic modification in the promoter region of Bdnf exon IV in rats exposed postnatally to anesthetic drugs. This BDNF reduction led to the insufficient drive for the synthesis of synaptic proteins (n = 6 to 8), thus contributing to the hippocampal synaptic (n = 8 to 11) and cognitive dysfunction (n = 10) induced by neonatal anesthesia. These effects were mitigated by the exposure to an enriched environment. The findings of this study elucidated the epigenetic mechanism underlying memory deficiency induced by neonatal anesthesia and propose EE as a potential therapeutic approach.

  2. Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats.

    Science.gov (United States)

    Ahn, So Yoon; Chang, Yun Sil; Sung, Dong Kyung; Sung, Se In; Ahn, Jee-Yin; Park, Won Soon

    2017-01-24

    Mesenchymal stem cell (MSC) transplantation protects against neonatal severe intraventricular hemorrhage (IVH)-induced brain injury by a paracrine rather than regenerative mechanism; however, the paracrine factors involved and their roles have not yet been delineated. This study aimed to identify the paracrine mediator(s) and to determine their role in mediating the therapeutic effects of MSCs in severe IVH. We first identified significant upregulation of brain-derived neurotrophic factor (BDNF) in MSCs compared with fibroblasts, in both DNA and antibody microarrays, after thrombin exposure. We then knocked down BDNF in MSCs by transfection with small interfering (si)RNA specific for human BDNF. The therapeutic effects of MSCs with or without BDNF knockdown were evaluated in vitro in rat neuronal cells challenged with thrombin, and in vivo in newborn Sprague-Dawley rats by injecting 200 μl of blood on postnatal day 4 (P4), and transplanting MSCs (1 × 105 cells) intraventricularly on P6. siRNA-induced BDNF knockdown abolished the in vitro benefits of MSCs on thrombin-induced neuronal cell death. BDNF knockdown also abolished the in vivo protective effects against severe IVH-induced brain injuries such as the attenuation of posthemorrhagic hydrocephalus, impaired behavioral test performance, increased astrogliosis, increased number of TUNEL cells, ED-1+ cells, and inflammatory cytokines, and reduced myelin basic protein expression. Our data indicate that BDNF secreted by transplanted MSCs is one of the critical paracrine factors that play a seminal role in attenuating severe IVH-induced brain injuries in newborn rats.

  3. Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available B-cell leukemia/lymphoma 11B (Bcl11b is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells.

  4. Meta-coexpression conservation analysis of microarray data: a "subset" approach provides insight into brain-derived neurotrophic factor regulation

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    Timmusk Tõnis

    2009-09-01

    Full Text Available Abstract Background Alterations in brain-derived neurotrophic factor (BDNF gene expression contribute to serious pathologies such as depression, epilepsy, cancer, Alzheimer's, Huntington and Parkinson's disease. Therefore, exploring the mechanisms of BDNF regulation represents a great clinical importance. Studying BDNF expression remains difficult due to its multiple neural activity-dependent and tissue-specific promoters. Thus, microarray data could provide insight into the regulation of this complex gene. Conventional microarray co-expression analysis is usually carried out by merging the datasets or by confirming the re-occurrence of significant correlations across datasets. However, co-expression patterns can be different under various conditions that are represented by subsets in a dataset. Therefore, assessing co-expression by measuring correlation coefficient across merged samples of a dataset or by merging datasets might not capture all correlation patterns. Results In our study, we performed meta-coexpression analysis of publicly available microarray data using BDNF as a "guide-gene" introducing a "subset" approach. The key steps of the analysis included: dividing datasets into subsets with biologically meaningful sample content (e.g. tissue, gender or disease state subsets; analyzing co-expression with the BDNF gene in each subset separately; and confirming co- expression links across subsets. Finally, we analyzed conservation in co-expression with BDNF between human, mouse and rat, and sought for conserved over-represented TFBSs in BDNF and BDNF-correlated genes. Correlated genes discovered in this study regulate nervous system development, and are associated with various types of cancer and neurological disorders. Also, several transcription factor identified here have been reported to regulate BDNF expression in vitro and in vivo. Conclusion The study demonstrates the potential of the "subset" approach in co-expression conservation

  5. Ciliary neurotrophic factor promotes the activation of corneal epithelial stem/progenitor cells and accelerates corneal epithelial wound healing.

    Science.gov (United States)

    Zhou, Qingjun; Chen, Peng; Di, Guohu; Zhang, Yangyang; Wang, Yao; Qi, Xia; Duan, Haoyun; Xie, Lixin

    2015-05-01

    Ciliary neurotrophic factor (CNTF), a well-known neuroprotective cytokine, has been found to play an important role in neurogenesis and functional regulations of neural stem cells. As one of the most innervated tissue, however, the role of CNTF in cornea epithelium remains unclear. This study was to explore the roles and mechanisms of CNTF in the activation of corneal epithelial stem/progenitor cells and wound healing of both normal and diabetic mouse corneal epithelium. In mice subjecting to mechanical removal of corneal epithelium, the corneal epithelial stem/progenitor cell activation and wound healing were promoted by exogenous CNTF application, while delayed by CNTF neutralizing antibody. In cultured corneal epithelial stem/progenitor cells, CNTF enhanced the colony-forming efficiency, stimulated the mitogenic proliferation, and upregulated the expression levels of corneal epithelial stem/progenitor cell-associated transcription factors. Furthermore, the promotion of CNTF on the corneal epithelial stem/progenitor cell activation and wound healing was mediated by the activation of STAT3. Moreover, in diabetic mice, the content of CNTF in corneal epithelium decreased significantly when compared with that of normal mice, and the supplement of CNTF promoted the diabetic corneal epithelial wound healing, accompanied with the advanced activation of corneal epithelial stem/progenitor cells and the regeneration of corneal nerve fibers. Thus, the capability of expanding corneal epithelial stem/progenitor cells and promoting corneal epithelial wound healing and nerve regeneration indicates the potential application of CNTF in ameliorating limbal stem cell deficiency and treating diabetic keratopathy. © 2014 AlphaMed Press.

  6. Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Ciliary Neurotrophic Factor in Astrocytes and Oligodendrocytes.

    Science.gov (United States)

    Modi, Khushbu K; Jana, Malabendu; Mondal, Susanta; Pahan, Kalipada

    2015-11-01

    Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that plays an important role in multiple sclerosis (MS). However, mechanisms by which CNTF expression could be increased in the brain are poorly understood. Recently we have discovered anti-inflammatory and immunomodulatory activities of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here, we delineate that NaB is also capable of increasing the mRNA and protein expression of CNTF in primary mouse astrocytes and oligodendrocytes and primary human astrocytes. Accordingly, oral administration of NaB and cinnamon led to the upregulation of astroglial and oligodendroglial CNTF in vivo in mouse brain. Induction of experimental allergic encephalomyelitis, an animal model of MS, reduced the level of CNTF in the brain, which was restored by oral administration of cinnamon. While investigating underlying mechanisms, we observed that NaB induced the activation of protein kinase A (PKA) and H-89, an inhibitor of PKA, abrogated NaB-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein by NaB, the recruitment of CREB and CREB-binding protein to the CNTF promoter by NaB and the abrogation of NaB-induced expression of CNTF in astrocytes by siRNA knockdown of CREB suggest that NaB increases the expression of CNTF via the activation of CREB. These results highlight a novel myelinogenic property of NaB and cinnamon, which may be of benefit for MS and other demyelinating disorders.

  7. Neurogenesis in the dentate gyrus depends on ciliary neurotrophic factor and signal transducer and activator of transcription 3 signaling.

    Science.gov (United States)

    Müller, Stephan; Chakrapani, Baby P S; Schwegler, Herbert; Hofmann, Hans-Dieter; Kirsch, Matthias

    2009-02-01

    In the neurogenic areas of the adult rodent brain, neural stem cells (NSCs) proliferate and produce new neurons throughout the lifetime. This requires a permanent pool of NSCs, the size of which needs to be tightly controlled. The gp130-associated cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) have been implicated in regulating NSC self-renewal and differentiation during embryonic development and in the adult brain. To study the relevance of the two cytokines in vivo, we analyzed precursor cell proliferation and neurogenesis in the dentate gyrus of CNTF- and LIF-deficient mouse mutants. The number of radial glia-like NSCs, proliferative activity, and generation of new neurons were all reduced in CNTF(-/-) mutants but unaltered in LIF(-/-) animals. Conditional ablation of the signal transducer and activator of transcription 3 (STAT3) gene under the control of the human glial fibrillary acidic protein promoter resulted in a reduction of neurogenesis similar to that in CNTF(-/-) mice. The size of the granule cell layer was decreased in both mutants. Treatment of neurosphere cultures prepared from adult forebrain with CNTF inhibited overall proliferative activity but increased the number of NSCs as indicated by enhanced secondary neurosphere formation and upregulated expression of stem cell markers. Knockdown of STAT3 with short interfering RNA inhibited CNTF effects on neurospheres, and knockdown of suppressor of cytokine signaling 3 (SOCS3) enhanced them. Our results provide evidence that CNTF-induced STAT3 signaling is essential for the formation and/or maintenance of the neurogenic subgranular zone in the adult dentate gyrus and suggest that CNTF is required to keep the balance between NSC self-renewal and the generation of neuronal progenitors.

  8. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    International Nuclear Information System (INIS)

    Rodriguez-Tebar, A.; Barde, Y.A.

    1988-01-01

    Brain-derived neurotrophic factor (BDNF), a protein known to support the survival of embryonic sensory neurons and retinal ganglion cells, was derivatized with 125I-Bolton-Hunter reagent and obtained in a biologically active, radioactive form (125I-BDNF). Using dorsal root ganglion neurons from chick embryos at 9 d of development, the basic physicochemical parameters of the binding of 125I-BDNF with its receptors were established. Two different classes of receptors were found, with dissociation constants of 1.7 x 10(-11) M (high-affinity receptors) and 1.3 x 10(-9) M (low-affinity receptors). Unlabeled BDNF competed with 125I-BDNF for binding to the high-affinity receptors with an inhibition constant essentially identical to the dissociation constant of the labeled protein: 1.2 x 10(-11) M. The association and dissociation rates from both types of receptors were also determined, and the dissociation constants calculated from these kinetic experiments were found to correspond to the results obtained from steady-state binding. The number of high-affinity receptors (a few hundred per cell soma) was 15 times lower than that of low-affinity receptors. No high-affinity receptors were found on sympathetic neurons, known not to respond to BDNF, although specific binding of 125I-BDNF to these cells was detected at a high concentration of the radioligand. These results are discussed and compared with those obtained with nerve growth factor on the same neuronal populations

  9. Regulation of brain-derived neurotrophic factor exon IV transcription through calcium responsive elements in cortical neurons.

    Directory of Open Access Journals (Sweden)

    Fei Zheng

    Full Text Available Activity-dependent transcription of brain-derived neurotrophic factor (BDNF has been studied as an important model to elucidate the mechanisms underlying numerous aspects of neuroplasticity. It has been extensively emphasized that Ca(2+ influx through different routes may have significantly different effects on BDNF transcription. Here, we examined the regulatory property of the major calcium responsive elements (CaRE in BDNF promoter IV in cultured rat cortical neurons. BDNF promoter IV, as well as CaRE1 and CaRE3, was significantly activated by Ca(2+ influx through L-type voltage-gated calcium channel (L-VGCC or NMDA receptor (NMDAR. However, the L-VGCC- and NMDAR-mediated activation of CaRE was differentially regulated by different Ca(2+-stimulated protein kinases. Specifically, PKA, CaMKI, and CaMKIV activity were required for L-VGCC-, but not NMDAR-mediated CaRE1 activation. CaMKI activity was required for NMDAR- but not L-VGCC-mediated CaRE3 activation. Surprisingly, the activation of CaRF, a previously identified transcription factor for CaRE1, was stimulated via L-VGCC but not NMDAR, and required MEK, PI3K and CaMKII activity. These results suggest a new working model that activity-dependent BDNF IV up-regulation may be coordinately mediated by CaRE1 and CaRE3 activity, which show different responses to Ca(2+-stimulated kinases. Our data also explain how the individual cis-element in BDNF promoter is distinctively coupled to different Ca(2+ routes.

  10. Distribution of glial cell line-derived neurotrophic factor receptor alpha-1 in the brain of adult zebrafish.

    Science.gov (United States)

    Lucini, Carla; Carla, Lucini; Facello, Bruna; Bruna, Facello; Maruccio, Lucianna; Lucianna, Maruccio; Langellotto, Fernanda; Fernanda, Langellotto; Sordino, Paolo; Paolo, Sordino; Castaldo, Luciana; Luciana, Castaldo

    2010-08-01

    Glial cell line-derived neurotrophic factor (GDNF) is a potent trophic factor for several types of neurons in the central and peripheral nervous systems. The biological activity of GDNF is mediated by a multicomponent receptor complex that includes a common transmembrane signaling component (the rearranged during transfection (RET) proto-oncogene product, a tyrosine kinase receptor) as well as a GDNF family receptor alpha (GFRalpha) subunit, a high-affinity glycosyl phosphatidylinositol (GPI)-linked binding element. Among the four known GFRalpha subunits, GFRalpha1 preferentially binds to GDNF. In zebrafish (Danio rerio) embryos, the expression of the GFRalpha1a and GFRalpha1b genes has been shown in primary motor neurons, the kidney, and the enteric nervous system. To examine the activity of GFRalpha in the adult brain of a lower vertebrate, we have investigated the localization of GFRalpha1a and GFRalpha1b mRNA and the GFRalpha1 protein in zebrafish. GFRalpha1a and GFRalpha1b transcripts were observed in brain extracts by reverse transcription-polymerase chain reaction. Whole-mount in-situ hybridization experiments revealed a wide distribution of GFRalpha1a and GFRalpha1b mRNAs in various regions of the adult zebrafish brain. These included the olfactory bulbs, dorsal and ventral telencephalic area (telencephalon), preoptic area, dorsal and ventral thalamus, posterior tuberculum and hypothalamus (diencephalon), optic tectum (mesencephalon), cerebellum, and medulla oblongata (rhombencephalon). Finally, expression patterns of the GFRalpha1 protein, detected immunohistochemically, correlated well with the mRNA expression and provided further insights into translational activity at the neuroanatomical level. In conclusion, the current study demonstrated that the presence of GFRalpha1 persists beyond the embryonic development of the zebrafish brain and, together with the GDNF ligand, is probably implicated in the brain physiology of an adult teleost fish.

  11. Jisuikang, a Chinese herbal formula, increases neurotrophic factor expression and promotes the recovery of neurological function after spinal cord injury

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    Yang Guo

    2017-01-01

    Full Text Available The Chinese medicine compound, Jisuikang, can promote recovery of neurological function by inhibiting lipid peroxidation, scavenging oxygen free radicals, and effectively improving the local microenvironment after spinal cord injury. However, the mechanism remains unclear. Thus, we established a rat model of acute spinal cord injury using a modified version of Allen's method. Jisuikang (50, 25, and 12.5 g/kg/d and prednisolone were administered 30 minutes after anesthesia. Basso, Beattie, and Bresnahan locomotor scale scores and the oblique board test showed improved motor function recovery in the prednisone group and moderate-dose Jisuikang group compared with the other groups at 3–7 days post-injury. The rats in the moderate-dose Jisuikang group recovered best at 14 days post-injury. Hematoxylin-eosin staining and transmission electron microscopy showed that the survival rate of neurons in treatment groups increased after 3–7 days of administration. Further, the structure of neurons and glial cells was more distinct, especially in prednisolone and moderate-dose Jisuikang groups. Western blot assay and immunohistochemistry showed that expression of brain-derived neurotrophic factor (BDNF in injured segments was maintained at a high level after 7–14 days of treatment. In contrast, expression of nerve growth factor (NGF was down-regulated at 7 days after spinal cord injury. Real-time fluorescence quantitative polymerase chain reaction showed that expression of BDNF and NGF mRNA was induced in injured segments by prednisolone and Jisuikang. At 3–7 days after injury, the effect of prednisolone was greater, while 14 days after injury, the effect of moderate-dose Jisuikang was greater. These results confirm that Jisuikang can upregulate BDNF and NGF expression for a prolonged period after spinal cord injury and promote repair of acute spinal cord injury, with its effect being similar to prednisolone.

  12. The effect of exercise training modality on serum brain derived neurotrophic factor levels in individuals with type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Damon L Swift

    Full Text Available Brain derived neurotrophic factor (BDNF has been implicated in memory, learning, and neurodegenerative diseases. However, the relationship of BDNF with cardiometabolic risk factors is unclear, and the effect of exercise training on BDNF has not been previously explored in individuals with type 2 diabetes.Men and women (N = 150 with type 2 diabetes were randomized to an aerobic exercise (aerobic, resistance exercise (resistance, or a combination of both (combination for 9 months. Serum BDNF levels were evaluated at baseline and follow-up from archived blood samples.Baseline serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures (all, p>0.05. Similarly, no significant change in serum BDNF levels was observed following exercise training in the aerobic (-1649.4 pg/ml, CI: -4768.9 to 1470.2, resistance (-2351.2 pg/ml, CI:-5290.7 to 588.3, or combination groups (-827.4 pg/ml, CI: -3533.3 to 1878.5 compared to the control group (-2320.0 pg/ml, CI: -5750.8 to 1110.8. However, reductions in waist circumference were directly associated with changes in serum BDNF following training (r = 0.25, p = 0.005.Serum BDNF was not associated with fitness, body composition, anthropometry, glucose control, or strength measures at baseline. Likewise, serum BDNF measures were not altered by 9 months of aerobic, resistance, or combination training. However, reductions in waist circumference were associated with decreased serum BDNF levels. Future studies should investigate the relevance of BDNF with measures of cognitive function specifically in individuals with type-2 diabetes.

  13. Influence of brain‐derived neurotrophic factor‐tyrosine receptor kinase B signalling in the nucleus tractus solitarius on baroreflex sensitivity in rats with chronic heart failure

    Science.gov (United States)

    Becker, Bryan K.; Tian, Changhai; Zucker, Irving H.

    2016-01-01

    Key points Impairment of baroreflex function is associated with the progression of chronic heart failure (CHF) and a poor prognosis. The baroreflex desensitization in CHF is at least partly the result of central neuronal network dysfunction.The dorsal medial nucleus tractus solitarius (dmNTS) has long been appreciated as a primary site of baroreceptor afferent termination in the central nervous system. However, the influence of neurotransmitters and neuromodulators in the dmNTS on baroreflex function both in normal and CHF states is not fully understood.The present study provides the first evidence showing a tonic sympatho‐inhibitory role for brain‐derived neurotrophic factor (BDNF) neurotransmission in the dmNTS. Most importantly, BDNF‐ tyrosine receptor kinase B (TrkB) signalling in the dmNTS is integral for normal baroreflex function as indicated by the blunting of baroreflex sensitivity (BRS) following the antagonization of TrkB, which inhibited baroreflex gain and range.Furthermore, we found that the tonic sympatho‐inhibition of BDNF was withdrawn in the CHF state, thus contributing to the increased sympathetic tone associated with CHF. Consistent with this finding, BDNF/TrkB antagonism had little effect on reducing BRS in CHF animals, which is corroborated by the observation of decreased TrkB expression in the dmNTS during CHF. Taken together, these results implicate a reduction in BDNF‐TrkB signalling in the dmNTS during CHF that contributes to sympatho‐excitation and baroreflex desensitization.The observation that the BDNF/TrkB pathway is impaired in the dmNTS during CHF provides a novel mechanism for understanding the central alterations that contribute to baroreflex desensitization during CHF. Abstract Chronic heart failure (CHF) results in blunting of arterial baroreflex sensitivity (BRS), which arises from alterations to both peripheral baroreceptors and central autonomic nuclei such as the nucleus tractus solitarius (NTS). Although

  14. Low plasma levels of brain derived neurotrophic factor are potential risk factors for diabetic retinopathy in Chinese type 2 diabetic patients.

    Science.gov (United States)

    Liu, Shao-Yi; Du, Xiao-Fang; Ma, Xiang; Guo, Jian-Lian; Lu, Jian-Min; Ma, Lu-Sheng

    2016-01-15

    Previous studies suggested that neurotrophins play a role in the diabetic retinopathy (DR). We therefore evaluated the role of plasma brain derived neurotrophic factor (BDNF) levels in Chinese type 2 diabetic patients with and without diabetic retinopathy (DR). Plasma levels of BDNF were determined in type 2 diabetic patients (N=344). At baseline, the demographical and clinical data were taken. Multivariate analyses were performed using logistic regression models. Receiver operating characteristic curves (ROC) was used to test the overall predict accuracy of BDNF and other markers. Diabetic patients with DR and vision-threatening diabetic retinopathy (VTDR) had significantly lower BDNF levels on admission (Pdiabetes duration for DR from 0.76 (95% confidence interval [CI], 0.71-0.82) to 0.89 (95% CI, 0.82-0.95; Pdiabetic patients, suggesting a possible role of BDNF in the pathogenesis of DR complications. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. In Utero Fine Particle Air Pollution and Placental Expression of Genes in the Brain-Derived Neurotrophic Factor Signaling Pathway: An ENVIRONAGE Birth Cohort Study.

    Science.gov (United States)

    Saenen, Nelly D; Plusquin, Michelle; Bijnens, Esmée; Janssen, Bram G; Gyselaers, Wilfried; Cox, Bianca; Fierens, Frans; Molenberghs, Geert; Penders, Joris; Vrijens, Karen; De Boever, Patrick; Nawrot, Tim S

    2015-08-01

    Developmental processes in the placenta and the fetal brain are shaped by the same biological signals. Recent evidence suggests that adaptive responses of the placenta to the maternal environment may influence central nervous system development. We studied the association between in utero exposure to fine particle air pollution with a diameter ≤ 2.5 μm (PM2.5) and placental expression of genes implicated in neural development. Expression of 10 target genes in the brain-derived neurotrophic factor (BDNF) signaling pathway were quantified in placental tissue of 90 mother-infant pairs from the ENVIRONAGE birth cohort using quantitative real-time polymerase chain reaction. Trimester-specific PM2.5 exposure levels were estimated for each mother's home address using a spatiotemporal model. Mixed-effects models were used to evaluate the association between the target genes and PM2.5 exposure measured in different time windows of pregnancy. A 5-μg/m3 increase in residential PM2.5 exposure during the first trimester of pregnancy was associated with a 15.9% decrease [95% confidence interval (CI): -28.7, -3.2%, p = 0.015] in expression of placental BDNF at birth. The corresponding estimate for synapsin 1 (SYN1) was a 24.3% decrease (95% CI: -42.8, -5.8%, p = 0.011). Placental expression of BDNF and SYN1, two genes implicated in normal neurodevelopmental trajectories, decreased with increasing in utero exposure to PM2.5. Future studies are needed to confirm our findings and evaluate the potential relevance of associations between PM2.5 and placental expression of BDNF and SYN1 on neurodevelopment. We provide the first molecular epidemiological evidence concerning associations between in utero fine particle air pollution exposure and the expression of genes that may influence neurodevelopmental processes.

  16. Immunomodulator CD200 promotes neurotrophic activity by interacting with and activating the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Björnsdóttir, Halla; Christensen, Claus

    2016-01-01

    in the suppression of microglia activation. We for the first time demonstrated that CD200 can interact with and transduce signaling through activation of the fibroblast growth factor receptor (FGFR), thereby inducing neuritogenesis and promoting neuronal survival in primary neurons. CD200-induced FGFR...

  17. High hydrostatic pressure enables almost 100% refolding of recombinant human ciliary neurotrophic factor from inclusion bodies at high concentration.

    Science.gov (United States)

    Wang, Qi; Liu, Yongdong; Zhang, Chun; Guo, Fangxia; Feng, Cui; Li, Xiunan; Shi, Hong; Su, Zhiguo

    2017-05-01

    Protein refolding from inclusion bodies (IBs) often encounters a problem of low recovery at high protein concentration. In this study, we demonstrated that high hydrostatic pressure (HHP) could simultaneously achieve high refolding concentration and high refolding yield for IBs of recombinant human ciliary neurotrophic factor (rhCNTF), a potential therapeutic for neurodegenerative diseases. The use of dilution refolding obtained 18% recovery at 3 mg/mL, even in the presence of 4 M urea. In contrast, HHP refolding could efficiently increase the recovery up to almost 100% even at 4 mg/mL. It was found that in the dilution, hydrophobic aggregates were the off-path products and their amount increased with the protein concentration. However, HHP could effectively minimize the formation of hydrophobic aggregates, leading to almost complete conversion of the rhCNTF IBs to the correct configuration. The stable operation range of concentration is 0.5-4.0 mg/mL, in which the refolding yield was almost 100%. Compared with the literatures where HHP failed to increase the refolding yield beyond 90%, the reason could be attributed to the structural difference that rhCNTF has no disulfide bond and is a monomeric protein. After purification by one-step of anionic chromatography, the purity of rhCNTF reached 95% with total process recovery of 54.1%. The purified rhCNTF showed similar structure and in vitro bioactivity to the native species. The whole process featured integration of solubilization/refolding, a high refolding yield of 100%, a high concentration of 4 mg/mL, and a simple chromatography to ensure a high productivity. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. TDP6, a brain-derived neurotrophic factor-based trkB peptide mimetic, promotes oligodendrocyte myelination.

    Science.gov (United States)

    Wong, Agnes W; Giuffrida, Lauren; Wood, Rhiannon; Peckham, Haley; Gonsalvez, David; Murray, Simon S; Hughes, Richard A; Xiao, Junhua

    2014-11-01

    Brain-derived neurotrophic factor (BDNF) plays critical roles in the development and maintenance of the central (CNS) and peripheral nervous systems (PNS). BDNF exerts its biological effects via tropomyosin-related kinase B (TrkB) and the p75 neurotrophin receptor (p75NTR). We have recently identified that BDNF promotes CNS myelination via oligodendroglial TrkB receptors. In order to selectively target TrkB to promote CNS myelination, we have used a putative TrkB agonist, a small multicyclic peptide (tricyclic dimeric peptide 6, TDP6) previously described by us that structurally mimics a region of BDNF that binds TrkB. We confirmed that TDP6 acts as a TrkB agonist as it provoked autophosphorylation of TrkB and its downstream signalling effector extracellular related-kinase 1 and 2 (Erk1/2) in primary oligodendrocytes. Using an in vitro myelination assay, we show that TDP6 significantly promotes myelination by oligodendrocytes in vitro, as evidenced by enhanced myelin protein expression and an increased number of myelinated axonal segments. In contrast, a second, structurally distinct BDNF mimetic (cyclo-dPAKKR) that targets p75NTR had no effect upon oligodendrocyte myelination in vitro, despite the fact that cyclo-dPAKKR is a very effective promoter of peripheral (Schwann cell) myelination. The selectivity of TDP6 was further verified by using TrkB-deficient oligodendrocytes, in which TDP6 failed to promote myelination, indicating that the pro-myelinating effect of TDP6 is oligodendroglial TrkB-dependent. Together, our results demonstrate that TDP6 is a novel BDNF mimetic that promotes oligodendrocyte myelination in vitro via targeting TrkB.

  19. Alteration of the irisin–brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients

    Science.gov (United States)

    Papp, Csaba; Pak, Krisztian; Erdei, Tamas; Juhasz, Bela; Seres, Ildiko; Szentpéteri, Anita; Kardos, Laszlo; Szilasi, Maria; Gesztelyi, Rudolf; Zsuga, Judit

    2017-01-01

    COPD is accompanied by limited physical activity, worse quality of life, and increased prevalence of depression. A possible link between COPD and depression may be irisin, a myokine, expression of which in the skeletal muscle and brain positively correlates with physical activity. Irisin enhances the synthesis of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in reward-related processes. Thus, we hypothesized that mood disturbances accompanying COPD are reflected by the changes in the irisin–BDNF axis. Case history, routine laboratory parameters, serum irisin and BDNF levels, pulmonary function, and disease-specific quality of life, measured by St George’s Respiratory Questionnaire (SGRQ), were determined in a cohort of COPD patients (n=74). Simple and then multiple linear regression were used to evaluate the data. We found that mood disturbances are associated with lower serum irisin levels (SGRQ’s Impacts score and reciprocal of irisin showed a strong positive association; β: 419.97; 95% confidence interval [CI]: 204.31, 635.63; P<0.001). This association was even stronger among patients in the lower 50% of BDNF levels (β: 434.11; 95% CI: 166.17, 702.05; P=0.002), while it became weaker for patients in the higher 50% of BDNF concentrations (β: 373.49; 95% CI: −74.91, 821.88; P=0.1). These results suggest that irisin exerts beneficial effect on mood in COPD patients, possibly by inducing the expression of BDNF in brain areas associated with reward-related processes involved in by depression. Future interventional studies targeting the irisin–BDNF axis (eg, endurance training) are needed to further support this notion. PMID:28744117

  20. Alteration of the irisin-brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients.

    Science.gov (United States)

    Papp, Csaba; Pak, Krisztian; Erdei, Tamas; Juhasz, Bela; Seres, Ildiko; Szentpéteri, Anita; Kardos, Laszlo; Szilasi, Maria; Gesztelyi, Rudolf; Zsuga, Judit

    2017-01-01

    COPD is accompanied by limited physical activity, worse quality of life, and increased prevalence of depression. A possible link between COPD and depression may be irisin, a myokine, expression of which in the skeletal muscle and brain positively correlates with physical activity. Irisin enhances the synthesis of brain-derived neurotrophic factor (BDNF), a neurotrophin involved in reward-related processes. Thus, we hypothesized that mood disturbances accompanying COPD are reflected by the changes in the irisin-BDNF axis. Case history, routine laboratory parameters, serum irisin and BDNF levels, pulmonary function, and disease-specific quality of life, measured by St George's Respiratory Questionnaire (SGRQ), were determined in a cohort of COPD patients (n=74). Simple and then multiple linear regression were used to evaluate the data. We found that mood disturbances are associated with lower serum irisin levels (SGRQ's Impacts score and reciprocal of irisin showed a strong positive association; β: 419.97; 95% confidence interval [CI]: 204.31, 635.63; P <0.001). This association was even stronger among patients in the lower 50% of BDNF levels (β: 434.11; 95% CI: 166.17, 702.05; P =0.002), while it became weaker for patients in the higher 50% of BDNF concentrations (β: 373.49; 95% CI: -74.91, 821.88; P =0.1). These results suggest that irisin exerts beneficial effect on mood in COPD patients, possibly by inducing the expression of BDNF in brain areas associated with reward-related processes involved in by depression. Future interventional studies targeting the irisin-BDNF axis (eg, endurance training) are needed to further support this notion.

  1. Relationship between Levels of Brain-Derived Neurotrophic Factor and Metabolic Parameters in Patients with Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Banu Boyuk

    2014-01-01

    Full Text Available Background and Aim. Studies have suggested that brain-derived neurotrophic factor (BDNF plays a role in glucose and lipid metabolism and inflammation. The aim of this study was to evaluate the relationship between serum BDNF levels and various metabolic parameters and inflammatory markers in patients with type 2 diabetes mellitus (T2DM. Materials and Methods. The study included 88 T2DM patients and 33 healthy controls. Fasting blood samples were obtained from the patients and the control group. The serum levels of BDNF were measured with an ELISA kit. The current paper introduces a receiver-operating characteristic (ROC generalization curve to identify cut-off for the BDNF values in type 2 diabetes patients. Results. The serum levels of BDNF were significantly higher in T2DM patients than in the healthy controls (206.81 ± 107.32 pg/mL versus 130.84 ± 59.81 pg/mL; P<0.001. They showed a positive correlation with the homeostasis model assessment of insulin resistance (HOMA-IR (r=0.28; P<0.05, the triglyceride level (r=0.265; P<0.05, and white blood cell (WBC count (r=0.35; P<0.001. In logistic regression analysis, age (P<0.05, body mass index (BMI (P<0.05, C-reactive protein (CRP (P<0.05, and BDNF (P<0.01 were independently associated with T2DM. In ROC curve analysis, BDNF cut-off was 137. Conclusion. The serum BDNF level was higher in patients with T2DM. The BDNF had a cut-off value of 137. The findings suggest that BDNF may contribute to glucose and lipid metabolism and inflammation.

  2. IL-27 structural analysis demonstrates similarities with ciliary neurotrophic factor (CNTF) and leads to the identification of antagonistic variants.

    Science.gov (United States)

    Rousseau, Francois; Basset, Laetitia; Froger, Josy; Dinguirard, Nathalie; Chevalier, Sylvie; Gascan, Hugues

    2010-11-09

    IL-27, consisting of the subunits IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3), is a heterodimeric cytokine belonging to the IL-6/IL-12 family of cytokines. IL-27p28 is a four-helical cytokine requiring association with the soluble receptor EBI3 to be efficiently secreted and functionally active. Computational and biological analyses of the IL-27 binding site 1 to its receptor revealed important structural proximities with the ciliary neurotrophic factor group of cytokines and highlighted the contribution of p28 Trp(97), as well as of EBI3 Phe(97), Asp(210), and Glu(159), as key residues in the interactions between both cytokine subunits. WSX-1 (IL-27R) and gp130 compose the IL-27 receptor-signaling complex, recruiting the STAT-1 and STAT-3 pathways. A study of IL-27 binding site 3 showed that Trp(197) was crucial for the cytokine's interaction with gp130, but that the mutated cytokine still recognized IL-27R on the cell surface. IL-27 exerts both pro- and anti-inflammatory functions, promoting proliferation and differentiation of Th1 and inhibiting Th17 differentiation. Our results led us to develop mutated forms of human and mouse IL-27 with antagonistic activities. Using an in vivo mouse model of concanavalin A-induced Th1-cell-mediated hepatitis, we showed that the murine IL-27 antagonist W195A decreased liver inflammation by downregulating the synthesis of CXCR3 ligands and several acute phase proteins. Together, these data suggest that IL-27 antagonism could be of interest in down-modulating acute IL-27-driven Th1-cell-mediated immune response.

  3. Purification and characterization of a long-acting ciliary neurotrophic factor via genetically fused with an albumin-binding domain.

    Science.gov (United States)

    Xu, Longfu; Zhang, Chun; Liu, Liping; Zhang, Yao; Wang, Qi; Wang, Jian; Liu, Yongdong; Su, Zhiguo

    2017-11-01

    Ciliary neurotrophic factor (CNTF) is a promising candidate for the treatment of neurodegenerative or metabolic diseases, but suffers rapid clearance in body. Herein we constructed a new long-acting recombinant human CNTF (rhCNTF) by genetic fusion with an albumin-binding domain (ABD) through a flexible peptide linker, hoping to endow the new molecule prolonged serum circulation time by binding with endogenous human serum albumin (HSA) and then utilizing the naturally long-half-life property of HSA. This fused protein rhCNTF-ABD was expressed in Escherichia coli mainly in the soluble form and purified through a two-step chromatography, with purity of 95% and a high yield of 90-100 mg/L culture. The in vitro binding ability of rhCNTF-ABD with HSA was firstly verified by incubation of the two components together followed by HP-SEC analysis. ABD-fused rhCNTF showed similar secondary and tertiary structure as the parent protein. It retained approximately 94.1% of the native bioactivity as demonstrated via CCK-8 cell viability assay analysis. In vivo studies in SD rats were performed and the terminal half-life of 483.89 min for rhCNTF-ABD was determined, which is about 14 folds longer than that of rhCNTF (34.28 min) and comparable with 20 k-40 kDa PEGylated rhCNTFs. The new constructed rhCNTF-ABD represents a potential therapeutic modality, and the proposed strategy may also have useful applications for other long-lasting biopharmaceutics' design. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Sustained striatal ciliary neurotrophic factor expression negatively affects behavior and gene expression in normal and R6/1 mice.

    Science.gov (United States)

    Denovan-Wright, Eileen M; Attis, Marissa; Rodriguez-Lebron, Edgardo; Mandel, Ronald J

    2008-06-01

    Huntington's disease (HD) is a neurodegenerative disorder caused by an elongation of CAG repeats in the HD gene, which encodes a mutant copy of huntingtin with an expanded polyglutatmine repeat. Individuals who are affected by the disease suffer from motor, cognitive, and emotional impairments. Levels of certain striatal-enriched mRNAs decrease in both HD patients and transgenic HD mice prior to the development of motor symptoms and neuronal cell death. Ciliary neurotrophic factor (CNTF) has been shown to protect neurons against chemically induced toxic insults in vitro and in vivo. To test the hypothesis that CNTF might protect neurons from the negative effects of the mutant huntingtin protein in vivo, CNTF was continuously expressed following transduction of the striatum by recombinant adeno-associated viral vectors (rAAV2). Wild-type and R6/1 HD transgenic (R6/1) mice that received bilateral or unilateral intrastriatal injections of rAAV2-CNTF experienced weight loss. The CNTF-treated R6/1 HD transgenic mice experienced motor impairments at an earlier age than expected compared with age-matched control R6/1 HD transgenic animals. CNTF also caused abnormal behavior in WT mice. In addition to behavioral impairments, in situ hybridization showed that, in both WT and R6/1 mice, CNTF expression caused a significant decrease in the levels of striatal-enriched transcripts. Overall, continuous expression of striatal CNTF at the dose mediated by the expression cassette used in this study was detrimental to HD and wild-type mice. (c) 2008 Wiley-Liss, Inc.

  5. Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush.

    Science.gov (United States)

    Lee, Nancy; Rydyznski, Carolyn E; Rasch, Matthew S; Trinh, Dennis S; MacLennan, A John

    2017-04-01

    Exogenous ciliary neurotrophic factor (CNTF) administration promotes the survival of motor neurons in a wide range of models. It also increases the expression of the critical neurotransmitter enzyme choline acetyltransferase (ChAT) by in vitro motor neurons, likely independent of its effects on their survival. We have used the adult mouse facial nerve crush model and adult-onset conditional disruption of the CNTF receptor α (CNTFRα) gene to directly examine the in vivo roles played by endogenous CNTF receptors in adult motor neuron survival and ChAT maintenance, independent of developmental functions. We have previously shown that adult activation of the CreER gene construct in floxed CNTFRα mice depletes this essential receptor subunit in a large subset of motor neurons (and all skeletal muscle, as shown in this study) but has no effect on the survival of intact or lesioned motor neurons, indicating that these adult CNTF receptors play no essential survival role in this model, in contrast to their essential role during embryonic development. Here we show that this same CNTFRα depletion does not affect ChAT labeling in nonlesioned motor neurons, but it significantly increases the loss of ChAT following nerve crush. The data suggest that, although neither motor neuron nor muscle CNTF receptors play a significant, nonredundant role in the maintenance of ChAT in intact adult motor neurons, the receptors become essential for ChAT maintenance when the motor neurons are challenged by nerve crush. Therefore, the data suggest that the receptors act as a critical component of an endogenous neuroprotective mechanism. J. Comp. Neurol. 525:1206-1215, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. Ciliary Neurotrophic Factor Stimulates Muscle Glucose Uptake by a PI3-Kinase–Dependent Pathway That Is Impaired With Obesity

    Science.gov (United States)

    Steinberg, Gregory R.; Watt, Matthew J.; Ernst, Matthias; Birnbaum, Morris J.; Kemp, Bruce E.; Jørgensen, Sebastian Beck

    2009-01-01

    OBJECTIVE Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gp130-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. RESEARCH DESIGN AND METHODS Mice were injected intraperitoneally with saline or CNTF, and blood glucose was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKα2 kinase-dead, gp130ΔSTAT, and lean and obese ob/ob and high-fat–fed mice. The effect of C2-ceramide on glucose uptake and gp130 signaling was also examined. RESULTS CNTF reduced blood glucose and increased glucose uptake in isolated muscles in a time- and dose-dependent manner with maximal effects after 30 min with 100 ng/ml. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (KD) and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt phosphorylation were substantially reduced in obesity (high-fat diet and ob/ob) despite normal induction of gp130/AMPK signaling—effects also observed when treating myotubes with C2-ceramide. CONCLUSIONS CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway that does not require AMPK. CNTF-stimulated glucose uptake is impaired in obesity-induced insulin resistance and by ceramide. PMID:19136654

  7. Rescue of axotomized rubrospinal neurons by brain-derived neurotrophic factor (BDNF) in the developing opossum, Didelphis virginiana.

    Science.gov (United States)

    Wang, X M; Terman, J R; Martin, G F

    1999-12-10

    Many rubrospinal neurons die in developing opossums when their axon is cut at thoracic levels of the spinal cord and in the present study we asked whether they can be rescued by brain-derived neurotrophic factor (BDNF). Bilateral injections of Fast Blue (FB) were made into the rostral lumbar cord to prelabel rubrospinal neurons and 5 days later the rubrospinal tract was cut unilaterally by hemisecting the thoracic cord. Immediately after hemisection, BDNF-soaked gelfoam was placed into the lesion cavity. Since pilot data indicated that one application of BDNF was not sufficient to produce a rescue effect, a second application was made 7 days later. Seven days after the second application the pups were killed by an overdose of anesthetic so that the red nucleus contralateral and ipsilateral to the lesion site could be examined for labeled neurons. The rubrospinal tract is almost entirely crossed, so the red nucleus contralateral to the lesion contained many axotomized neurons, whereas the red nucleus ipsilateral to it did not. Age-matched controls were subjected to the same procedures, but the gelfoam applied to the lesion site in the experimental animals was soaked only in the vehicle used to deliver BDNF. In all cases, labeled neurons were fewer in number in the red nucleus contralateral to the lesion than ipsilateral to it. It was of particular interest, however, that labeled neurons contralateral to the lesion were more numerous in the animals treated with BDNF than in the controls. We conclude that BDNF rescues at least some rubrospinal neurons from axotomy-induced cell death in developing opossums suggesting that loss of access to BDNF, and perhaps other neurotrophins, contributes to failure of rubrospinal neurons to survive axotomy.

  8. Brain-Derived Neurotrophic Factor Mediated Perfluorooctane Sulfonate Induced-Neurotoxicity via Epigenetics Regulation in SK-N-SH Cells

    Directory of Open Access Journals (Sweden)

    Xin-Xin Guo

    2017-04-01

    Full Text Available Perfluorooctane sulfonate (PFOS, a new kind of persistent organic pollutant, is widely distributed in the environment and exists in various organisms, where it is also a neurotoxic compound. However, the potential mechanism of its neurotoxicity is still unclear. To examine the role of epigenetics in the neurotoxicity induced by PFOS, SK-N-SH cells were treated with different concentrations of PFOS or control medium (0.1% DMSO for 48 h. The mRNA levels of DNA methyltransferases (DNMTs and Brain-derived neurotrophic factor (BDNF, microRNA-16, microRNA-22, and microRNA-30a-5p were detected by Quantitative PCR (QPCR. Enzyme Linked Immunosorbent Assay (ELISA was used to measure the protein levels of BDNF, and a western blot was applied to analyze the protein levels of DNMTs. Bisulfite sequencing PCR (BSP was used to detect the methylation status of the BDNF promoter I and IV. Results of MTT assays indicated that treatment with PFOS could lead to a significant decrease of cell viability, and the treated cells became shrunk. In addition, PFOS exposure decreased the expression of BDNF at mRNA and protein levels, increased the expression of microRNA-16, microRNA-22, microRNA-30a-5p, and decreased the expression of DNMT1 at mRNA and protein levels, but increased the expression of DNMT3b at mRNA and protein levels. Our results also demonstrate that PFOS exposure changes the methylation status of BDNF promoter I and IV. The findings of the present study suggest that methylation regulation of BDNF gene promoter and increases of BDNF-related-microRNA might underlie the mechanisms of PFOS-induced neurotoxicity.

  9. Physical training prevents depressive symptoms and a decrease in brain-derived neurotrophic factor in Parkinson's disease.

    Science.gov (United States)

    Tuon, T; Valvassori, S S; Dal Pont, G C; Paganini, C S; Pozzi, B G; Luciano, T F; Souza, P S; Quevedo, J; Souza, C T; Pinho, R A

    2014-09-01

    Depression is a neuropsychiatric disorder that is commonly found in patients with Parkinson's disease (PD). Many studies have suggested that physical exercise can have an antidepressant effect by increasing the levels of brain-derived neurotrophic factor (BDNF), and may also prevent neurodegenerative disease. However, different forms of training may promote different changes in the brain. The aim of this study was to investigate the effects of two types of physical training on depressive-like behavior, and on the levels of proBDNF, BDNF, and its receptor, TrkB, in a mouse model of PD. C57BL/6 mice were subjected to 60 days of exercise: either running on a treadmill or performing a strength exercise. PD was induced by striatal administration of 6-OHDA 24h after the last physical exercise session. Seven days after 6-OHDA injection, depressive-like behavior and apomorphine-induced rotational behavior were evaluated. The levels of proBDNF, BDNF, and TRKB were measured in the striatum and the hippocampus of mice by immunoblotting assay. The 6-OHDA-treated animals showed a significant increase in immobility time and rotational behavior compared with the control group. In addition, significant decreases in the levels of proBDNF, BDNF, and its receptor, TrkB were observed in the 6-OHDA group. Both types of physical exercise prevented depressive-like behavior and restored the levels of proBDNF, BDNF, and TrkB in the striatum and hippocampus of mice administered 6-OHDA. Our results demonstrate that exercise training was effective for neuroprotection in the striatum and the hippocampus in an experimental model of PD. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Neural Stem Cell Transplantation Promotes Functional Recovery from Traumatic Brain Injury via Brain Derived Neurotrophic Factor-Mediated Neuroplasticity.

    Science.gov (United States)

    Xiong, Liu-Lin; Hu, Yue; Zhang, Piao; Zhang, Zhuo; Li, Li-Hong; Gao, Guo-Dong; Zhou, Xin-Fu; Wang, Ting-Hua

    2017-04-18

    Traumatic brain injury (TBI) induces cognitive impairments, motor and behavioral deficits. Previous evidences have suggested that neural stem cell (NSC) transplantation could facilitate functional recovery from brain insults, but their underlying mechanisms remains to be elucidated. Here, we established TBI model by an electromagnetic-controlled cortical impact device in the rats. Then, 5 μl NSCs (5.0 × 10 5 /μl), derived from green fluorescent protein (GFP) transgenic mouse, was transplanted into the traumatic brain regions of rats at 24 h after injury. After differentiation of the NSCs was determined using immunohistochemistry, neurological severity scores (NSS) and rotarod test were conducted to detect the neurological behavior. Western blot and RT-PCR as well as ELASA were used to evaluate the expression of synaptophysin and brain-derived neurotrophic factor (BDNF). In order to elucidate the role of BDNF on the neural recovery after NSC transplantation, BDNF knockdown in NSC was performed and transplanted into the rats with TBI, and potential mechanism for BDNF knockdown in the NSC was analyzed using microassay analysis. Meanwhile, BDNF antibody blockade was conducted to further confirm the effect of BDNF on neural activity. As a result, an increasing neurological function improvement was seen in NSC transplanted rats, which was associated with the upregulation of synaptophysin and BDNF expression. Moreover, transplantation of BDNF knockdown NSCs and BDNF antibody block reduced not only the level of synaptophysin but also exacerbated neurological function deficits. Microassay analysis showed that 14 genes such as Wnt and Gsk3-β were downregulated after BDNF knockdown. The present data therefore showed that BDNF-mediated neuroplasticity underlie the mechanism of NSC transplantation for the treatment of TBI in adult rats.

  11. Hippocampal brain-derived neurotrophic factor mediates recovery from chronic stress-induced spatial reference memory deficits.

    Science.gov (United States)

    Ortiz, J Bryce; Mathewson, Coy M; Hoffman, Ann N; Hanavan, Paul D; Terwilliger, Ernest F; Conrad, Cheryl D

    2014-11-01

    Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain-derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the dorsal hippocampal cornu ammonis (CA)3 region with an adeno-associated viral vector containing the sequence for a short hairpin RNA (shRNA) directed against BDNF or a scrambled sequence (Scr). Rats were then chronically restrained (wire mesh, 6 h/day for 21 days) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trials. Rats in the Str-Imm group, regardless of adeno-associated viral contents, committed more errors in the spatial reference memory domain on the single retention trial during day 3 than did the non-stressed controls. Importantly, the typical improvement in spatial memory following the recovery from chronic stress was blocked with the shRNA against BDNF, as Str-Rec-shRNA performed worse on the RAWM compared with the non-stressed controls or Str-Rec-Scr. The stress effects were specific for the reference memory domain, but knockdown of hippocampal BDNF in unstressed controls briefly disrupted spatial working memory as measured by repeated entry errors on day 2 of training. These results demonstrated that hippocampal BDNF was necessary for the recovery from stress-induced hippocampal-dependent spatial memory deficits in the reference memory domain. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  12. Association of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism with early-onset bipolar disorder.

    Science.gov (United States)

    Nassan, Malik; Croarkin, Paul E; Luby, Joan L; Veldic, Marin; Joshi, Paramjit T; McElroy, Susan L; Post, Robert M; Walkup, John T; Cercy, Kelly; Geske, Jennifer R; Wagner, Karen D; Cuellar-Barboza, Alfredo B; Casuto, Leah; Lavebratt, Catharina; Schalling, Martin; Jensen, Peter S; Biernacka, Joanna M; Frye, Mark A

    2015-09-01

    Brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) functional polymorphism has been implicated in early-onset bipolar disorder. However, results of studies are inconsistent. We aimed to further explore this association. DNA samples from the Treatment of Early Age Mania (TEAM) and Mayo Clinic Bipolar Disorder Biobank were investigated for association of rs6265 with early-onset bipolar disorder. Bipolar cases were classified as early onset if the first manic or depressive episode occurred at age ≤19 years (versus adult-onset cases at age >19 years). After quality control, 69 TEAM early-onset bipolar disorder cases, 725 Mayo Clinic bipolar disorder cases (including 189 early-onset cases), and 764 controls were included in the analysis of association, assessed with logistic regression assuming log-additive allele effects. Comparison of TEAM cases with controls suggested association of early-onset bipolar disorder with the rs6265 minor allele [odds ratio (OR) = 1.55, p = 0.04]. Although comparison of early-onset adult bipolar disorder cases from the Mayo Clinic versus controls was not statistically significant, the OR estimate indicated the same direction of effect (OR = 1.21, p = 0.19). When the early-onset TEAM and Mayo Clinic early-onset adult groups were combined and compared with the control group, the association of the minor allele rs6265 was statistically significant (OR = 1.30, p = 0.04). These preliminary analyses of a relatively small sample with early-onset bipolar disorder are suggestive that functional variation in BDNF is implicated in bipolar disorder risk and may have a more significant role in early-onset expression of the disorder. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Alterations in brain-derived neurotrophic factor in the mouse hippocampus following acute but not repeated benzodiazepine treatment.

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    Stephanie C Licata

    Full Text Available Benzodiazepines (BZs are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP, an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p. injections of diazepam (10 mg/kg + 5 mg/kg or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg, acute i.p. administration of both triazolam (0.03 mg/kg and ZP (1.0 mg/kg decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2 with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly.

  14. Brain-derived neurotrophic factor from bone marrow-derived cells promotes post-injury repair of peripheral nerve.

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    Yoshinori Takemura

    Full Text Available Brain-derived neurotrophic factor (BDNF stimulates peripheral nerve regeneration. However, the origin of BNDF and its precise effect on nerve repair have not been clarified. In this study, we examined the role of BDNF from bone marrow-derived cells (BMDCs in post-injury nerve repair. Control and heterozygote BDNF knockout mice (BDNF+/- received a left sciatic nerve crush using a cerebral blood clip. Especially, for the evaluation of BDNF from BMDCs, studies with bone marrow transplantation (BMT were performed before the injury. We evaluated nerve function using a rotarod test, sciatic function index (SFI, and motor nerve conduction velocity (MNCV simultaneously with histological nerve analyses by immunohistochemistry before and after the nerve injury until 8 weeks. BDNF production was examined by immunohistochemistry and mRNA analyses. After the nerve crush, the controls showed severe nerve dysfunction evaluated at 1 week. However, nerve function was gradually restored and reached normal levels by 8 weeks. By immunohistochemistry, BDNF expression was very faint before injury, but was dramatically increased after injury at 1 week in the distal segment from the crush site. BDNF expression was mainly co-localized with CD45 in BMDCs, which was further confirmed by the appearance of GFP-positive cells in the BMT study. Variant analysis of BDNF mRNA also confirmed this finding. BDNF+/- mice showed a loss of function with delayed histological recovery and BDNF+/+→BDNF+/- BMT mice showed complete recovery both functionally and histologically. These results suggested that the attenuated recovery of the BDNF+/- mice was rescued by the transplantation of BMCs and that BDNF from BMDCs has an essential role in nerve repair.

  15. Inhibition of Inwardly Rectifying Potassium (Kir 4.1 Channels Facilitates Brain-Derived Neurotrophic Factor (BDNF Expression in Astrocytes

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    Masato Kinboshi

    2017-12-01

    Full Text Available Inwardly rectifying potassium (Kir 4.1 channels in astrocytes regulate neuronal excitability by mediating spatial potassium buffering. Although dysfunction of astrocytic Kir4.1 channels is implicated in the development of epileptic seizures, the functional mechanisms of Kir4.1 channels in modulating epileptogenesis remain unknown. We herein evaluated the effects of Kir4.1 inhibition (blockade and knockdown on expression of brain-derived neurotrophic factor (BDNF, a key modulator of epileptogenesis, in the primary cultures of mouse astrocytes. For blockade of Kir4.1 channels, we tested several antidepressant agents which reportedly bound to and blocked Kir4.1 channels in a subunit-specific manner. Treatment of astrocytes with fluoxetine enhanced BDNF mRNA expression in a concentration-dependent manner and increased the BDNF protein level. Other antidepressants (e.g., sertraline and imipramine also increased the expression of BDNF mRNA with relative potencies similar to those for inhibition of Kir4.1 channels. In addition, suppression of Kir4.1 expression by the transfection of small interfering RNA (siRNA targeting Kir4.1 significantly increased the mRNA and protein levels of BDNF. The BDNF induction by Kir4.1 siRNA transfection was suppressed by the MEK1/2 inhibitor U0126, but not by the p38 MAPK inhibitor SB202190 or the JNK inhibitor SP600125. The present results demonstrated that inhibition of Kir4.1 channels facilitates BDNF expression in astrocytes primarily by activating the Ras/Raf/MEK/ERK pathway, which may be linked to the development of epilepsy and other neuropsychiatric disorders.

  16. Brain derived neurotrophic factor contributes to the cardiogenic potential of adult resident progenitor cells in failing murine heart.

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    Rasmita Samal

    Full Text Available Resident cardiac progenitor cells show homing properties when injected into the injured but not to the healthy myocardium. The molecular background behind this difference in behavior needs to be studied to elucidate how adult progenitor cells can restore cardiac function of the damaged myocardium. Since the brain derived neurotrophic factor (BDNF moderates cardioprotection in injured hearts, we focused on delineating its regulatory role in the damaged myocardium.Comparative gene expression profiling of freshly isolated undifferentiated Sca-1 progenitor cells derived either from heart failure transgenic αMHC-CyclinT1/Gαq overexpressing mice or wildtype littermates revealed transcriptional variations. Bdnf expression was up regulated 5-fold during heart failure which was verified by qRT-PCR and confirmed at protein level. The migratory capacity of Sca-1 cells from transgenic hearts was improved by 15% in the presence of 25 ng/ml BDNF. Furthermore, BDNF-mediated effects on Sca-1 cells were studied via pulsed Stable Isotope Labeling of Amino acids in Cell Culture (pSILAC proteomics approach. After BDNF treatment significant differences between newly synthesized proteins in Sca-1 cells from control and transgenic hearts were observed for CDK1, SRRT, HDGF, and MAP2K3 which are known to regulate cell cycle, survival and differentiation. Moreover BDNF repressed the proliferation of Sca-1 cells from transgenic hearts.Comparative profiling of resident Sca-1 cells revealed elevated BDNF levels in the failing heart. Exogenous BDNF (i stimulated migration, which might improve the homing ability of Sca-1 cells derived from the failing heart and (ii repressed the cell cycle progression suggesting its potency to ameliorate heart failure.

  17. Differential brain-derived neurotrophic factor expression in limbic brain regions following social defeat or territorial aggression.

    Science.gov (United States)

    Taylor, Stacie L; Stanek, Lisa M; Ressler, Kerry J; Huhman, Kim L

    2011-12-01

    Syrian hamsters readily form dominant-subordinate relationships under laboratory conditions. Winning or losing in agonistic encounters can have striking, long-term effects on social behavior, but the mechanisms underlying this experience-induced behavioral plasticity are unclear. The present study tested the hypothesis that changes in brain-derived neurotrophic factor (BDNF) may at least in part mediate this plasticity. Male hamsters were paired for 15-min using a resident-intruder model, and individuals were identified as winners or losers on the basis of their behavior. BDNF was examined with in situ hybridization 2 hr after treatment during the consolidation period of emotional learning. Losing animals had significantly more BDNF mRNA in the basolateral (BLA) and medial (MeA) nuclei of the amygdala when compared with winning animals as well as novel cage and home cage controls. Interestingly, winning animals had significantly more BDNF mRNA in the dentate gyrus of the dorsal hippocampus than did losing animals, novel, and home cage controls. No conflict-related changes in BDNF mRNA were observed in several other regions including the bed nucleus of the stria terminalis and central amygdala. Next, we demonstrated that K252a, a Trk receptor antagonist, significantly reduced the acquisition of conditioned defeat when administered within the BLA. These data support a model in which BDNF-mediated plasticity within the BLA supports learning of submission or subordinate social status in losing animals, whereas BDNF-mediated plasticity within the hippocampus may instantiate aspects of winning such as control of a territory in dominant animals. PsycINFO Database Record (c) 2011 APA, all rights reserved.

  18. Opposite effects of a high-fat diet and calorie restriction on ciliary neurotrophic factor signalling in the mouse hypothalamus

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    Ilenia eSeveri

    2013-12-01

    Full Text Available In the mouse hypothalamus, ciliary neurotrophic factor (CNTF is mainly expressed by ependymal cells and tanycytes of the ependymal layer covering the third ventricle. Since exogenously administered CNTF causes reduced food intake and weight loss, we tested whether endogenous CNTF might be involved in energy balance regulation. We thus evaluated CNTF production and responsiveness in the hypothalamus of mice fed a high-fat diet (HFD, of ob/ob obese mice, and of mice fed a calorie restriction (CR regimen. RT-PCR showed that CNTF mRNA increased significantly in HFD mice and decreased significantly in CR animals. Western blotting confirmed that CNTF expression was higher in HFD mice and reduced in CR mice, but high interindividual variability blunted the significance of these differences. By immunohistochemistry, hypothalamic tuberal and mammillary region tanycytes stained strongly for CNTF in HFD mice, whereas CR mice exhibited markedly reduced staining. RT-PCR and Western blotting disclosed that changes in CNTF expression were paralleled by changes in the expression of its specific receptor, CNTF receptor α (CNTFRα. Injection of recombinant CNTF and detection of phospho-signal transducer and activator of transcription 3 (P-STAT3 showed that CNTF responsiveness by the ependymal layer, mainly by tanycytes, was higher in HFD than CR mice. In addition, in HFD mice CNTF administration induced distinctive STAT3 signalling in a large neuron population located in the dorsomedial and ventromedial nuclei, perifornical area and mammillary body. The hypothalamic expression of CNTF and CNTFRα did not change in the hyperphagic, leptin-deficient ob/ob obese mice; accordingly, P-STAT3 immunoreactivity in CNTF-treated ob/ob mice was confined to ependymal layer and arcuate neurons. Collectively, these data suggest that hypothalamic CNTF is involved in controlling the energy balance and that CNTF signalling plays a role in HFD obese mice at specific sites.

  19. Brain-derived neurotrophic factor serum levels in genetically isolated populations: gender-specific association with anxiety disorder subtypes but not with anxiety levels or Val66Met polymorphism

    OpenAIRE

    Carlino, Davide; Francavilla, Ruggiero; Baj, Gabriele; Kulak, Karolina; d?Adamo, Pio; Ulivi, Sheila; Cappellani, Stefania; Gasparini, Paolo; Tongiorgi, Enrico

    2015-01-01

    Anxiety disorders (ADs) are disabling chronic disorders with exaggerated behavioral response to threats. This study was aimed at testing the hypothesis that ADs may be associated with reduced neurotrophic activity, particularly of Brain-derived neurotrophic factor (BDNF), and determining possible effects of genetics on serum BDNF concentrations. In 672 adult subjects from six isolated villages in North-Eastern Italy with high inbreeding, we determined serum BDNF levels and identified subjects...

  20. Association of Functional Polymorphisms from Brain-Derived Neurotrophic Factor and Serotonin-Related Genes with Depressive Symptoms after a Medical Stressor in Older Adults

    Science.gov (United States)

    Rawson, Kerri S.; Dixon, David; Nowotny, Petra; Ricci, William M.; Binder, Ellen F.; Rodebaugh, Thomas L.; Wendleton, Leah; Doré, Peter; Lenze, Eric J.

    2015-01-01

    Depressive symptoms are common in older adults after a disabling medical event and interfere with rehabilitation and recovery from the disability. This prospective study examined the role of genetic polymorphisms implicated in synaptic integrity and stress-associated depression as predictors of depressive symptoms after hip fracture. We recruited healthy comparisons from the community and participants with hip fracture after surgical fixation from Saint Louis, Missouri hospitals. We examined the valine (Val) to methionine (Met) polymorphism in brain-derived neurotrophic factor (BDNF), serotonin 1A receptor (5HT1a-rs6295) polymorphism, and the serotonin transporter-linked polymorphic region (5HTTLPR) interaction with the rs25531 A to G single nucleotide polymorphism (5HTTLPR-rs25531) as predictors of depressive symptoms. We also examined whether depressive symptoms mediate the influence of BDNF genotype on functional recovery. Among 429 participants with hip fracture, BDNF Met/Met carriers developed significantly more depressive symptoms than Val/Val carriers during a four-week period after the fracture (p=.012). BDNF genotype also predicted functional recovery over the ensuing year, mediated by its effects on depressive symptoms (CI: 0.07-3.37). Unlike prior studies of stressful life events, the S′ 5HTTLPR-rs25531 variant did not predict higher levels of depressive symptoms; instead, we report an exploratory finding of an epistatic effect between BDNF and 5HTTLPR-rs25531 whereby the compounded effects of two LA alleles and BDNF Met/Met genotype elevate risk of depressive symptoms after hip fracture (p=.006). No differences between 5HT1a genotypes were found. Our findings suggest plasticity-related genetic factors contribute to the neural mechanisms of mental and functional well-being after a disabling medical stressor. PMID:25781924

  1. Effects of Resistance Training on Muscle Strength, Endurance, and Motor Unit According to Ciliary Neurotrophic Factor Polymorphism in Male College Students

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    Ae-Rim Hong, Sang-Min Hong, Yun-A Shin

    2014-09-01

    Full Text Available Changes in muscle mass and strength across the adult age span are variable and related to the ciliary neurotrophic factor (CNTF genotype. In particular, a single CNTF haplotype (1357 G→A is important for neuronal and muscular developments and may be associated with muscle strength response to resistance training. We examined whether CNTF genotype differentially influences the effect of resistance training on neuromuscular improvement in male college students. Resistance training of the upper extremities comprised 3 sets at 75%–85% intensity per 1 repetition maximum, 3 times a week, for a total of 8 weeks. We measured isokinetic muscle function of the elbow joint with regard to strength (60°/s and endurance (180°/s by using an isokinetic dynamometer. The biceps brachii (BB and brachioradialis muscles were studied using surface electromyography with spike-triggered averaging to assess surface-detected motor unit potential (SMUP area. After resistance training, the SMUP of the BB increased significantly at 60°/s (p < 0.05, but no difference in the CNTF genotype was observed. The SMUP of the BB at 180°/s increased significantly in the GG/AA genotype group compared with that in the GA genotype group (p < 0.05. The average power of the elbow flexor at 180°/s increased significantly after resistance training (p < 0.05, but again, no difference in the CNTF genotype was observed. Thus, improvements in muscle strength and endurance may have resulted directly from resistance training rather than from genetic factors related to nerves in muscle tissue.

  2. Neurokinin-1 (NK-1 receptor and brain-derived neurotrophic factor (BDNF gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain

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    McCarson Kenneth E

    2007-10-01

    Full Text Available Abstract Persistent pain produces complex alterations in sensory pathways of the central nervous system (CNS through activation of various nociceptive mechanisms. However, the effects of pain on higher brain centers, particularly the influence of the stressful component of pain on the limbic system, are poorly understood. Neurokinin-1 (NK-1 receptors and brain-derived neurotrophic factor (BDNF, known neuromediators of hyperalgesia and spinal central sensitization, have also been implicated in the plasticity and neurodegeneration occurring in the hippocampal formation during exposures to various stressors. Results of this study showed that injections of complete Freund's adjuvant (CFA into the hind paw increased NK-1 receptor and BDNF mRNA levels in the ipsilateral dorsal horn, supporting an important role for these nociceptive mediators in the amplification of ascending pain signaling. An opposite effect was observed in the hippocampus, where CFA down-regulated NK-1 receptor and BDNF gene expression, phenomena previously observed in immobilization models of stress and depression. Western blot analyses demonstrated that in the spinal cord, CFA also increased levels of phosphorylated cAMP response element-binding protein (CREB, while in the hippocampus the activation of this transcription factor was significantly reduced, further suggesting that tissue specific transcription of either NK-1 or BDNF genes may be partially regulated by common intracellular transduction mechanisms mediated through activation of CREB. These findings suggest that persistent nociception induces differential regional regulation of NK-1 receptor and BDNF gene expression and CREB activation in the CNS, potentially reflecting varied roles of these neuromodulators in the spinal cord during persistent sensory activation vs. modulation of the higher brain structures such as the hippocampus.

  3. Molecular phylogeny of the antiangiogenic and neurotrophic serpin, pigment epithelium derived factor in vertebrates

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    Barnstable Colin J

    2006-10-01

    Full Text Available Abstract Background Pigment epithelium derived factor (PEDF, a member of the serpin family, regulates cell proliferation, promotes survival of neurons, and blocks growth of new blood vessels in mammals. Defining the molecular phylogeny of PEDF by bioinformatic analysis is one approach to understanding the link between its gene structure and its function in these biological processes. Results From a comprehensive search of available DNA databases we identified a single PEDF gene in all vertebrate species examined. These included four mammalian and six non-mammalian vertebrate species in which PEDF had not previously been described. A five gene cluster around PEDF was found in an approximate 100 kb region in mammals, birds, and amphibians. In ray-finned fish these genes are scattered over three chromosomes although only one PEDF gene was consistently found. The PEDF gene is absent in invertebrates including Drosophila melanogaster (D. melanogaster, Caenorhabditis elegans (C. elegans, and sea squirt (C. intestinalis. The PEDF gene is transcribed in all vertebrate phyla, suggesting it is biologically active throughout vertebrate evolution. The multiple actions of PEDF are likely conserved in evolution since it has the same gene structure across phyla, although the size of the gene ranges from 48.3 kb in X. tropicalis to 2.9 kb in fugu, with human PEDF at a size of 15.6 kb. A strong similarity in the proximal 200 bp of the PEDF promoter in mammals suggests the existence of a possible regulatory region across phyla. Using a non-synonymous/synonymous substitution rate ratio we show that mammalian and fish PEDFs have similar ratios of Conclusion The PEDF gene first appears in vertebrates and our studies suggest that the regulation and biological actions of this gene are preserved across vertebrates. This comprehensive analysis of the PEDF gene across phyla provides new information that will aid further characterization of common functional motifs of

  4. Postresuscitative Changes of Brain-Derived Neurotrophic Factor (BDNF Protein Expression: Association With Neuronal Death

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    M. Sh. Avrushchenko

    2017-01-01

    populations. The results suggest that the level of BDNF expression is one of factors that have a significant effect on neuronal resistance to ischemia-reperfusion. A possibility of induction of the endogenous BDNF expression in order to prevent neuronal death is discussed. 

  5. Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence

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    Timothy eDurazzo

    2012-10-01

    Full Text Available Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF and catechol-o-methyltransferase (COMT are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of these polymorphisms on neurocognition in alcohol dependence is unclear. The goal of this report was to investigate the associations of single nucleotide polymorphisms (SNP in BDNF Val66Met and COMT Val158Met with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. Smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains. COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that observed COMT Met carriers showed better performance on measures of executive skills and general intelligence. Overall, the findings support to the expanding clinical movement to make smoking cessation programs available at the inception of

  6. Brain-Derived Neurotrophic Factor Val66Met Polymorphism Affects the Relationship Between an Anxiety-Related Personality Trait and Resting Regional Cerebral Blood Flow.

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    Wei, Shau-Ming; Eisenberg, Daniel P; Nabel, Katherine G; Kohn, Philip D; Kippenhan, J Shane; Dickinson, Dwight; Kolachana, Bhaskar; Berman, Karen F

    2017-03-01

    Brain-derived neurotrophic factor (BDNF) is an important modulator of constitutive stress responses mediated by limbic frontotemporal circuits, and its gene contains a functional polymorphism (Val66Met) that may influence trait stress sensitivity. Reports of an association of this polymorphism with anxiety-related personality traits have been controversial and without clear neurophysiological support. We, therefore, determined the relationship between resting regional cerebral blood flow (rCBF) and a well-validated measure of anxiety-related personality, the TPQ Harm Avoidance (HA) scale, as a function of BDNF Val66Met genotype. Sixty-four healthy participants of European ancestry underwent resting H215O positron emission tomography scans. For each genotype group separately, we first determined the relationship between participants' HA scores and their resting rCBF values in each voxel across the entire brain, and then directly compared these HA-rCBF relationships between Val66Met genotype groups. HA-rCBF relationships differed between Val homozygotes and Met carriers in several regions relevant to stress regulation: subgenual cingulate, orbital frontal cortex, and the hippocampal/parahippocampal region. In each of these areas, the relationship was positive in Val homozygotes and negative in Met carriers. These data demonstrate a coupling between trait anxiety and basal resting blood flow in frontolimbic neurocircuitry that may be determined in part by genetically mediated BDNF signaling. Published by Oxford University Press 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  7. Brain-derived neurotrophic factor Val⁶⁶Met polymorphism affects resting regional cerebral blood flow and functional connectivity differentially in women versus men.

    Science.gov (United States)

    Wei, Shau-Ming; Eisenberg, Daniel P; Kohn, Philip D; Kippenhan, Jonathan S; Kolachana, Bhaskar S; Weinberger, Daniel R; Berman, Karen F

    2012-05-16

    The human Val⁶⁶Met single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts BDNF signaling at the cellular level. At the neural-systems level, it is associated with differences in prefrontal cortex (PFC) and hippocampal function during performance of cognitive and affective tasks. Because the impact of this variant on basal prefrontal and hippocampal activity is not known but may be relevant to understanding the function of this gene in health and disease, we studied 94 healthy individuals with H₂ ¹⁵O PET to assess regional cerebral blood flow (rCBF) during rest and tested for between-genotype differences. Because BDNF and gonadal steroid hormones conjointly influence neuronal growth, survival, and plasticity in hippocampus and PFC, we also tested for sex × genotype interactions. Finally, in light of the known impact of BDNF on plasticity and dendritic arborization, we complimented direct rCBF comparisons with connectivity analyses to determine how activity in hippocampal and prefrontal regions showing between-genotype group differences covaries with rCBF in other nodes throughout the brain in a genotype- or sex-dependent manner. Compared with Val homozygotes, Met carriers had higher rCBF in prefrontal (BA25 extending into BA10) and hippocampal/parahippocampal regions. Moreover, there were significant sex × genotype interactions in regions (including frontal, parahippocampal, and lateral temporal cortex) in which Val homozygotes showed higher rCBF in females than males, but Met carriers showed the opposite relationship. Functional connectivity analysis demonstrated that correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes and negative for Met carriers. In addition, sex × genotype analysis of functional connectivity revealed that genotype affected directionality of the inter-regional correlations differentially in men versus women. Our data indicate

  8. Resveratrol Produces Neurotrophic Effects on Cultured Dopaminergic Neurons through Prompting Astroglial BDNF and GDNF Release

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    Feng Zhang

    2012-01-01

    Full Text Available Increasing evidence indicated astroglia-derived neurotrophic factors generation might hold a promising therapy for Parkinson’s disease (PD. Resveratrol, naturally present in red wine and grapes with potential benefit for health, is well known to possess a number of pharmacological activities. Besides the antineuroinflammatory properties, we hypothesized the neuroprotective potency of resveratrol is partially due to its additional neurotrophic effects. Here, primary rat midbrain neuron-glia cultures were applied to investigate the neurotrophic effects mediated by resveratrol on dopamine (DA neurons and further explore the role of neurotrophic factors in its actions. Results showed resveratrol produced neurotrophic effects on cultured DA neurons. Additionally, astroglia-derived neurotrophic factors release was responsible for resveratrol-mediated neurotrophic properties as evidenced by the following observations: (1 resveratrol failed to exert neurotrophic effects on DA neurons in the cultures without astroglia; (2 the astroglia-conditioned medium prepared from astroglia-enriched cultures treated with resveratrol produced neurotrophic effects in neuron-enriched cultures; (3 resveratrol increased neurotrophic factors release in the concentration- and time-dependent manners; (4 resveratrol-mediated neurotrophic effects were suppressed by blocking the action of the neurotrophic factors. Together, resveratrol could produce neurotrophic effects on DA neurons through prompting neurotrophic factors release, and these effects might open new alternative avenues for neurotrophic factor-based therapy targeting PD.

  9. Human ciliary neurotrophic factor-overexpressing stable bone marrow stromal cells in the treatment of a rat model of traumatic spinal cord injury.

    Science.gov (United States)

    Abbaszadeh, Hojjat-Allah; Tiraihi, Taki; Noori-Zadeh, Ali; Delshad, Ali Reza; Sadeghizade, Majid; Taheri, Taher

    2015-07-01

    Traumatic injury to the central nervous system (CNS) often causes motor dysfunctions. However, because of the CNS complexity and variability in the clinical presentations, efforts to repair damaged CNS tissue and restoring its functions are particularly demanding. On the other hand, recent progress in the regenerative therapy field have led to novel approaches for the treatment of traumatic CNS injury and renewed hopes to overcome the obstacles. It appears that the balance between neurite re-growth-inhibiting and neurite re-growth-inducing molecules determines the axonal re-growth fate. Neurotrophic factors can tilt this balance and indeed promote cell survival and axonal re-growth over neurodegeneration. One of the promising neurotrophic factors in this field is ciliary neurotrophic factor (CNTF). We transfected rat bone marrow stromal cells with a mammalian expression vector-inserted human CNTF gene through the use of a non-viral method to prepare human CNTF-overexpressing stem cells under ex vivo conditions. We transplanted these modified cells to the rat model of spinal cord traumatic injury to explore functional recovery after contusion induction. Our data from immunocytochemistry and behavioral tests showed that such cells can act as a powerful potential approach to treat traumatic CNS injuries because these modified cells improved the behavioral test scores in the rat model of spinal cord injury. CNTF-overexpressing bone marrow stromal cells can ameliorate spinal cord traumatic injury and can be used in the treatment of traumatic CNS injuries in the near future. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  10. Intravitreal Ciliary Neurotrophic Factor Transiently Improves Cone-Mediated Function in a CNGB3−/− Mouse Model of Achromatopsia

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    Marangoni, Dario; Vijayasarathy, Camasamudram; Bush, Ronald A.; Wei, Lisa L.; Wen, Rong; Sieving, Paul A.

    2015-01-01

    Purpose Ciliary neurotrophic factor (CNTF) was recently shown to augment cone function in CNGB3 mutant achromat dogs. However, testing CNTF-releasing implant in human CNGB3 achromats failed to show benefit. We evaluated the effects of CNTF protein on the retinal function in an additional achromatopsia model, the CNGB3−/− mouse. Methods Fifty-nine CNGB3−/− mice (postnatal day [PD] ± SD = 30 ± 7) received a unilateral intravitreal injection of 1 or 2 μg CNTF protein, and 15 wild-type (WT) mice (PD = 34 ± 3) received 1 μg CNTF. Retinal function was evaluated by flash ERG and photopic flicker ERG (fERG) at 7 and 14 days after treatment. Results Seven days post CNTF, the photopic b-wave Vmax was significantly increased in CNGB3−/− mice (P < 0.01), whereas it was reduced in WT mice (P < 0.05). Ciliary neurotrophic factor significantly increased the amplitude of photopic fERG and the photopic oscillatory potentials (OPs) in CNGB3−/− mice. Ciliary neurotrophic factor did not alter the scotopic a-wave in either CNGB3−/− or WT mice, but it increased the scotopic b-wave k (P < 0.01) in CNGB3−/− mice, indicating diminished scotopic sensitivity, and reduced the scotopic b-wave Vmax in WT mice (P < 0.05). No difference was found in ERG parameters between 1 or 2 μg CNTF. Fourteen days after CNTF injection the ERG changes in CNGB3−/− mice were lost. Conclusions Intravitreal bolus CNTF protein caused a small and transient improvement of cone-mediated function in CNGB3−/− mice, whereas it reduced rod-mediated function. The increase in photopic OPs and the lack of changes in scotopic a-wave suggest a CNTF effect on the inner retina. PMID:26567794

  11. Brain-Derived Neurotrophic Factor Elevates Activating Transcription Factor 4 (ATF4 in Neurons and Promotes ATF4-Dependent Induction of Sesn2

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    Jin Liu

    2018-03-01

    Full Text Available Activating transcription factor 4 (ATF4 plays important physiologic roles in the brain including regulation of learning and memory as well as neuronal survival and death. Yet, outside of translational regulation by the eIF2α-dependent stress response pathway, there is little information about how its levels are controlled in neurons. Here, we show that brain-derived neurotrophic factor (BDNF promotes a rapid and sustained increase in neuronal ATF4 transcripts and protein levels. This increase is dependent on tropomyosin receptor kinase (TrkB signaling, but independent of levels of phosphorylated eIF2α. The elevation in ATF4 protein occurs both in nuclei and processes. Transcriptome analysis revealed that ATF4 mediates BDNF-promoted induction of Sesn2 which encodes Sestrin2, a protector against oxidative and genotoxic stresses and a mTor complex 1 inhibitor. In contrast, BDNF-elevated ATF4 did not affect expression of a number of other known ATF4 targets including several with pro-apoptotic activity. The capacity of BDNF to elevate neuronal ATF4 may thus represent a means to maintain this transcription factor at levels that provide neuroprotection and optimal brain function without risk of triggering neurodegeneration.

  12. Neuroprotective and axon growth-promoting effects following inflammatory stimulation on mature retinal ganglion cells in mice depend on ciliary neurotrophic factor and leukemia inhibitory factor.

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    Leibinger, Marco; Müller, Adrienne; Andreadaki, Anastasia; Hauk, Thomas G; Kirsch, Matthias; Fischer, Dietmar

    2009-11-11

    After optic nerve injury retinal ganglion cells (RGCs) normally fail to regenerate axons in the optic nerve and undergo apoptosis. However, lens injury (LI) or intravitreal application of zymosan switch RGCs into an active regenerative state, enabling these neurons to survive axotomy and to regenerate axons into the injured optic nerve. Several factors have been proposed to mediate the beneficial effects of LI. Here, we investigated the contribution of glial-derived ciliary neurotrophic factor (CNTF) to LI-mediated regeneration and neuroprotection using wild-type and CNTF-deficient mice. In wild-type mice, CNTF expression was strongly upregulated in retinal astrocytes, the JAK/STAT3 pathway was activated in RGCs, and RGCs were transformed into an active regenerative state after LI. Interestingly, retinal LIF expression was correlated with CNTF expression after LI. In CNTF-deficient mice, the neuroprotective and axon growth-promoting effects of LI were significantly reduced compared with wild-type animals, despite an observed compensatory upregulation of LIF expression in CNTF-deficient mice. The positive effects of LI and also zymosan were completely abolished in CNTF/LIF double knock-out mice, whereas LI-induced glial and macrophage activation was not compromised. In culture CNTF and LIF markedly stimulated neurite outgrowth of mature RGCs. These data confirm a key role for CNTF in directly mediating the neuroprotective and axon regenerative effects of inflammatory stimulation in the eye and identify LIF as an additional contributing factor.

  13. Chronic heroin and cocaine abuse is associated with decreased serum concentrations of the nerve growth factor and brain-derived neurotrophic factor.

    Science.gov (United States)

    Angelucci, Francesco; Ricci, Valerio; Pomponi, Massimiliano; Conte, Gianluigi; Mathé, Aleksander A; Attilio Tonali, Pietro; Bria, Pietro

    2007-11-01

    Chronic cocaine and heroin users display a variety of central nervous system (CNS) dysfunctions including impaired attention, learning, memory, reaction time, cognitive flexibility, impulse control and selective processing. These findings suggest that these drugs may alter normal brain functions and possibly cause neurotoxicity. Neurotrophins are a class of proteins that serve as survival factors for CNS neurons. In particular, nerve growth factor (NGF) plays an important role in the survival and function of cholinergic neurons while brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity and in the maintenance of midbrain dopaminergic and cholinergic neurons. In the present study, we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF levels in serum of three groups of subjects: heroin-dependent patients, cocaine-dependent patients and healthy volunteers. Our goal was to identify possible change in serum neurotrophins in heroin and cocaine users. BDNF was decreased in heroin users whereas NGF was decreased in both heroin and cocaine users. These findings indicate that NGF and BDNF may play a role in the neurotoxicity and addiction induced by these drugs. In view of the neurotrophin hypothesis of schizophrenia the data also suggest that reduced level of neurotrophins may increase the risk of developing psychosis in drug users.

  14. Alteration of the irisin–brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients

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    Papp C

    2017-07-01

    Full Text Available Csaba Papp,1 Krisztian Pak,2 Tamas Erdei,2 Bela Juhasz,2 Ildiko Seres,3 Anita Szentpéteri,3 Laszlo Kardos,4 Maria Szilasi,5 Rudolf Gesztelyi,2 Judit Zsuga1 1Department of Health Systems Management and Quality Management for Health Care, Faculty of Public Health, 2Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, 3Department of Internal Medicine, Faculty of Medicine, University of Debrecen, 4Department of Clinical Pharmacology, Infectious Diseases and Allergology, Kenezy Gyula Teaching County Hospital and Outpatient Clinic, 5Department of Pulmonology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Abstract: COPD is accompanied by limited physical activity, worse quality of life, and increased prevalence of depression. A possible link between COPD and depression may be irisin, a myokine, expression of which in the skeletal muscle and brain positively correlates with physical activity. Irisin enhances the synthesis of brain-derived neurotrophic factor (BDNF, a neurotrophin involved in reward-related processes. Thus, we hypothesized that mood disturbances accompanying COPD are reflected by the changes in the irisin–BDNF axis. Case history, routine laboratory parameters, serum irisin and BDNF levels, pulmonary function, and disease-specific quality of life, measured by St George’s Respiratory Questionnaire (SGRQ, were determined in a cohort of COPD patients (n=74. Simple and then multiple linear regression were used to evaluate the data. We found that mood disturbances are associated with lower serum irisin levels (SGRQ’s Impacts score and reciprocal of irisin showed a strong positive association; β: 419.97; 95% confidence interval [CI]: 204.31, 635.63; P<0.001. This association was even stronger among patients in the lower 50% of BDNF levels (β: 434.11; 95% CI: 166.17, 702.05; P=0.002, while it became weaker for patients in the higher 50% of BDNF concentrations (β: 373.49; 95% CI: -74.91, 821.88; P=0

  15. Brain-Derived Neurotrophic Factor (BDNF) protein levels in anxiety disorders: systematic review and meta-regression analysis

    Science.gov (United States)

    Suliman, Sharain; Hemmings, Sian M. J.; Seedat, Soraya

    2013-01-01

    Background: Brain-Derived Neurotrophic Factor (BDNF) is a neurotrophin that is involved in the synaptic plasticity and survival of neurons. BDNF is believed to be involved in the pathogenesis of several neuropsychiatric disorders. As findings of BDNF levels in anxiety disorders have been inconsistent, we undertook to conduct a systematic review and meta-analysis of studies that assessed BDNF protein levels in these disorders. Methods: We conducted the review using electronic databases and searched reference lists of relevant articles for any further studies. Studies that measured BDNF protein levels in any anxiety disorder and compared these to a control group were included. Effect sizes of the differences in BDNF levels between anxiety disorder and control groups were calculated. Results: Eight studies with a total of 1179 participants were included. Initial findings suggested that BDNF levels were lower in individuals with any anxiety disorder compared to those without [Standard Mean Difference (SMD) = −0.94 (−1.75, −0.12), p ≤ 0.05]. This was, however, dependent on source of BDNF protein [plasma: SMD = −1.31 (−1.69, −0.92), p ≤ 0.01; serum: SMD = −1.06 (−2.27, 0.16), p ≥ 0.01] and type of anxiety disorder [PTSD: SMD = −0.05 (−1.66, 1.75), p ≥ 0.01; OCD: SMD = −2.33 (−4.21, −0.45), p ≤ 0.01]. Conclusion: Although BDNF levels appear to be reduced in individuals with an anxiety disorder, this is not consistent across the various anxiety disorders and may largely be explained by the significantly lowered BDNF levels found in OCD. Results further appear to be mediated by differences in sampling methods. Findings are, however, limited by the lack of research in this area, and given the potential for BDNF as a biomarker of anxiety disorders, it would be useful to clarify the relationship further. PMID:23908608

  16. The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men.

    Science.gov (United States)

    Schmolesky, Matthew T; Webb, David L; Hansen, Rodney A

    2013-01-01

    This study examined the combined effects of aerobic exercise intensity and duration on serum brain-derived neurotrophic factor (sBDNF) levels in healthy human adult males aged 18-25 years. Forty five participants were randomly assigned to one of six exercise conditions based on varying intensity (80% or 60% of heart rate reserve, or control) and duration (20 or 40 min). Vigorous (80% heart rate reserve, "Vig") and moderate (60% heart rate reserve, "Mod") exercise was carried out on cycle ergometers. Control subjects remained seated and at rest during the exercise period. Pre- and post-exercise blood draws were conducted and sBDNF measured. Physical exercise caused an average ~ 32% increase in sBDNF levels relative to baseline that resulted in concentrations that were 45% higher than control conditions. Comparing the six conditions, sBDNF levels rose consistently among the four exercise conditions (Vig20 = 26.38 ± 34.89%, Vig40 = 28.48 ± 19.11%, Mod20 = 41.23 ± 59.65%, Mod40 = 30.16 ± 72.11%) and decreased consistently among the controls (Con20 = -14.48 ± 16.50, Con40 = -10.51 ± 26.78). Vig conditions had the highest proportion of subjects that experienced a significant (? 10%) increase in sBDNF levels, followed by Mod and control conditions. An analysis of modeled sBDNF integrals (area under the curve) demonstrated substantially greater values for Vig40 and Mod40 conditions compared to Vig20 and Mod20 conditions. Collectively, these results demonstrate that neither duration (20 vs. 40 min) nor intensity (60 vs. 80% HR reserve) significantly affects the benefits of exercise if only the sBDNF increase at a single post-exercise time point is considered. However, when comparing either the probability of achieving a significant BDNF gain or the integral (i.e. the volume of circulating BDNF over time) the Vig40 condition offers maximal benefits. Thus, we conclude that the future study of aerobic exercise effects on BDNF-mediated neuroprotection should take the

  17. Regulation of fear extinction by long-term depression: The roles of endocannabinoids and brain derived neurotrophic factor.

    Science.gov (United States)

    Bennett, Maxwell R; Arnold, Jonathon; Hatton, Sean N; Lagopoulos, Jim

    2017-02-15

    The extinction of a conditioned fear response is of great interest in the search for a means of ameliorating adverse neurobiological changes resulting from stress. The discovery that endocannibinoid (EC) levels are inversely related to the extent of such stress, and that the amygdala is a primary site mediating stress, suggests that ECs in this brain region might play a major role in extinction. Supporting this are the observations that the basolateral complex of the amygdala shows an increase in ECs only during extinction and that early clinical trials indicate that cannabinoid-like agents, when taken orally by patients suffering from post traumatic stress disorder (PTSD), reduce insomnia and nightmares. In order to optimize the potential of these agents to ameliorate symptoms of PTSD four important questions need to be answered: first, what is the identity of the cells that release ECs in the amygdala during extinction; second, what are their sites of action; third, what roles do the ECs play in the alleviation of long- depression (LTD), a process central to extinction; and finally, to what extent does brain derived neurotrophic factor (BDNF) facilitate the release of ECs? A review of the relevant literature is presented in an attempt to answer these questions. It is suggested that the principal cell involved in EC synthesis and release during extinction is the so-called excitatory extinction neuron in the basal nucleus of the amygdala. Furthermore that the main site of action of the ECs is the adjacent calcitonin gene-related peptide inhibitory interneurons, whose normal role of blocking the excitatory neurons is greatly diminished. The molecular pathways leading (during extinction trials) to the synthesis and release of ECs from synaptic spines of extinction neurons, that is potentiated by BDNF, are also delineated in this review. Finally, consideration is given to how the autocrine action of BDNF, linked to the release of ECs, can lead to the sustained release

  18. Toll like receptor-2 regulates production of glial-derived neurotrophic factors in murine intestinal smooth muscle cells.

    Science.gov (United States)

    Brun, Paola; Gobbo, Serena; Caputi, Valentina; Spagnol, Lisa; Schirato, Giulia; Pasqualin, Matteo; Levorato, Elia; Palù, Giorgio; Giron, Maria Cecilia; Castagliuolo, Ignazio

    2015-09-01

    those from WT-EGCs or WT-MΦ/DCs corrected the altered neuronal phenotype of TLR2(-/-) mice. Supplementation of TLR2(-/-) neuronal cultures with GDNF recapitulated the WT-SMC co-culture effect whereas the knockdown of GDNF expression in WT-SMCs using shRNA interference abolished the effect on TLR2(-/-) neurons. These data revealed that by exploiting the repertoire of TLRs to decode gut-microbial signals, intestinal SMCs elaborate a cocktail of neurotrophic factors that in turn supports neuronal phenotype. In this view, the SMCs represent an attractive target for novel therapeutic strategies. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Effect of Fluoxetine on Expression of Brain-derived Neurotrophic Factor in Patients with Post-stroke Depression

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    DING Zhaosheng

    2014-12-01

    Full Text Available Objective: To observe the effect of Fluoxetine on the expression brain-derived neurotrophic factor (BDNF in patients with post-stroke depression (PSD. Methods: A total of 62 patients with ischemic stroke and post depression were divided into PSD group (32 cases given fluoxetine combined with rehabilitation and Non-PSD group (30 cases given rehabilitation treatment according to the presence of depression after stroke. The degree of depression, activities of daily living and the motor function were evaluated by Hamilton Depression Scale 17 (HAMD-17, Modified Barthel Index (MBI and Fugl-Meyer Assessment (FMA before and after treatment, respectively. And the levels of BDNF were examined using enzyme-linked immunosorbent assay (ELISA. Results: Before treatment, HAMD-17 score and MBI scores were markedly higher in PSD group than in Non-PSD group (P<0.05 or P<0.01. Compared with treatment before, HAMD-17 score decreased significantly, while FMA score increased markedly in PSD group after 3, 6 and 12-month treatment, and MBI score increased from the first-month treatment, and increased along with the time (P<0.05,P<0.01. In Non-PSD group, MBI and FMA scores increased from 1-month treatment and along with the time (P<0.05,P<0.01. Comparison between two groups showed that 12 months after treatment, there were no significant differences in HAMD-17, MBI and FMA scores (P>0.05. After 3, 6 and 12-month treatment, BDNF concentrations in PSD group were significantly higher than in Non-PSD group (P<0.01. Relevant analysis showed that BDNF in patients with PSD was in negative relationship with HAMD-17 (r=-0.784, P=0.000 and in positive association with BMI and FMA (r=0.761, P=0.000; r=0.789, P=0.000. Conclusion: Fluoxetine combined with rehabilitation can regulate depression, improve motor function and activities of daily living through increasing the concentration of BNDF in treating PSD patients.

  20. Human ciliary neurotrophic factor: Localization to the proximal region of the long arm of chromosome 11 and association with CA/GT dinucleotide repeat

    Energy Technology Data Exchange (ETDEWEB)

    Lev, A.A.; Rosen, D.R.; Kos, C.; Brown, R.H. Jr.; Clifford, E.; Landes, G.; Hauser, S.L.

    1993-05-01

    Ciliary neurotrophic factor (CNTF) promotes survival and differentiation of several types of sensory, motor, sympathetic, and parasympathetic neurons. The authors have used the polymerase chain reaction to amplify, clone, and partially sequence CNTF cDNA from human muscle. Using a rodent-human mapping panel and fluorescence in situ hybridization, they have localized a single copy of the gene for human CNTF to the proximal long arm of chromosome 11. They have also identified a polymorphic tandem CA/GT dinucleotide repeat associated with the human CNTF gene. 14 refs., 1 fig.

  1. Identification of a putative invertebrate helical cytokine similar to the ciliary neurotrophic factor/leukemia inhibitory factor family by PSI-BLAST-based approach.

    Science.gov (United States)

    Cheng, Gong; Zhao, Xin; Li, Zuofeng; Liu, Xinyi; Yan, Weiyao; Zhang, Xiaoyan; Zhong, Yang; Zheng, Zhaoxin

    2009-08-01

    Most of our knowledge of helical cytokine-like molecules in invertebrates relies on functional assays and similarities at the physicochemical level. It is hard to predict helical cytokines in invertebrates based on sequences from mammals and vertebrates, because of their long evolutionary divergence. In this article, we collected 12 kinds of fish cytokines and constructed their respective consensus sequences using hidden Markov models; then, the conserved domains region of each consensus sequence were further extracted by the SMART tool, and used as the query sequence for PSI-BLAST analysis in Drosophila melanogaster. After two filtering processes based on the properties of helical cytokines, we obtained one protein named CG14629, which shares 25% identities/46% positives to fish M17 cytokine in the half length of the N-terminus. Considering the homology between M17 and LIF/CNTF (leukemia inhibitory factor/ciliary neurotrophic factor), and the close relationship between Dome, the putative cytokine receptor in Drosophila cells, and LIFR/CNTFR (LIF receptor/CNTF receptor), the results suggest that CG14629 is a good candidate for the helical cytokine ortholog in D. melanogaster.

  2. Comparison of Brain-Derived Neurotrophic Factor (BDNF and Insulin-like Growth Factor 1 (IGF-1 Responses to Different Endurance Training Intensities in Runner Men

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    M. Habibian

    2017-04-01

    Full Text Available Aims: Blood neurotrophins, such as Brain-Derived Neurotrophic Factor (BDNF and Insulin-like Growth Factor 1 (IGF-1, mediate exercise- induced health benefits in humans. The purpose of this study was to compare the response of BDNF and IGF-1 to different endurance training intensities in runner men. Materials & Methods: In this semi-experimental study with pre-test-posttest design in 2015, 10 people of male runners from Gorgan were selected through purposeful and accessible sampling. The endurance training protocol was 6 km running with moderate (70-75% of heart rate reserve or severe (80-85% of heart rate reserve intensity, which was performed within a week's interval. Fasting blood samples were collected before and immediately after both acute training sessions and serum levels of BDNF and IGF-1 were measured by ELISA and radioimmunoassay enzyme. Data were analyzed by SPSS 20 software using independent t-test and paired t-test. Findings: Both acute endurance training significantly increased serum levels of BDNF and IGF-1 in runners, but high intensity endurance exercises increased BDNF levels in comparison with moderate intensity (p0.05. Conclusion: Serum BDNF response in endurance athletes is affected by the intensity of exercise, so that the effect of high intensity endurance training on BDNF levels is greater than moderate intensity exercise, but the response of IGF-1 to acute endurance training is independent of the intensity of exercise.

  3. Neurotrophic Factors NGF, GDNF and NTN Selectively Modulate HSV1 and HSV2 Lytic Infection and Reactivation in Primary Adult Sensory and Autonomic Neurons

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    Andy A. Yanez

    2017-02-01

    Full Text Available Herpes simplex viruses (HSV1 and HSV2 establish latency in peripheral ganglia after ocular or genital infection, and can reactivate to produce different patterns and frequencies of recurrent disease. Previous studies showed that nerve growth factor (NGF maintains HSV1 latency in embryonic sympathetic and sensory neurons. However, adult sensory neurons are no longer dependent on NGF for survival, some populations cease expression of NGF receptors postnatally, and the viruses preferentially establish latency in different populations of sensory neurons responsive to other neurotrophic factors (NTFs. Thus, NGF may not maintain latency in adult sensory neurons. To identify NTFs important for maintaining HSV1 and HSV2 latency in adult neurons, we investigated acute and latently-infected primary adult sensory trigeminal (TG and sympathetic superior cervical ganglia (SCG after NTF removal. NGF and glial cell line-derived neurotrophic factor (GDNF deprivation induced HSV1 reactivation in adult sympathetic neurons. In adult sensory neurons, however, neurturin (NTN and GDNF deprivation induced HSV1 and HSV2 reactivation, respectively, while NGF deprivation had no effects. Furthermore, HSV1 and HSV2 preferentially reactivated from neurons expressing GFRα2 and GFRα1, the high affinity receptors for NTN and GDNF, respectively. Thus, NTN and GDNF play a critical role in selective maintenance of HSV1 and HSV2 latency in primary adult sensory neurons.

  4. Neuroplasticity - exercise-induced response of peripheral brain-derived neurotrophic factor: a systematic review of experimental studies in human subjects.

    Science.gov (United States)

    Knaepen, Kristel; Goekint, Maaike; Heyman, Elsa Marie; Meeusen, Romain

    2010-09-01

    Exercise is known to induce a cascade of molecular and cellular processes that support brain plasticity. Brain-derived neurotrophic factor (BDNF) is an essential neurotrophin that is also intimately connected with central and peripheral molecular processes of energy metabolism and homeostasis, and could play a crucial role in these induced mechanisms. This review provides an overview of the current knowledge on the effects of acute exercise and/or training on BDNF in healthy subjects and in persons with a chronic disease or disability. A systematic and critical literature search was conducted. Articles were considered for inclusion in the review if they were human studies, assessed peripheral (serum and/or plasma) BDNF and evaluated an acute exercise or training intervention. Nine RCTs, one randomized trial, five non-randomized controlled trials, five non-randomized non-controlled trials and four retrospective observational studies were analysed. Sixty-nine percent of the studies in healthy subjects and 86% of the studies in persons with a chronic disease or disability, showed a 'mostly transient' increase in serum or plasma BDNF concentration following an acute aerobic exercise. The two studies regarding a single acute strength exercise session could not show a significant influence on basal BDNF concentration. In studies regarding the effects of strength or aerobic training on BDNF, a difference should be made between effects on basal BDNF concentration and training-induced effects on the BDNF response following an acute exercise. Only three out of ten studies on aerobic or strength training (i.e. 30%) found a training-induced increase in basal BDNF concentration. Two out of six studies (i.e. 33%) reported a significantly higher BDNF response to acute exercise following an aerobic or strength training programme (i.e. compared with the BDNF response to an acute exercise at baseline). A few studies of low quality (i.e. retrospective observational studies) show that

  5. Ciliary neurotrophic factor fused to a protein transduction domain retains full neuroprotective activity in the absence of cytokine-like side effects.

    Science.gov (United States)

    Rezende, Alexandre C; Peroni, Daniele; Vieira, Andrè S; Rogerio, Fabio; Talaisys, Rafael L; Costa, Fabio T M; Langone, Francesco; Skaper, Stephen D; Negro, Alessandro

    2009-06-01

    Ciliary neurotrophic factor (CNTF) is a multifunctional cytokine that can regulate the survival and differentiation of many types of developing and adult neurons. CNTF prevents the degeneration of motor neurons after axotomy and in mouse mutant progressive motor neuronopathy, which has encouraged trials of CNTF for human motor neuron disease. Given systemically, however, CNTF causes severe side effects, including cachexia and a marked immune response, which has limited its clinical application. The present work describes a novel approach for administering recombinant human CNTF (rhCNTF) while conserving neurotrophic activity and avoiding deleterious side effects. rhCNTF was fused to a protein transduction domain derived from the human immunodeficiency virus-1 TAT (transactivator) protein. The resulting fusion protein (TAT-CNTF) crosses the plasma membrane within minutes and displays a nuclear localization. TAT-CNTF was equipotent to rhCNTF in supporting the survival of cultured chicken embryo dorsal root ganglion neurons. Local or subcutaneous administration of TAT-CNTF, like rhCNTF rescued motor neurons from death in neonatal rats subjected to sciatic nerve transection. In contrast to subcutaneous rhCNTF, which caused a 20-30% decrease in body weight in neonatal rats between postnatal days 2 and 7 together with a considerable fat mobilization in brown adipose tissue, TAT-CNTF lacked such side effects. Together, these results indicate that rhCNTF fused with the protein transduction domain/TAT retains neurotrophic activity in the absence of CNTFs cytokine-like side effects and may be a promising candidate for the treatment of motor neuron and other neurodegenerative diseases.

  6. Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro

    DEFF Research Database (Denmark)

    Wolf, N; Krohn, K; Bieger, S

    1999-01-01

    by the neuroendocrine chromaffin cells, which also express the transforming growth factor-beta receptor type II. In contrast to the developmentally related sympathetic neurons, chromaffin cells continue to proliferate throughout postnatal life. Using 5-bromo-2'-deoxyuridine pulse labeling and tyrosine hydroxylase......Transforming growth factor-betas are members of a superfamily of multifunctional cytokines regulating cell growth and differentiation. Their functions in neural and endocrine cells are not well understood. We show here that transforming growth factor-betas are synthesized, stored and released...... immunocytochemistry as a marker for young postnatal rat chromaffin cells, we show that treatment with fibroblast growth factor-2 (1 nM) and insulin-like growth factor-II (10 nM) increased the fraction of 5-bromo-2'-deoxyuridine-labeled nuclei from 1% to about 40% of the cells in the absence of serum. In the presence...

  7. A Standardized Chinese Herbal Decoction, Kai-Xin-San, Restores Decreased Levels of Neurotransmitters and Neurotrophic Factors in the Brain of Chronic Stress-Induced Depressive Rats

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    Kevin Yue Zhu

    2012-01-01

    Full Text Available Kai-xin-san (KXS, a Chinese herbal decoction being prescribed by Sun Simiao in Beiji Qianjin Yaofang about 1400 years ago, contains Ginseng Radix et Rhizoma, Polygalae Radix, Acori tatarinowii Rhizoma, and Poria. KXS has been used to treat stress-related psychiatric disease with the symptoms of depression and forgetfulness in ancient China until today. However, the mechanism of its antidepression action is still unknown. Here, the chronic mild-stress-(CMS- induced depressive rats were applied in exploring the action mechanisms of KXS treatment. Daily intragastric administration of KXS for four weeks significantly alleviated the CMS-induced depressive symptoms displayed by enhanced sucrose consumption. In addition, the expressions of those molecular bio-markers relating to depression in rat brains were altered by the treatment of KXS. These KXS-regulated brain biomarkers included: (i the levels of dopamine, norepinephrine, and serotonin (ii the transcript levels of proteins relating to neurotransmitter metabolism; (iii the transcript levels of neurotrophic factors and their receptors. The results suggested that the anti-depressant-like action of KXS might be mediated by an increase of neurotransmitters and expression of neurotrophic factors and its corresponding receptors in the brain. Thus, KXS could serve as alternative medicine, or health food supplement, for patients suffering from depression.

  8. Either brain-derived neurotrophic factor or neurotrophin-3 only neurotrophin-producing grafts promote locomotor recovery in untrained spinalized cats.

    Science.gov (United States)

    Ollivier-Lanvin, Karen; Fischer, Itzhak; Tom, Veronica; Houlé, John D; Lemay, Michel A

    2015-01-01

    Background. Transplants of cellular grafts expressing a combination of 2 neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) have been shown to promote and enhance locomotor recovery in untrained spinalized cats. Based on the time course of recovery and the absence of axonal growth through the transplants, we hypothesized that recovery was due to neurotrophin-mediated plasticity within the existing locomotor circuitry of the lumbar cord. Since BDNF and NT-3 have different effects on axonal sprouting and synaptic connectivity/strengthening, it becomes important to ascertain the contribution of each individual neurotrophins to recovery. Objective. We studied whether BDNF or NT-3 only producing cellular grafts would be equally effective at restoring locomotion in untrained spinal cats. Methods. Rat fibroblasts secreting one of the 2 neurotrophins were grafted into the T12 spinal transection site of adult cats. Four cats in each group (BDNF alone or NT-3 alone) were evaluated. Locomotor recovery was tested on a treadmill at 3 and 5 weeks post-transection/grafting. Results. Animals in both groups were capable of plantar weight-bearing stepping at speed up to 0.8 m/s as early as 3 weeks and locomotor capabilities were similar at 3 and 5 weeks for both types of graft. Conclusions. Even without locomotor training, either BDNF or NT-3 only producing grafts promote locomotor recovery in complete spinal animals. More clinically applicable delivery methods need to be developed. © The Author(s) 2014.

  9. Targeting neurotrophic factors and their receptors, but not cholinesterase or neurotransmitter, in the neurotoxicity of TDCPP in Chinese rare minnow adults (Gobiocypris rarus).

    Science.gov (United States)

    Yuan, Lilai; Li, Jiasu; Zha, Jinmiao; Wang, Zijian

    2016-01-01

    Organophosphate flame retardants (OPFRs) have been detected at high concentrations in various environmental and biotic samples, but little is known about their toxicity. In this study, the potential neurotoxicity of three OPFRs (TCEP, TDCPP, and TPP) and Chlorpyrifos (CPF, an organophosphate pesticide) were compared in Chinese rare minnow using an acute toxicity test and a 21-day fish assay. The acute test demonstrated significant inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by CPF. Although significant AChE inhibition at high concentration of TPP was also observed, none of the OPFRs had effects similar to CPF on these enzymes, indicating that their acute toxicities to Chinese rare minnow may be unrelated to cholinesterase inhibition. In addition, the 21-day fish assay with TDCPP demonstrated no significant effects on cholinesterase activities or neurotransmitter levels. Nonetheless, this OPFR exhibited widespread effects on the neurotrophic factors and their receptors (e.g., ntf3, ntrk1, ntrk2, ngfr, and fgf2, fgf11, fgf22, fgfr4), indicating that TDCPP or other OPFRs may elicit neurological effects by targeting neurotrophic factors and their receptors in Chinese rare minnow. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Electroacupuncture stimulation of the brachial plexus trunk on the healthy side promotes brain-derived neurotrophic factor mRNA expression in the ischemic cerebral cortex of a rat model of cerebral ischemia/reperfusion injury.

    Science.gov (United States)

    Guo, Zongjun; Wang, Lumin

    2012-07-25

    A rat model of cerebral ischemia/reperfusion was established by suture occlusion of the left middle cerebral artery. In situ hybridization results showed that the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic rat cerebral cortex increased after cerebral ischemia/ reperfusion injury. Low frequency continuous wave electroacupuncture (frequency 2-6 Hz, current intensity 2 mA) stimulation of the brachial plexus trunk on the healthy (right) side increased the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic cerebral cortex 14 days after cerebral ischemia/reperfusion injury. At the same time, electroacupuncture stimulation of the healthy brachial plexus truck significantly decreased neurological function scores and alleviated neurological function deficits. These findings suggest that electroacupuncture stimulation of the brachial plexus trunk on the healthy (right) side can greatly increase brain-derived neurotrophic factor mRNA expression and improve neurological function.

  11. Identification of Relationships Between Interleukin 15 mRNA and Brain-Derived Neurotrophic Factor II mRNA Levels With Formal Components of Temperament in Asthmatic Patients.

    Science.gov (United States)

    Panek, Michał; Jonakowski, Mateusz; Zioło, Jan; Pietras, Tadeusz; Wieteska, Łukasz; Małachowska, Beata; Mokros, Łukasz; Szemraj, Janusz; Kuna, Piotr

    2017-04-01

    Asthma is a chronic inflammatory and heterogeneous disease developing mostly through allergic inflammation, which modifies the expression of various cytokines and neurotrophins. Previous studies suggest the involvement of interleukin (IL)-15 in the regulation of immune response in asthma. Brain-derived neurotrophic factor (BDNF) II plays an important role as a regulator of development and survival of neurons as well as maintenance of their physiological activity. Chronic stress associated with asthma and elevated IL-15 mRNA and BDNFII mRNA levels may affect the mood and a subjective sensation of dyspnoea-inducing anxiety. Psychopathological variables and numerous cytokine/neurotrophin interactions influence the formation of temperament and strategies of coping with stress. The aim of the study was to identify the role of IL-15 mRNA and BDNFII mRNA expressions and their effect on components of temperament and strategies of coping with stress in asthmatics. A total of 352 subjects (176 healthy volunteers and 176 asthmatic patients) participated in the study. The Formal Characteristic of Behaviour-Temperament Inventory (FCB-TI), Coping Inventory for Stressful Situations (CISS), Beck Depression Inventory, State-Trait Anxiety Inventory, and Borg Rating of Perceived Exertion (RPE) Scale were applied in all the subjects. The expression of IL-15 and BDNFII gene was measured using quantitative real-time polymerase chain reaction (qRT-PCR). Different levels of IL-15 and BDNFII expressions between healthy volunteers and patients were revealed in the study. IL-15 enhanced the BDNFII mRNA expression among patients with bronchial asthma. The depression level negatively correlated with the BDNFII mRNA expression. This neurotrophin modified the temperament variable. BDNFII significantly affected (proportional relationship) the level of briskness in asthmatic patients. BDNFII might influence the level and style of coping with stress (emotion-oriented style). This hypothesis

  12. Transforming growth factor-beta, but not ciliary neurotrophic factor, inhibits DNA synthesis of adrenal medullary cells in vitro

    DEFF Research Database (Denmark)

    Wolf, N; Krohn, K; Bieger, S

    1999-01-01

    of fibroblast growth factor-2 and insulin-like growth factor-II, transforming growth factor-beta1 (0.08 nM) reduced 5-bromo-2'-deoxyuridine labeling by about 50%, without interfering with chromaffin cell survival or death. Doses lower and higher than 0.08 nM were less effective. Similar effects were seen...... immunocytochemistry as a marker for young postnatal rat chromaffin cells, we show that treatment with fibroblast growth factor-2 (1 nM) and insulin-like growth factor-II (10 nM) increased the fraction of 5-bromo-2'-deoxyuridine-labeled nuclei from 1% to about 40% of the cells in the absence of serum. In the presence...... by the neuroendocrine chromaffin cells, which also express the transforming growth factor-beta receptor type II. In contrast to the developmentally related sympathetic neurons, chromaffin cells continue to proliferate throughout postnatal life. Using 5-bromo-2'-deoxyuridine pulse labeling and tyrosine hydroxylase...

  13. Novel Bioconjugation Strategy Using Elevated Hydrostatic Pressure: A Case Study for the Site-Specific Attachment of Polyethylene Glycol (PEGylation) of Recombinant Human Ciliary Neurotrophic Factor.

    Science.gov (United States)

    Wang, Qi; Zhang, Chun; Guo, Fangxia; Li, Zenglan; Liu, Yongdong; Su, Zhiguo

    2017-11-15

    In this paper, we reported a novel strategy for the site-specific attachment of polyethylene glycol (PEGylation) of proteins using elevated hydrostatic pressure. The process was similar to the conventional one except the reactor was under elevated hydrostatic pressure. The model protein was recombinant human ciliary neurotrophic factor (rhCNTF), and the reagent was monomethoxy-polyethylene glycol-maleimide (mPEG-MAL). PEGylation with mPEG (40 kDa)-MAL at pH 7.0 under normal pressure for 5 h achieved a less than 5% yield. In comparison, when the pressure was elevated, the PEGylation yield was increased dramatically, reaching nearly 90% at 250 MPa. Furthermore, the following phenomena were observed: (1) high-hydrostatic-pressure PEGylation (HHPP) could operate at a low reactant ratio of 1:1.2 (rhCNTF to mPEG-MAL), while the conventional process needs a much-higher ratio. (2) Short and long chains of PEG gave a similar yield of 90% in HHPP, while the conventional yield for the short chain of the PEG was higher than that of the long chain. (3) The reaction pH in the range of 7.0 to 8.0 had almost no influence upon the yield of HHPP, while the PEGylation yield was significantly increased by a factor of three from pH 7.0 to 8.0 at normal pressure. Surface accessibility analysis was performed using GRASP2 software, and we found that Cys17 of rhCNTF was located at the concave patches, which may have steric hindrance for the PEG to approach. The speculated benefit of HHPP was the facilitation of target-site exposure, reducing the steric hindrance and making the reaction much easier. Structure and activity analysis demonstrated that the HHPP product was comparable to the PEGylated rhCNTF prepared through a conventional method. Overall, this work demonstrated that HHPP, as we proposed, may have application potentials in various conjugations of biomacromolecules.

  14. Brain-Derived Neurotrophic Factor Facilitates Functional Recovery from ALS-Cerebral Spinal Fluid-Induced Neurodegenerative Changes in the NSC-34 Motor Neuron Cell Line.

    Science.gov (United States)

    Shruthi, Shanmukha; Sumitha, R; Varghese, Anu Mary; Ashok, S; Chandrasekhar Sagar, B K; Sathyaprabha, T N; Nalini, A; Kramer, Boris W; Raju, Trichur R; Vijayalakshmi, K; Alladi, Phalguni Anand

    2017-01-01

    The survival of motor neurons is dependent upon neurotrophic factors both during childhood and adolescence and during adult life. In disease conditions, such as in patients with amyotrophic lateral sclerosis (ALS), the mRNA levels of trophic factors like brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), fibroblast growth factor-2 (FGF-2), and vascular endothelial growth factor are downregulated. This was replicated in our in vivo experimental system following the injection of cerebral spinal fluid (CSF) of sporadic ALS (ALS-CSF) patients. To evaluate the protective role of BDNF in a model of sporadic ALS patients. The expressions of endogenous BDNF, its receptor TrkB, the enzyme choline acetyl transferase (ChAT), and phosphorylated neurofilaments were studied in NSC-34 cells. The calcium-buffering and proapoptotic effects were assessed by calbindin-D28K and caspase-3 expression, respectively. ALS-CSF considerably depleted the endogenous BDNF protein, while its effect on IGF-1 and FGF-2 was inconsequential; this indirectly indicates a key role for BDNF in supporting motor neuronal survival. The exogenous supplementation of BDNF reversed autocrine expression; however, it may not be completely receptor mediated, as the TrkB levels were not restored. BDNF completely revived ChAT expression. It may inhibit apoptosis by restoring Ca2+ homeostasis, since caspase-3 and calbindin-D28K expression was back to normal. The organellar ultrastructural changes were only partially reversed. Our study provides evidence that BDNF supplementation ameliorates most but not all degenerative changes. The incomplete revival at the ultrastructural level signifies the requirement of factors other than BDNF for near-total protection of motor neurons, and, to an extent, it explains why only a partial success is achieved in clinical trials with BDNF in ALS patients. © 2016 S. Karger AG, Basel.

  15. Decrease of urinary nerve growth factor but not brain-derived neurotrophic factor in patients with interstitial cystitis/bladder pain syndrome treated with hyaluronic acid.

    Directory of Open Access Journals (Sweden)

    Yuan-Hong Jiang

    Full Text Available To investigate urinary nerve growth factor (NGF and brain-derived neurotrophic factor (BDNF levels in interstitial cystitis/bladder pain syndrome (IC/BPS patients after hyaluronic acid (HA therapy.Thirty-three patients with IC/BPS were prospectively studied; a group of 45 age-matched healthy subjects served as controls. All IC/BPS patients received nine intravesical HA instillations during the 6-month treatment regimen. Urine samples were collected for measuring urinary NGF and BDNF levels at baseline and 2 weeks after the last HA treatment. The clinical parameters including visual analog scale (VAS of pain, daily frequency nocturia episodes, functional bladder capacity (FBC and global response assessment (GRA were recorded. Urinary NGF and BDNF levels were compared between IC/BPS patients and controls at baseline and after HA treatment.Urinary NGF, NGF/Cr, BDNF, and BDNF/Cr levels were significantly higher in IC/BPS patients compared to controls. Both NGF and NGF/Cr levels significantly decreased after HA treatment. Urinary NGF and NGF/Cr levels significantly decreased in the responders with a VAS pain reduction by 2 (both p < 0.05 and the GRA improved by 2 (both p < 0.05, but not in non-responders. Urinary BDNF and BDNF/Cr did not decrease in responders or non-responders after HA therapy.Urinary NGF, but not BDNF, levels decreased significantly after HA therapy; both of these factors remained higher than in controls even after HA treatment. HA had a beneficial effect on IC/BPS, but it was limited. The reduction of urinary NGF levels was significant in responders, with a reduction of pain and improved GRA.

  16. Decrease of Urinary Nerve Growth Factor but Not Brain-Derived Neurotrophic Factor in Patients with Interstitial Cystitis/Bladder Pain Syndrome Treated with Hyaluronic Acid

    Science.gov (United States)

    Jiang, Yuan-Hong; Liu, Hsin-Tzu; Kuo, Hann-Chorng

    2014-01-01

    Aims To investigate urinary nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) levels in interstitial cystitis/bladder pain syndrome (IC/BPS) patients after hyaluronic acid (HA) therapy. Methods Thirty-three patients with IC/BPS were prospectively studied; a group of 45 age-matched healthy subjects served as controls. All IC/BPS patients received nine intravesical HA instillations during the 6-month treatment regimen. Urine samples were collected for measuring urinary NGF and BDNF levels at baseline and 2 weeks after the last HA treatment. The clinical parameters including visual analog scale (VAS) of pain, daily frequency nocturia episodes, functional bladder capacity (FBC) and global response assessment (GRA) were recorded. Urinary NGF and BDNF levels were compared between IC/BPS patients and controls at baseline and after HA treatment. Results Urinary NGF, NGF/Cr, BDNF, and BDNF/Cr levels were significantly higher in IC/BPS patients compared to controls. Both NGF and NGF/Cr levels significantly decreased after HA treatment. Urinary NGF and NGF/Cr levels significantly decreased in the responders with a VAS pain reduction by 2 (both p < 0.05) and the GRA improved by 2 (both p < 0.05), but not in non-responders. Urinary BDNF and BDNF/Cr did not decrease in responders or non-responders after HA therapy. Conclusions Urinary NGF, but not BDNF, levels decreased significantly after HA therapy; both of these factors remained higher than in controls even after HA treatment. HA had a beneficial effect on IC/BPS, but it was limited. The reduction of urinary NGF levels was significant in responders, with a reduction of pain and improved GRA. PMID:24614892

  17. Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors - Hyogo Sleep Cardio-Autonomic Atherosclerosis study.

    Directory of Open Access Journals (Sweden)

    Masafumi Kurajoh

    Full Text Available Brain-derived neurotrophic factor (BDNF has been shown to have protective effects against cardiovascular diseases and death through neural and non-neural pathways via tropomyosin-related kinase B signaling. However, it is not known whether plasma BDNF concentration is a predictor of chronic kidney disease (CKD.This study was conducted as a prospective cohort study as part of the Hyogo Sleep Cardio-Autonomic Atherosclerosis.We measured plasma BDNF concentration in 324 patients without CKD, defined as an estimated glomerular filtration rate (eGFR less than 60 ml/min/1.73m2, and with cardiovascular risk factors. As potential confounders, sleep condition, nocturnal hypertension, and autonomic function were quantitatively examined. The patients were followed for a median 37 months (range 2-59 months and occurrence of CKD was noted.Plasma BDNF concentration was significantly and independently associated with CKD development, which occurred in 38 patients (11.7%. Kaplan-Meier analysis revealed that patients with reduced plasma BDNF concentration exhibited a significantly (p = 0.029 greater number of CKD events as compared to those with a higher concentration. Moreover, comparisons of key subgroups showed that the risk of CKD in association with low plasma BDNF concentration was more prominent in patients with a greater reduction of nocturnal systolic blood pressure, better movement index, higher standard deviations of the NN(RR interval or average NN(RR interval for each 5-minute period, and without past cardiovascular disease events, smoking habit, or albuminuria.Plasma BDNF concentration is an independent predictor for development of CKD in patients with cardiovascular risk factors.

  18. Reduced cerebrospinal fluid levels of brain-derived neurotrophic factor is associated with cognitive impairment in late-life major depression.

    Science.gov (United States)

    Diniz, Breno S; Teixeira, Antonio L; Machado-Vieira, Rodrigo; Talib, Leda L; Radanovic, Marcia; Gattaz, Wagner F; Forlenza, Orestes V

    2014-11-01

    Late-life depression (LLD) is associated with reduced neurotrophic support and abnormalities in neurodegenerative cascades. The aim of the present study is to determine the concentrations of brain-derived neurotrophic factor (BDNF), amyloid-β42, total Tau, and phosphorylated Tau in the cerebrospinal fluid (CSF) of patients with LLD and cognitive impairment compared to healthy older adults. We included 25 antidepressant-free patients with LLD (10 with mild cognitive impairment [LLD + MCI] and 15 with no cognitive decline [LLD + NCD]) and 25 healthy older adults as a comparison group. Depressive symptoms were assessed by the 21-item Hamilton Depression Rating Scale (HDRS-21) and cognitive performance by a comprehensive cognitive battery. Patients with LLD + MCI showed significantly lower CSF BDNF levels compared to LLD + NCD and healthy controls (p = .003). There were no significant differences in Alzheimer's disease-related CSF biomarkers between groups. CSF BDNF concentrations were positively correlated with Cambridge Cognitive Test (CAMCOG) scores (r = .36, p = .02). The present study adds to the growing body of evidence that abnormalities in the BDNF system are involved in the pathophysiology of LLD. The reduction of the availability of BDNF in the central nervous system may indicate increased vulnerability to the development of several age-related neuropsychiatric disorders as well as to adverse cognitive outcomes. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. The Brain-Uterus Connection: Brain Derived Neurotrophic Factor (BDNF) and Its Receptor (Ntrk2) Are Conserved in the Mammalian Uterus

    Science.gov (United States)

    Wessels, Jocelyn M.; Wu, Liang; Leyland, Nicholas A.; Wang, Hongmei; Foster, Warren G.

    2014-01-01

    The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2). Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat. PMID:24714156

  20. The brain-uterus connection: brain derived neurotrophic factor (BDNF) and its receptor (Ntrk2) are conserved in the mammalian uterus.

    Science.gov (United States)

    Wessels, Jocelyn M; Wu, Liang; Leyland, Nicholas A; Wang, Hongmei; Foster, Warren G

    2014-01-01

    The neurotrophins are neuropeptides that are potent regulators of neurite growth and survival. Although mainly studied in the brain and nervous system, recent reports have shown that neurotrophins are expressed in multiple target tissues and cell types throughout the body. Additionally, dysregulation of neurotrophins has been linked to several disease conditions including Alzheimer's, Parkinson's, Huntington's, psychiatric disorders, and cancer. Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family that elicits its actions through the neurotrophic tyrosine receptor kinase type 2 (Ntrk2). Together BDNF and Ntrk2 are capable of activating the adhesion, angiogenesis, apoptosis, and proliferation pathways. These pathways are prominently involved in reproductive physiology, yet a cross-species examination of BDNF and Ntrk2 expression in the mammalian uterus is lacking. Herein we demonstrated the conserved nature of BDNF and Ntrk2 across several mammalian species by mRNA and protein sequence alignment, isolated BDNF and Ntrk2 transcripts in the uterus by Real-Time PCR, localized both proteins to the glandular and luminal epithelium, vascular smooth muscle, and myometrium of the uterus, determined that the major isoforms expressed in the human endometrium were pro-BDNF, and truncated Ntrk2, and finally demonstrated antibody specificity. Our findings suggest that BDNF and Ntrk2 are transcribed, translated, and conserved across mammalian species including human, mouse, rat, pig, horse, and the bat.

  1. The use of laminin modified linear ordered collagen scaffolds loaded with laminin-binding ciliary neurotrophic factor for sciatic nerve regeneration in rats.

    Science.gov (United States)

    Cao, Jiani; Sun, Changkai; Zhao, Hui; Xiao, Zhifeng; Chen, Bing; Gao, Jian; Zheng, Tiezheng; Wu, Wei; Wu, Shuang; Wang, Jingyu; Dai, Jianwu

    2011-06-01

    Nerve conduit provides a promising strategy for nerve injury repair in the peripheral nervous system (PNS). However, simply bridging the transected nerve with an empty conduit is hard to satisfy functional recovery. The regenerated axons may disperse during regeneration in the empty lumen, limiting the functional recovery. Our previous work had reported that linear ordered collagen scaffold (LOCS) could be used as a nerve guidance material. Here we cross-linked LOCS fibers with laminin which was a major component of the extracellular matrix in nervous system. Ciliary neurotrophic factor (CNTF) plays a critical role in peripheral nerve regeneration. But the lack of efficient CNTF delivery approach limits its clinical applications. To retain CNTF on the scaffold, a laminin binding domain (LBD) was fused to the N-terminal of CNTF. Compared with NAT-CNTF, LBD-CNTF exhibited specific laminin-binding ability and comparable neurotrophic bioactivity. We combined LBD-CNTF with the laminin modified LOCS fibers to construct a double-functional bio-scaffold. The functional scaffold was filled in silicon conduit and tested in the rat sciatic nerve transection model. Results showed that this functional biomaterial could guide the axon growth, retain more CNTF on the scaffolds and enhance the nerve regeneration as well as functional recovery. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. The role of jab1, a putative downstream effector of the neurotrophic cytokine macrophage migration inhibitory factor (MIF) in zebrafish inner ear hair cell development.

    Science.gov (United States)

    Weber, Loren J; Marcy, Hannah K; Shen, Yu-Chi; Tomkovich, Sarah E; Brooks, Kristina M; Hilk, Kelly E; Barald, Kate F

    2018-03-01

    Macrophage migration inhibitory factor (MIF) is a neurotrophic cytokine essential for inner ear hair cell (HC) development and statoacoustic ganglion (SAG) neurite outgrowth, and SAG survival in mouse, chick and zebrafish. Another neurotrophic cytokine, Monocyte chemoattractant protein 1 (MCP1) is known to synergize with MIF; but MCP1 alone is insufficient to support mouse/chick SAG neurite outgrowth or neuronal survival. Because of the relatively short time over which the zebrafish inner ear develops (~30hpf), the living zebrafish embryo is an ideal system to examine mif and mcp1 cytokine pathways and interactions. We used a novel technique: direct delivery of antisense oligonucleotide morpholinos (MOs) into the embryonic zebrafish otocyst to discover downstream effectors of mif as well as to clarify the relationship between mif and mcp1 in inner ear development. MOs for mif, mcp1 and the presumptive mif and mcp1 effector, c-Jun activation domain-binding protein-1 (jab1), were injected and then electroporated into the zebrafish otocyst 25-48hours post fertilization (hpf). We found that although mif is important at early stages (before 30hpf) for auditory macular HC development, jab1 is more critical for vestibular macular HC development before 30hpf. After 30hpf, mcp1 becomes important for HC development in both maculae. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Activity-dependent neurotrophic factor, ADNF, determines the structure characteristics of Colivelin, a fusion protein of ADNF9 and Humanin analog.

    Science.gov (United States)

    Arakawa, Tsutomu; Niikura, Takako; Arisaka, Fumio; Kita, Yoshiko

    2008-05-01

    A 24-amino acid long peptide, Humanin, protects neurons from Alzheimer's disease (AD)-related cell toxicities at sub-nM-uM concentrations. Activity-dependent neurotrophic factor (ADNF) is a glia-derived neurotrophic peptide, which protects neurons from tetrodoxin treatment and AD-related and amyotrophic lateral sclerosis-related insults at fM concentrations. An attempt was made to further improve the activity of Humanin by fusing this peptide to ADNF9, a 9-amino acid long core peptide of the ADNF. This fusion resulted in a novel molecule, termed Colivelin, with the neuroprotective activity at fM range, which is approximately 10(3)-10(7) fold higher than the activity of Humanin and Humanin analogs and follows the activity profile of fM-active ADNF9. We have characterized the structural properties of Colivelin and compared with those of ADNF9 and Humanin in water and phosphate-buffered saline (PBS). The secondary structure of Colivelin was similar to that of ADNF9, but not that of Humanin, and hence was not the average of the contributions of the two peptides fused. Colivelin was stable and monomeric in PBS, consistent with the monomeric property of ADNF9, while Humanin showed strong tendency to self-associate. Thus, it is evident that the structural properties of Colivelin resemble those of ADNF9, rather than those of Humanin.

  4. The association between serum brain-derived neurotrophic factor and a cluster of cardiovascular risk factors in adolescents

    DEFF Research Database (Denmark)

    Pedersen, Natascha Holbæk; Tarp, Jakob; Andersen, Lars Bo

    2017-01-01

    .034) and HOMA-IR (Std. β = 0.19, P = 0.004), and negatively associated with CRF (Std. β = -0.15, P = 0.026). In females, BDNF was positively associated with TG (Std. β = 0.14, P = 0.030) and negatively associated with waist circumference (WC) (Std. β = -0.16, P = 0.012). CONCLUSION: Serum BDNF was positively...... associated with a composite z-score of cardiovascular risk factors. This association seems to be mainly driven by the association between TG, HOMA-IR and serum BDNF, and particularly for males. Further longitudinal research is warranted to determine the temporal relationship between BDNF and cardiovascular...

  5. Human factors influencing decision making

    OpenAIRE

    Jacobs, Patricia A.

    1998-01-01

    This report supplies references and comments on literature that identifies human factors influencing decision making, particularly military decision making. The literature has been classified as follows (the classes are not mutually exclusive): features of human information processing; decision making models which are not mathematical models but rather are descriptive; non- personality factors influencing decision making; national characteristics influencing decision makin...

  6. Up-regulation of brain-derived neurotrophic factor in the dorsal root ganglion of the rat bone cancer pain model

    Directory of Open Access Journals (Sweden)

    Tomotsuka N

    2014-07-01

    Full Text Available Naoto Tomotsuka,1 Ryuji Kaku,1 Norihiko Obata,1 Yoshikazu Matsuoka,1 Hirotaka Kanzaki,2 Arata Taniguchi,1 Noriko Muto,1 Hiroki Omiya,1 Yoshitaro Itano,1 Tadasu Sato,3 Hiroyuki Ichikawa,3 Satoshi Mizobuchi,1 Hiroshi Morimatsu1 1Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; 2Department of Pharmacy, Okayama University Hospital, Okayama, Japan; 3Department of Oral and Craniofacial Anatomy, Tohoku University Graduate School of Dentistry, Sendai, Japan Abstract: Metastatic bone cancer causes severe pain, but current treatments often provide insufficient pain relief. One of the reasons is that mechanisms underlying bone cancer pain are not solved completely. Our previous studies have shown that brain-derived neurotrophic factor (BDNF, known as a member of the neurotrophic family, is an important molecule in the pathological pain state in some pain models. We hypothesized that expression changes of BDNF may be one of the factors related to bone cancer pain; in this study, we investigated changes of BDNF expression in dorsal root ganglia in a rat bone cancer pain model. As we expected, BDNF mRNA (messenger ribonucleic acid and protein were significantly increased in L3 dorsal root ganglia after intra-tibial inoculation of MRMT-1 rat breast cancer cells. Among the eleven splice-variants of BDNF mRNA, exon 1–9 variant increased predominantly. Interestingly, the up-regulation of BDNF is localized in small neurons (mostly nociceptive neurons but not in medium or large neurons (non-nociceptive neurons. Further, expression of nerve growth factor (NGF, which is known as a specific promoter of BDNF exon 1–9 variant, was significantly increased in tibial bone marrow. Our findings suggest that BDNF is a key molecule in bone cancer pain, and NGF-BDNF cascade possibly develops bone cancer pain. Keywords: BDNF, bone cancer pain, chronic pain, nerve growth

  7. Cerebrospinal fluid levels of glial cell-derived neurotrophic factor correlate with spinal cord stimulation frequency in patients with neuropathic pain: a preliminary report.

    Science.gov (United States)

    McCarthy, K F; McCrory, C

    2014-08-01

    Case series. To evaluate relationships between spinal cord stimulation (SCS) parameters and levels of glial cell-derived neurotrophic factor (GDNF). Ambulatory pain clinic of St James's Hospital, Dublin, Ireland. Nine patients with an implanted SCS and Failed Back Surgery Syndrome (FBSS) were administered the Brief Pain Inventory and Short Form (36) Health Survey. Following a lumbar puncture, levels of GDNF in cerebrospinal fluid (CSF) were assayed and correlated with stimulation parameters. Controls were patients with arthritic back pain who were matched for age, gender and SF-36 score. Concentrations of GDNF in CSF are higher in patients with FBSS than controls (P=0.002) and correlate with SCS frequency (P=0.029). Concentrations of GDNF in CSF are higher in neuropathic pain and appear to be related to stimulation frequency. Further work is needed to evaluate this potential relationship, both in neuropathic pain and in other contexts such as locomotor dysfunction.

  8. Delayed administration of glial cell line-derived neurotrophic factor (GDNF) protects retinal ganglion cells in a pig model of acute retinal ischemia

    DEFF Research Database (Denmark)

    Kyhn, Maria Voss; Klassen, Henry; Johansson, Ulrica Englund

    2009-01-01

    This study investigates whether intravitreal administration of glial cell line-derived neurotrophic factor (GDNF) enhances survival of NeuN positive retinal cells in a porcine model of retinal ischemia. 16 pigs were subjected to an ischemic insult where intraocular pressure was maintained at 5 mm...... electroretinography (mfERG), quantification of NeuN positive cells and evaluation of the degree of retinal perivasculitis and inflammation 6 weeks after the insult. In the post-injection eyes (days 14, 28 and 42), the ratios of the iN1 and the iP2 amplitudes were 0.10 (95% CI: 0.05-0.15) and 0.09 (95% CI: 0.......04-0.16) in eyes treated with blank microspheres, and 0.24 (95% CI: 0.18-0.32) and 0.23 (95% CI: 0.15-0.33) in eyes treated with GDNF microspheres. These differences were statistically significant (P eyes...

  9. Temporal expression of brain-derived neurotrophic factor (BDNF) mRNA in the rat hippocampus after treatment with selective and mixed monoaminergic antidepressants

    DEFF Research Database (Denmark)

    Larsen, Marianne Hald; Hay-Schmidt, Anders; Rønn, Lars Christian B

    2008-01-01

    Strong evidence suggests that antidepressants work by induction of neuroplastic changes mediated through regulation of brain-derived neurotrophic factor (BDNF). This study was undertaken to investigate the time-course of the effect of three antidepressants; fluoxetine, imipramine and venlafaxine...... treatment with venlafaxine (7, 14 and 21 days) and imipramine (14 and 21 days), but not after treatment with fluoxetine, indicating that stimulation of BDNF mRNA expression is dependent on the pharmacological profile and on the time-course of drug treatment. A transient increase in synaptophysin m......RNA was observed after treatment with venlafaxine and fluoxetine whereas imipramine had no effect. In the CA3 region a reduction of GAP-43 mRNA was observed after treatment with imipramine (21 days) and fluoxetine (7 and 14 days). These results suggest that venlafaxine and imipramine, but not fluoxetine, induce...

  10. Kai-Xin-San, a Chinese Herbal Decoction Containing Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria, Stimulates the Expression and Secretion of Neurotrophic Factors in Cultured Astrocytes

    Directory of Open Access Journals (Sweden)

    Kevin Yue Zhu

    2013-01-01

    Full Text Available Kai-xin-san (KXS, a Chinese herbal decoction prescribed by Sun Simiao in Beiji Qianjin Yaofang about 1400 years ago, contains Ginseng Radix et Rhizoma, Polygalae Radix, Acori Tatarinowii Rhizoma, and Poria. In China, KXS has been used to treat stress-related psychiatric diseases with the symptoms of depression and forgetfulness. Although animal study has supported the antidepression function of KXS, the mechanism in cellular level is still unknown. Here, a chemically standardized water extract of KXS was applied onto cultured astrocytes in exploring the action mechanisms of KXS treatment, which significantly stimulated the expression and secretion of neurotrophic factors, including NGF, BDNF, and GDNF, in a dose-dependent manner: the stimulation was both in mRNA and protein levels. In addition, the water extracts of four individual herbs did not significantly stimulate the expression of neurotrophic factors, which could explain the optimized effect of KXS in a herbal decoction. The KXS-induced expression of neurotrophic factors did not depend on signaling mediated by estrogen receptor or protein kinase. The results suggested that the antidepressant-like action of KXS might be mediated by an increase of expression of neurotrophic factors in astrocytes, which fully supported the clinical usage of this decoction.

  11. Effects of new beta-type Ti-40Nb implant materials, brain-derived neurotrophic factor, acetylcholine and nicotine on human mesenchymal stem cells of osteoporotic and non osteoporotic donors.

    Science.gov (United States)

    Kauschke, Vivien; Gebert, Annett; Calin, Mariana; Eckert, Jürgen; Scheich, Sebastian; Heiss, Christian; Lips, Katrin Susanne

    2018-01-01

    Treatment of osteoporotic fractures is still challenging and an urgent need exists for new materials, better adapted to osteoporotic bone by adjusted Young's modulus, appropriate surface modification and pharmaceuticals. Titanium-40-niobium alloys, mechanically ground or additionally etched and titanium-6-aluminium-4-vanadium were analyzed in combination with brain-derived neurotrophic factor, acetylcholine and nicotine to determine their effects on human mesenchymal stem cells in vitro over 21 days using lactate dehydrogenase and alkaline phosphatase assays, live cell imaging and immunofluorescence microscopy. Cell number of human mesenchymal stem cells of osteoporotic donors was increased after 14 d in presence of ground titanium-40-niobium or titanium-6-aluminium-4-vanadium, together with brain-derived neurotrophic factor. Cell number of human mesenchymal stem cells of non osteoporotic donors increased after 21 d in presence of titanium-6-aluminium-4-vanadium without pharmaceuticals. No significant increase was measured for ground or etched titanium-40-niobium after 21 d. Osteoblast differentiation of osteoporotic donors was significantly higher than in non osteoporotic donors after 21 d in presence of etched, ground titanium-40-niobium or titanium-6-aluminium-4-vanadium accompanied by all pharmaceuticals tested. In presence of all alloys tested brain-derived neurotrophic factor, acetylcholine and nicotine increased differentiation of cells of osteoporotic donors and accelerated it in non osteoporotic donors. We conclude that ground titanium-40-niobium and brain-derived neurotrophic factor might be most suitable for subsequent in vivo testing.

  12. Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associated with elevated expression of brain-derived neurotrophic factor mRNA in muscle fibers and activated satellite cells

    NARCIS (Netherlands)

    Copray, S; Liem, R; Brouwer, N; Greenhaff, P; Habens, F; Fernyhough, P

    The expression of brain-derived neurotrophic factor (BDNF) is elevated in the soleus muscle of streptozotocin-diabetic rats. To determine whether this diabetes-induced elevation was associated with or enhanced by muscle activity we have induced high-intensity muscle contraction by electrically

  13. Ginsenoside Rg1 reverses stress-induced depression-like behaviours and brain-derived neurotrophic factor expression within the prefrontal cortex.

    Science.gov (United States)

    Zhu, Xiuzhi; Gao, Rui; Liu, Zhuxi; Cheng, Ziyi; Qi, Yihang; Fan, Cuiqin; Yu, Shu Yan

    2016-07-01

    Depression is a major neuropsychiatric disorder that exerts deleterious effects upon public health. However, the neuronal mechanisms of depression remain largely uncharacterized, which has retarded the identification and development of effective therapeutic tools for the treatment of this disorder. The aim of this study was to explore the neuronal mechanisms underlying the protective effects of ginsenoside Rg1, a natural steroidal saponin found in ginseng, against chronic stress-induced depression.The results showed that chronic administration of ginsenoside Rg1 (40 mg/kg, i.p., 5 weeks) significantly ameliorated depression-like behaviours in rats as assessed in the sucrose preference and forced swim tests. Furthermore, chronic stress decreased the phosphorylation levels of the extracellular signal-regulated kinase and cAMP-response element-binding protein in the prefrontal cortex as well as producing a reduction of brain-derived neurotrophic factor expression. Of particular importance, all reductions in these parameters were significantly reversed by pre-treatment with ginsenoside Rg1. Taken together, the results of the present study suggest that the antidepressant-like effect of ginsenoside Rg1 might be mediated, at least in part, by activating the cAMP-response element-binding protein-brain-derived neurotrophic factor system within the prefrontal cortex. These findings not only reveal some of the underlying neuronal mechanisms of depression, but also the therapeutic potential of ginsenoside Rg1 as a preventive agent in the treatment of depression. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  14. S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions.

    Science.gov (United States)

    Paintlia, Manjeet K; Paintlia, Ajaib S; Singh, Avtar K; Singh, Inderjit

    2013-02-08

    Accumulating evidence suggests that reactive astrogliosis has beneficial and detrimental outcomes in various CNS disorders, but the mechanism behind this dichotomy is unclear. Recent advances in this direction suggested that NO signaling is critical to regulate the outcomes of reactive astrogliosis in vivo. Using biochemical and genetic approaches, we here investigated the effect of S-nitrosoglutathione (GSNO; a physiological NO donor) in astrocytes in vitro settings. GSNO enhanced the expressions of glial fibrillary acidic protein and neurotrophic factors including ciliary neurotrophic factor (CNTF) in astrocytes in a dose-dependent manner. The enhanced CNTF expression in GSNO-treated astrocytes was ascribed to NO-mediated sGC/cGMP/PKG signaling. It was associated with p38 MAPK-dependent increased peroxisome proliferator-activated receptor-γ transactivation. In addition, the chromatin accessibility of peroxisome proliferator-activated receptor-γ accompanied with ATF2 and CREB (cAMP-response element-binding protein) was enhanced across the CNTF gene promoter in GSNO treated astrocytes. Interestingly, secreted CNTF was responsible for increased expression of glial fibrillary acidic protein in GSNO-treated astrocytes in an autocrine manner via a JAK2- and STAT3-dependent mechanism. In addition, CNTF secreted by GSNO-treated astrocytes enhanced the differentiation of immature oligodendrocytes in vitro. These effects of GSNO were consistent with an endogenously produced NO in astrocytes stimulated with proinflammatory cytokines in vitro. We conclude that NO signaling induces CNTF expression in astrocytes that favors the beneficial outcomes of reactive astrogliosis in vivo. Our data suggest that the endogenously produced NO or its exogenous source has potential to modulate the outcomes of reactive astrogliosis to protect CNS under pathological conditions.

  15. S-Nitrosoglutathione Induces Ciliary Neurotrophic Factor Expression in Astrocytes, Which Has Implications to Protect the Central Nervous System under Pathological Conditions*

    Science.gov (United States)

    Paintlia, Manjeet K.; Paintlia, Ajaib S.; Singh, Avtar K.; Singh, Inderjit

    2013-01-01

    Accumulating evidence suggests that reactive astrogliosis has beneficial and detrimental outcomes in various CNS disorders, but the mechanism behind this dichotomy is unclear. Recent advances in this direction suggested that NO signaling is critical to regulate the outcomes of reactive astrogliosis in vivo. Using biochemical and genetic approaches, we here investigated the effect of S-nitrosoglutathione (GSNO; a physiological NO donor) in astrocytes in vitro settings. GSNO enhanced the expressions of glial fibrillary acidic protein and neurotrophic factors including ciliary neurotrophic factor (CNTF) in astrocytes in a dose-dependent manner. The enhanced CNTF expression in GSNO-treated astrocytes was ascribed to NO-mediated sGC/cGMP/PKG signaling. It was associated with p38 MAPK-dependent increased peroxisome proliferator-activated receptor-γ transactivation. In addition, the chromatin accessibility of peroxisome proliferator-activated receptor-γ accompanied with ATF2 and CREB (cAMP-response element-binding protein) was enhanced across the CNTF gene promoter in GSNO treated astrocytes. Interestingly, secreted CNTF was responsible for increased expression of glial fibrillary acidic protein in GSNO-treated astrocytes in an autocrine manner via a JAK2- and STAT3-dependent mechanism. In addition, CNTF secreted by GSNO-treated astrocytes enhanced the differentiation of immature oligodendrocytes in vitro. These effects of GSNO were consistent with an endogenously produced NO in astrocytes stimulated with proinflammatory cytokines in vitro. We conclude that NO signaling induces CNTF expression in astrocytes that favors the beneficial outcomes of reactive astrogliosis in vivo. Our data suggest that the endogenously produced NO or its exogenous source has potential to modulate the outcomes of reactive astrogliosis to protect CNS under pathological conditions. PMID:23264628

  16. Albumin endocytosis via megalin in astrocytes is caveola- and Dab-1 dependent and is required for the synthesis of the neurotrophic factor oleic acid.

    Science.gov (United States)

    Bento-Abreu, André; Velasco, Ana; Polo-Hernández, Erica; Lillo, Concepción; Kozyraki, Renata; Tabernero, Arantxa; Medina, José M

    2009-10-01

    The synthesis and release of the neurotrophic factor oleic acid requires internalization of albumin into the astrocyte, which is mediated by megalin. In this study, we show that the binding and internalization of albumin involve its interaction with megalin, caveolin-1, caveolin-2 and cavin, but not with clathrin in astrocytes from primary culture. Electron microscopy analyses revealed albumin-gold complexes localized in caveolae, but not in clathrin-coated vesicles. Neither chlorpromazine nor silencing clathrin expression modified albumin uptake. Silencing caveolin-1 strongly reduced the binding and internalization of albumin and the distribution of megalin in the plasma membrane. However, silencing caveolin-2 only decreased albumin internalization, suggesting that caveolin-1 is responsible for megalin recruitment to the caveolae and that caveolin-2 participates in caveolae internalization. In most tissues, the cytosolic adaptor protein disabled (Dab)-2 connects megalin to clathrin, astrocytes lack Dab-2; instead, they express Dab-1, which interacts with caveolin-1 and megalin and is required for albumin internalization. The transcytosis of albumin in astrocytes, including the passage through the endoplasmic reticulum, which is a compulsory step for oleic acid synthesis, was confirmed by electron microscopy analyses. Thus, whereas silencing clathrin did not modify the synthesis and release of oleic acid, the knock-down of caveolin-1, caveolin-2 and Dab-1 strongly reduced the synthesis and release of this neurotrophic factor. In conclusion, caveola-mediated endocytosis of albumin requires megalin and the adaptor protein Dab-1 in cultured astrocytes. Albumin endocytosis may be a key step in brain development because it stimulates the synthesis of oleic acid, which in turn promotes neuronal differentiation.

  17. Hypothyroidism in the adult rat causes incremental changes in brain-derived neurotrophic factor, neuronal and astrocyte apoptosis, gliosis, and deterioration of postsynaptic density.

    Science.gov (United States)

    Cortés, Claudia; Eugenin, Eliseo; Aliaga, Esteban; Carreño, Leandro J; Bueno, Susan M; Gonzalez, Pablo A; Gayol, Silvina; Naranjo, David; Noches, Verónica; Marassi, Michelle P; Rosenthal, Doris; Jadue, Cindy; Ibarra, Paula; Keitel, Cecilia; Wohllk, Nelson; Court, Felipe; Kalergis, Alexis M; Riedel, Claudia A

    2012-09-01

    Adult hypothyroidism is a highly prevalent condition that impairs processes, such as learning and memory. Even though tetra-iodothyronine (T(4)) treatment can overcome the hypothyroidism in the majority of cases, it cannot fully recover the patient's learning capacity and memory. In this work, we analyzed the cellular and molecular changes in the adult brain occurring with the development of experimental hypothyroidism. Adult male Sprague-Dawley rats were treated with 6-propyl-2-thiouracil (PTU) for 20 days to induce hypothyroidism. Neuronal and astrocyte apoptosis were analyzed in the hippocampus of control and hypothyroid adult rats by confocal microscopy. The content of brain-derived neurotrophic factor (BDNF) was analyzed using enzyme-linked immunosorbent assay (ELISA) and in situ hybridization. The glutamatergic synapse and the postsynaptic density (PSD) were analyzed by electron microscopy. The content of PSD proteins like tyrosine receptor kinase B (TrkB), p75, and N-methyl-D-aspartate receptor (NMDAr) were analyzed by immunoblot. We observed that the hippocampus of hypothyroid adult rats displayed increased apoptosis levels in neurons and astrocyte and reactive gliosis compared with controls. Moreover, we found that the amount of BDNF mRNA was higher in the hippocampus of hypothyroid rats and the content of TrkB, the receptor for BDNF, was reduced at the PSD of the CA3 region of hypothyroid rats, compared with controls. We also observed that the glutamatergic synapses from the stratum radiatum of CA3 from hypothyroid rats, contained thinner PSDs than control rats. This observation was in agreement with a reduced content of NMDAr subunits at the PSD in hypothyroid animals. Our data suggest that adult hypothyroidism affects the hippocampus by a mechanism that alters the composition of PSD, reduces neuronal and astrocyte survival, and alters the content of the signaling neurotrophic factors, such as BDNF.

  18. The Effect of Rosa Damascena Extract on Expression of Neurotrophic Factors in the CA1 Neurons of Adult Rat Hippocampus Following Ischemia

    Directory of Open Access Journals (Sweden)

    Seyedeh Farzaneh Moniri

    2018-01-01

    Full Text Available Ischemic stroke is an important cause of death and disability in the world. Brain ischemia causes damage to brain cell, and among brain neurons, pyramidal neurons of the hippocampal CA1 region are more susceptive to ischemic injury. Recent findings suggest that neurotrophic factors protect against ischemic cell death. A dietary component of Rosa damascene extract possibly is associated with expression of neurotrophic factors mRNA following ischemia, so it can have therapeutic effect on cerebral ischemia. The present study attempts to evaluate the neuroprotective effect of Rosa damascene extract on adult rat hippocampal neurons following ischemic brain injury. Forty-eight adult male Wistar rats (weighing 250±20 gr and ages 10-12 weeks used in this study, animals randomly were divided into 6 groups including Control, ischemia/ reperfusion (IR, vehicle and three treated groups (IR+0.5, 1, 2 mg/ml extract. Global ischemia was induced by bilateral common carotid arteries occlusion for 20 minutes. The treatment was done by different doses of Rosa damascena extract for 30 days. After 30 days cell death and gene expression in neurons of the CA1 region of the hippocampus were evaluated by Nissl staining and real time PCR assay. We found a significant decrease in NGF, BDNF and NT3 mRNA expression in neurons of CA1 region of the hippocampus in ischemia group compared to control group (P<0.0001. Our results also revealed that the number of dark neurons significantly increases in ischemia group compared to control group (P<0.0001. Following treatment with Rosa damascene extract reduced the number of dark neurons that was associated with NGF, NT3, and BDNF mRNA expression. All doses level had positive effects, but the most effective dose of Rosa damascena extract was 1 mg/ml. Our results suggest that neuroprotective activity of Rosa damascena can enhance hippocampal CA1 neuronal survival after global ischemia.

  19. Ciliary neurotrophic factor inhibits brain and peripheral tumor necrosis factor production and, when coadministered with its soluble receptor, protects mice from lipopolysaccharide toxicity.

    Science.gov (United States)

    Benigni, F; Villa, P; Demitri, M T; Sacco, S; Sipe, J D; Lagunowich, L; Panayotatos, N; Ghezzi, P

    1995-07-01

    The receptor of ciliary neurotrophic factor (CNTF) contains the signal transduction protein gp130, which is also a component of the receptors of cytokines such as interleukin (IL)-6, leukemia-inhibitory factor (LIF), IL-11, and oncostatin M. This suggests that these cytokines might share common signaling pathways. We previously reported that CNTF augments the levels of corticosterone (CS) and of IL-6 induced by IL-1 and induces the production of the acute-phase protein serum amyloid A (SAA). Since the elevation of serum CS is an important feedback mechanism to limit the synthesis of proinflammatory cytokines, particularly tumor necrosis factor (TNF), we have investigated the effect of CNTF on both TNF production and lipopolysaccharide (LPS) toxicity. To induce serum TNF levels, LPS was administered to mice at 30 mg/kg i.p. and CNTF was administered as a single dose of 10 micrograms/mouse i.v., either alone or in combination with its soluble receptor sCNTFR alpha at 20 micrograms/mouse. Serum TNF levels were the measured by cytotoxicity on L929 cells. In order to measure the effects of CNTF on LPS-induced TNF production in the brain, mice were injected intracerebroventricularly (i.c.v.) with 2.5 micrograms/kg LPS. Mouse spleen cells cultured for 4 hr with 1 microgram LPS/ml, with or without 10 micrograms CNTF/ml, were also analyzed for TNF production. CNTF, administered either alone or in combination with its soluble receptor, inhibited the induction of serum TNF levels by LPS. This inhibition was also observed in the brain when CNTF and LPS were administered centrally. In vitro, CNTF only marginally affected TNF production by LPS-stimulated mouse splenocytes, but it acted synergistically with dexamethasone (DEX) in inhibiting TNF production. Most importantly, CNTF administered together with sCNTFR alpha protected mice against LPS-induced mortality. These data suggest that CNTF might act as a protective cytokine against TNF-mediated pathologies both in the brain and

  20. Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, D.A. [Univ. Medical Center, New Orleans, LA (United States); Gross, L.; Wittrock, D.A.; Windebank, A.J. [Mayo Clinic, Rochester, MN (United States)

    1996-08-01

    Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease. 20 refs., 4 figs., 1 tab.

  1. Factors Influencing Army Maintenance

    Science.gov (United States)

    1989-01-01

    Harz (1981), reports the results of questioning largc- numbers of Subject Matter Experts (SMEs) involved in the maintenance process. The second type of...identified maintenance problems (e.g., Kokenes, 1987; Harz , 1981). The second step was the identificatl i of demand factors that affect the actual...Kokenes, 1987; Harz , 1981). Second, if any of the data on which allocations are based are faulty, or budgetary decisions require a cutback in

  2. Brain-derived neurotrophic factor Val66Met polymorphism and cognitive function in persons with cardiovascular disease.

    Science.gov (United States)

    Szabo, Ashley J; Alosco, Michael L; Miller, Lindsay A; McGeary, John E; Poppas, Athena; Cohen, Ronald A; Gunstad, John

    2013-12-01

    Cognitive impairment is common among persons with cardiovascular disease (CVD), and several potential aetiological mechanisms have been described, including contributions of genetic markers such as variations in the brain-derived neurotrophic (BDNF) gene. This current study examined the associations of BDNF genotype with cognitive function among individuals with CVD. This study included 110 participants with CVD who completed a comprehensive neuropsychological battery that assessed global cognitive function, attention/executive function, memory, language, and visuospatial abilities. All participants also underwent blood draw to provide a DNA sample that was used to determine BDNF genotype. Carriers of either one or two copies of the methionine allele of BDNF were categorized into one group (n = 33); non-carriers were categorized into a second group (n = 77). After adjustment for demographic and medical characteristics, hierarchical regression analyses revealed persons with one or more methionine alleles displayed better performance than valine/valine individuals for attention/executive function (β = 0.22, P = 0.047) and memory (β = 0.25, P = 0.03), as well as a trend for language (β = 0.19, P = 0.08) and visuospatial abilities (β = 0.21, P = 0.06). BDNF Val66Met had little impact on cognitive functioning in a sample of older adults with CVD, and significant findings contradicted that predicted by past work. Future work is much needed to clarify the mechanisms of these findings, particularly studies examining both circulating BDNF levels and genetic variation in the BDNF gene and cognitive function over time. © 2013 The Authors. Psychogeriatrics © 2013 Japanese Psychogeriatric Society.

  3. Glial cell line-derived neurotrophic factor induced the differentiation of amniotic fluid-derived stem cells into vascular endothelial-like cells in vitro.

    Science.gov (United States)

    Zhang, Ruyu; Lu, Ying; Li, Ju; Wang, Jia; Liu, Caixia; Gao, Fang; Sun, Dong

    2016-02-01

    Amniotic fluid-derived stem cells (AFSCs) are a novel source of stem cells that are isolated and cultured from second trimester amniocentesis. Glial cell line-derived neurotrophic factor (GDNF) acts as a tissue morphogen and regulates stem cell proliferation and differentiation. This study investigated the effect of an adenovirus-mediated GDNF gene, which was engineered into AFSCs, on the cells' biological properties and whether GDNF in combination with AFSCs can be directionally differentiated into vascular endothelial-like cells in vitro. AFSCs were isolated and cultured using the plastic adherence method in vitro and identified by the transcription factor Oct-4, which is the primary marker of pluripotent stem cells. AFSCs were efficiently transfected by a GFP-labeled plasmid system of an adenovirus vector carrying the GDNF gene (Ad-GDNF-GFP). Transfected AFSCs stably expressed GDNF. Transfected AFSCs were cultured in endothelial growth medium-2 containing vascular endothelial growth factor. After 1 week, AFSCs were positive for von Willebrand factor (vWF) and CD31, which are markers of endothelial cells, and the recombinant GDNF group was significantly higher than undifferentiated controls and the GFP only group. These results demonstrated that AFSCs differentiated into vascular endothelial-like cells in vitro, and recombinant GDNF promoted differentiation. The differentiation-induced AFSCs may be used as seed cells to provide a new manner of cell and gene therapies for transplantation into the vascular injury site to promote angiogenesis.

  4. Effect of Interval and Continuous Aerobic Training on Basal Serum and Plasma Brain-Derived Neurotrophic Factor Values in Seniors: A Systematic Review of Intervention Studies.

    Science.gov (United States)

    Enette, Lievyn; Vogel, Thomas; Fanon, Jean Luc; Lang, Pierre Olivier

    2017-12-01

    The purpose of this systematic review was to provide a comprehensive analysis of the available clinical trials analyzing, in seniors, the effect of interval aerobic training (IAT) and continuous aerobic training (CAT) on peripheral brain-derived neurotrophic factor (BDNF) concentration. We identified 14 randomized or not-randomized intervention studies published up to January 2017 through a computer-assisted search (PUBMED, Pedro, and Science direct data bases). The five trials considering IAT and the nine considering CAT totalized 988 individuals (age range: 58.1-77 years). The parameters of aerobic training (AT) protocol in terms of frequency and intensity are the primary determinants of the BDNF response to AT. The interpretation of the relationship between AT and BDNF signaling pathway was very challenging when specific health conditions were taken into consideration. This was more particularly true with mild cognitive impairment or depressive symptoms. These findings argue in favor of a generalization of the practice of AT and show that the type of training is not the main determining factor of the increase in BDNF level, which results more from the combination of several factors such as intensity and frequency of sessions, duration of programs, and also some genetic determinant coding for BDNF protein. All these factors have to be carefully addressed in future researches in that field. Thus, further researches are still necessary to better the signaling pathway by which AT contributes to better health outcomes.

  5. Effects of acute aerobic exercise on a task-switching protocol and brain-derived neurotrophic factor concentrations in young adults with different levels of cardiorespiratory fitness.

    Science.gov (United States)

    Tsai, Chia-Liang; Pan, Chien-Yu; Chen, Fu-Chen; Wang, Chun-Hao; Chou, Feng-Ying

    2016-07-01

    What is the central question of this study? Neurocognitive functions can be enhanced by acute aerobic exercise, which could be associated with changes in serum brain-derived neurotrophic factor (BDNF) concentrations. We aimed to explore acute exercise-induced changes in BDNF concentrations, neuropsychological and neurophysiological performances when individuals with different levels of cardiorespiratory fitness performed a cognitive task. What is the main finding and its importance? Only young adults with higher cardiorespiratory fitness could attain switching cost and neurophysiological benefits via acute aerobic exercise. The mechanisms might be fitness dependent. Although acute aerobic exercise could enhance serum BDNF concentrations, changes in peripheral BDNF concentrations could not be the potential factor involved in the beneficial effects on neurocognitive performance. This study investigated the effects of acute aerobic exercise on neuropsychological and neurophysiological performances in young adults with different cardiorespiratory fitness levels when performing a task-switching protocol and explored the potential associations between acute aerobic exercise-induced changes in serum brain-derived neurotrophic factor (BDNF) concentrations and various neurocognitive outcomes. Sixty young adults were categorized into one control group (i.e. non-exercise-intervention; n = 20) and two exercise-intervention (EI) groups [i.e. higher (EIH , n = 20) and lower (EIL , n = 20) cardiorespiratory fitness] according to their maximal oxygen consumption. At baseline and after either an acute bout of 30 min of moderate-intensity aerobic exercise or a control period, the neuropsychological and neurophysiological performances and serum BDNF concentrations were measured when the participants performed a task-switching protocol involving executive control and greater demands on working memory. The results revealed that although acute aerobic exercise decreased reaction

  6. Circulating brain-derived neurotrophic factor and indices of metabolic and cardiovascular health: data from the Baltimore Longitudinal Study of Aging.

    Directory of Open Access Journals (Sweden)

    Erin Golden

    2010-04-01

    Full Text Available Besides its well-established role in nerve cell survival and adaptive plasticity, brain-derived neurotrophic factor (BDNF is also involved in energy homeostasis and cardiovascular regulation. Although BDNF is present in the systemic circulation, it is unknown whether plasma BDNF correlates with circulating markers of dysregulated metabolism and an adverse cardiovascular profile.To determine whether circulating BDNF correlates with indices of metabolic and cardiovascular health, we measured plasma BDNF levels in 496 middle-age and elderly subjects (mean age approximately 70, in the Baltimore Longitudinal Study of Aging. Linear regression analysis revealed that plasma BDNF is associated with risk factors for cardiovascular disease and metabolic syndrome, regardless of age. In females, BDNF was positively correlated with BMI, fat mass, diastolic blood pressure, total cholesterol, and LDL-cholesterol, and inversely correlated with folate. In males, BDNF was positively correlated with diastolic blood pressure, triglycerides, free thiiodo-thyronine (FT3, and bioavailable testosterone, and inversely correlated with sex-hormone binding globulin, and adiponectin.Plasma BDNF significantly correlates with multiple risk factors for metabolic syndrome and cardiovascular dysfunction. Whether BDNF contributes to the pathogenesis of these disorders or functions in adaptive responses to cellular stress (as occurs in the brain remains to be determined.

  7. rs10767664 Gene Variant in Brain-Derived Neurotrophic Factor Is Associated with Diabetes Mellitus Type 2 in Caucasian Females with Obesity.

    Science.gov (United States)

    de Luis, Daniel Antonio; Aller, Rocío; Izaola, Olatz; Primo, David; Romero, Enrique

    2017-01-01

    The role of brain-derived neurotrophic factor (BDNF) variants on diabetes prevalence, basal adipokine levels, body weight, and cardiovascular risk factors remains unclear in obese patients. This study is aimed at analyzing the effects of rs10767664 BDNF gene polymorphism on diabetes mellitus prevalence, body weight, cardiovascular risk factors, and serum adipokine levels in obese female patients. A total of 507 obese women were enrolled in a prospective way. Biochemical evaluation and anthropometric measures were recorded. The frequency of diabetes mellitus in the group of patients with non-T allele was 20.1 and 28.3% in T-allele carriers. Logistic regression showed a risk of diabetes mellitus of 1.33 (95% CI 1.17-2.08) in subjects with T allele adjusted by age and body mass index (BMI). T-allele carriers with diabetes mellitus have a higher weight, BMI, waist circumference, blood pressure, glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and C-reactive protein (CRP) levels than non-T-allele carriers. rs10767664 polymorphism of BDNF gene is associated with prevalence of diabetes mellitus in obese female patients. T-allele carriers with diabetes mellitus have a higher weight, fat mass, blood pressure, level of insulin, glucose, HOMA-IR, and CRP than non-T-allele carriers. © 2017 S. Karger AG, Basel.

  8. The niche-derived glial cell line-derived neurotrophic factor (GDNF induces migration of mouse spermatogonial stem/progenitor cells.

    Directory of Open Access Journals (Sweden)

    Lisa Dovere

    Full Text Available In mammals, the biological activity of the stem/progenitor compartment sustains production of mature gametes through spermatogenesis. Spermatogonial stem cells and their progeny belong to the class of undifferentiated spermatogonia, a germ cell population found on the basal membrane of the seminiferous tubules. A large body of evidence has demonstrated that glial cell line-derived neurotrophic factor (GDNF, a Sertoli-derived factor, is essential for in vivo and in vitro stem cell self-renewal. However, the mechanisms underlying this activity are not completely understood. In this study, we show that GDNF induces dose-dependent directional migration of freshly selected undifferentiated spermatogonia, as well as germline stem cells in culture, using a Boyden chamber assay. GDNF-induced migration is dependent on the expression of the GDNF co-receptor GFRA1, as shown by migration assays performed on parental and GFRA1-transduced GC-1 spermatogonial cell lines. We found that the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP is specifically expressed in undifferentiated spermatogonia. VASP belongs to the ENA/VASP family of proteins implicated in actin-dependent processes, such as fibroblast migration, axon guidance, and cell adhesion. In intact seminiferous tubules and germline stem cell cultures, GDNF treatment up-regulates VASP in a dose-dependent fashion. These data identify a novel role for the niche-derived factor GDNF, and they suggest that GDNF may impinge on the stem/progenitor compartment, affecting the actin cytoskeleton and cell migration.

  9. Ciliary neurotrophic factor (CNTF) plus soluble CNTF receptor alpha increases cyclooxygenase-2 expression, PGE2 release and interferon-gamma-induced CD40 in murine microglia.

    Science.gov (United States)

    Lin, Hsiao-Wen; Jain, Mohit Raja; Li, Hong; Levison, Steven W

    2009-03-06

    Ciliary neurotrophic factor (CNTF) has been regarded as a potent trophic factor for motor neurons. However, recent studies have shown that CNTF exerts effects on glial cells as well as neurons. For instance, CNTF stimulates astrocytes to secrete FGF-2 and rat microglia to secrete glial cell line-derived neurotrophic factor (GDNF), which suggest that CNTF exerts effects on astrocytes and microglia to promote motor neuron survival indirectly. As CNTF is structurally related to IL-6, which can stimulate immune functions of microglia, we hypothesized that CNTF might exert similar effects. We performed 2-D and 1-D proteomic experiments with western blotting and flow cytometry to examine effects of CNTF on primary microglia derived from neonatal mouse brains. We show that murine microglia express CNTF receptor alpha (CNTFRalpha), which can be induced by interferon-gamma (IFNgamma). Whereas IL-6 activated STAT-3 and ERK phosphorylation, CNTF did not activate these pathways, nor did CNTF increase p38 MAP kinase phosphorylation. Using 2-D western blot analysis, we demonstrate that CNTF induced the dephosphorylation of a set of proteins and phosphorylation of a different set. Two proteins that were phosphorylated upon CNTF treatment were the LYN substrate-1 and beta-tubulin 5. CNTF weakly stimulated microglia, whereas a stronger response was obtained by adding exogenous soluble CNTFRalpha (sCNTFRalpha) as has been observed for IL-6. When used in combination, CNTF and sCNTFRalpha collaborated with IFNgamma to increase microglial surface expression of CD40 and this effect was quite pronounced when the microglia were differentiated towards dendritic-like cells. CNTF/sCNTFRalpha complex, however, failed to increase MHC class II expression beyond that induced by IFNgamma. The combination of CNTF and sCNTFRalpha, but not CNTF alone, enhanced microglial Cox-2 protein expression and PGE2 secretion (although CNTF was 30 times less potent than LPS). Surprisingly, Cox-2 production was

  10. Ciliary neurotrophic factor (CNTF plus soluble CNTF receptor α increases cyclooxygenase-2 expression, PGE2 release and interferon-γ-induced CD40 in murine microglia

    Directory of Open Access Journals (Sweden)

    Li Hong

    2009-03-01

    Full Text Available Abstract Background Ciliary neurotrophic factor (CNTF has been regarded as a potent trophic factor for motor neurons. However, recent studies have shown that CNTF exerts effects on glial cells as well as neurons. For instance, CNTF stimulates astrocytes to secrete FGF-2 and rat microglia to secrete glial cell line-derived neurotrophic factor (GDNF, which suggest that CNTF exerts effects on astrocytes and microglia to promote motor neuron survival indirectly. As CNTF is structurally related to IL-6, which can stimulate immune functions of microglia, we hypothesized that CNTF might exert similar effects. Methods We performed 2-D and 1-D proteomic experiments with western blotting and flow cytometry to examine effects of CNTF on primary microglia derived from neonatal mouse brains. Results We show that murine microglia express CNTF receptor α (CNTFRα, which can be induced by interferon-γ (IFNγ. Whereas IL-6 activated STAT-3 and ERK phosphorylation, CNTF did not activate these pathways, nor did CNTF increase p38 MAP kinase phosphorylation. Using 2-D western blot analysis, we demonstrate that CNTF induced the dephosphorylation of a set of proteins and phosphorylation of a different set. Two proteins that were phosphorylated upon CNTF treatment were the LYN substrate-1 and β-tubulin 5. CNTF weakly stimulated microglia, whereas a stronger response was obtained by adding exogenous soluble CNTFRα (sCNTFRα as has been observed for IL-6. When used in combination, CNTF and sCNTFRα collaborated with IFNγ to increase microglial surface expression of CD40 and this effect was quite pronounced when the microglia were differentiated towards dendritic-like cells. CNTF/sCNTFRα complex, however, failed to increase MHC class II expression beyond that induced by IFNγ. The combination of CNTF and sCNTFRα, but not CNTF alone, enhanced microglial Cox-2 protein expression and PGE2 secretion (although CNTF was 30 times less potent than LPS. Surprisingly, Cox-2

  11. APOEε4 Impacts Up-Regulation of Brain-Derived Neurotrophic Factor After a Six-Month Stretch and Aerobic Exercise Intervention in Mild Cognitively Impaired Elderly African Americans: A Pilot Study

    OpenAIRE

    Allard, Joanne S.; Ntekim, Oyonumo; Johnson, Steven P.; Ngwa, Julius S.; Bond, Vernon; Pinder, Dynell; Gillum, Richard F.; Fungwe, Thomas V.; Kwagyan, John; Obisesan, Thomas O.

    2016-01-01

    Possession of the Apolipoprotein E (APOE) gene ε4 allele is the most prevalent genetic risk factor for late onset Alzheimer’s disease (AD). Recent evidence suggests that APOE genotype differentially affects the expression of brain-derived neurotrophic factor (BDNF). Notably, aerobic exercise-induced upregulation of BDNF is well documented; and exercise has been shown to improve cognitive function. As BDNF is known for its role in neuroplasticity and survival, its upregulation is a proposed me...

  12. Brain-derived neurotrophic factor modulation of Kv1.3 channel is disregulated by adaptor proteins Grb10 and nShc

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    Marks David R

    2009-01-01

    Full Text Available Abstract Background Neurotrophins are important regulators of growth and regeneration, and acutely, they can modulate the activity of voltage-gated ion channels. Previously we have shown that acute brain-derived neurotrophic factor (BDNF activation of neurotrophin receptor tyrosine kinase B (TrkB suppresses the Shaker voltage-gated potassium channel (Kv1.3 via phosphorylation of multiple tyrosine residues in the N and C terminal aspects of the channel protein. It is not known how adaptor proteins, which lack catalytic activity, but interact with members of the neurotrophic signaling pathway, might scaffold with ion channels or modulate channel activity. Results We report the co-localization of two adaptor proteins, neuronal Src homology and collagen (nShc and growth factor receptor-binding protein 10 (Grb10, with Kv1.3 channel as demonstrated through immunocytochemical approaches in the olfactory bulb (OB neural lamina. To further explore the specificity and functional ramification of adaptor/channel co-localization, we performed immunoprecipitation and Western analysis of channel, kinase, and adaptor transfected human embryonic kidney 293 cells (HEK 293. nShc formed a direct protein-protein interaction with Kv1.3 that was independent of BDNF-induced phosphorylation of Kv1.3, whereas Grb10 did not complex with Kv1.3 in HEK 293 cells. Both adaptors, however, co-immunoprecipitated with Kv1.3 in native OB. Grb10 was interestingly able to decrease the total expression of Kv1.3, particularly at the membrane surface, and subsequently eliminated the BDNF-induced phosphorylation of Kv1.3. To examine the possibility that the Src homology 2 (SH2 domains of Grb10 were directly binding to basally phosphorylated tyrosines in Kv1.3, we utilized point mutations to substitute multiple tyrosine residues with phenylalanine. Removal of the tyrosines 111–113 and 449 prevented Grb10 from decreasing Kv1.3 expression. In the absence of either adaptor protein

  13. Targeting brain-derived neurotrophic factor in the medial thalamus for the treatment of central poststroke pain in a rodent model.

    Science.gov (United States)

    Shih, Hsi-Chien; Kuan, Yung-Hui; Shyu, Bai-Chung

    2017-07-01

    Approximately 7% to 10% of patients develop a chronic pain syndrome after stroke. This chronic pain condition is called central poststroke pain (CPSP). Recent studies have observed an abnormal increase in the secretion of brain-derived neurotrophic factor (BDNF) in spinal cord tissue after spinal cord injury. An animal model of CPSP was established by an intrathalamus injection of collagenase. Mechanical and thermal allodynia was induced after lesions of the thalamic ventral basal complex in rats. Four weeks after the injection, the number of neurons decreased, the number of astrocytes, microglia, and P2X4 receptors increased, and BDNF mRNA expression increased in the brain lesion area. Nociceptive activity in the medial thalamus (MT) and the coherence coefficient of spontaneous field potential oscillations in the anterior cingulate cortex were enhanced in CPSP animals, and these enhancements were blocked by an acute injection of TrkB-Fc and TrkB antagonist Tat Cyclotraxin-B. Instead of being inhibited by the γ-aminobutyric acid (GABA) system in normal rats, multiunit activity in the MT was enhanced after a microinjection of muscimol, a GABAA receptor agonist, in CPSP animals. After CPSP, BDNF expression was enhanced in the MT, whereas the expression of GABAA channels and the cotransporter KCC2 decreased in the same area. These findings suggest that neuronal plasticity in the MT that was induced by BDNF overexpression after the thalamic lesion was a key factor in CPSP.

  14. Is the Val66Met polymorphism of the brain-derived neurotrophic factor gene associated with panic disorder? A meta-analysis.

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    Chen, Kaiyuan; Wang, Na; Zhang, Jie; Hong, Xiaohong; Xu, Haiyun; Zhao, Xiaofeng; Huang, Qingjun

    2017-06-01

    Although emerging evidence has suggested an association between the Val66Met (rs6265) polymorphisms in brain-derived neurotrophic factor (BDNF) gene and the panic disorder, the conclusion is inclusive given the mixed results. This meta-analysis reviewed and analyzed the recent studies addressing the potential association between the Val66Met polymorphisms and panic disorder susceptibility. Related case-control studies were retrieved by database searching and selected according to established inclusion criteria. Six articles were identified, which explored the association between the BDNF Val66Met polymorphism and panic disorder. Statistical analyses revealed no association for the allele contrast and the dominant model. However, the recessive model showed a significant association between the BDNF Val66Met polymorphism and panic disorder (odds ratio = 1.26, 95% confidence interval = 1.04-1.52, z = 2.39, P = 0.02). Despite of some limitations, this meta-analysis suggests that the Val66Met polymorphism of BDNF gene is a susceptibility factor for panic disorder. © 2015 Wiley Publishing Asia Pty Ltd.

  15. Protective effect of ciliary neurotrophic factor (CNTF) in a model of endotoxic shock: action mechanisms and role of CNTF receptor alpha.

    Science.gov (United States)

    Demitri, M T; Benigni, F; Meazza, C; Zinetti, M; Fratelli, M; Villa, P; Acheson, A; Panayotatos, N; Ghezzi, P

    1998-01-01

    Ciliary neurotrophic factor (CNTF) inhibits the production of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-treated mice and protects against LPS lethality when coadministered with its soluble receptor (sCNTFR alpha). Both of these activities are abolished in adrenalectomized (ADX) mice. LPS-induced pulmonary polymorphonuclear neutrophil (PMN) infiltration and nitric oxide (NO) production were also inhibited by CNTF + sCNTFR alpha but not by CNTF alone. sCNTFR alpha did not alter the clearance or tissue distribution of CNTF. Furthermore, CNTF variants coadministered with sCNTFR alpha protected against LPS toxicity in a manner related to their affinity for the beta components of CNTFR. Thus, inhibition of TNF production and protection against LPS lethality by CNTF/sCNTFR alpha require an intact hypothalamus-pituitary-adrenal axis (HPAA) and may be mediated by endogenous glucocorticoids. This protective effect is, at least in part, due to the inhibition of PMN infiltration and NO production, and appears to be mediated by cells displaying only beta-receptor subtypes.

  16. Differential expression of neurotrophic factors and inflammatory cytokines by myelin basic protein-specific and other recruited T cells infiltrating the central nervous system during experimental autoimmune encephalomyelitis.

    Science.gov (United States)

    Muhallab, S; Lundberg, C; Gielen, A W; Lidman, O; Svenningsson, A; Piehl, F; Olsson, T

    2002-03-01

    Recent evidence suggests that autoimmune reactions in the central nervous system (CNS) not only have detrimental consequences but can also be neuroprotective, and that this effect is mediated by the expression of neuronal growth factors by infiltrating leucocytes. Here we dissect these two phenomena in guinea pig myelin basic protein peptide (gpMBP 63-88)-induced experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. Real-time TaqMan polymerase chain reaction (PCR) was used to measure mRNA for the nerve growth factors, brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3. As reference, the well-known proinflammatory mediator molecules interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha were quantified. In whole lumbar cord tissue, both the nerve growth factors and the proinflammatory cytokines, IFN-gamma and TNF-alpha, displayed similar expression patterns, peaking at the height of the disease. Among the infiltrating inflammatory cells isolated and sorted from the CNS, alphabeta+/T-cell receptor (TCR)BV8S2+, but not alphabeta+/TCRBV8S2-, recognized the encephalitogenic MBP peptide. Interestingly, these two populations displayed contrasting expression patterns of nerve growth factors and proinflammatory cytokines with higher inflammatory cytokine mRNA levels in alphabeta+/TCRBV8S2+ cells at all time intervals, whereas the levels of BDNF and NT3 were higher in alphabeta+/TCRBV8S2- cells. We conclude that a potentially important neuroprotective facet of CNS inflammation dominantly prevails within other non-MBP peptide-specific lymphoid cells and that there are independent regulatory mechanisms for neurotrophin and inflammatory cytokine expression during EAE.

  17. Is serum brain-derived neurotrophic factor related to craving for or use of alcohol, cocaine, or methamphetamine?

    Directory of Open Access Journals (Sweden)

    Gangwani P

    2011-06-01

    Full Text Available Craig Hilburn, Vicki A Nejtek, Wendy A Underwood, Meharvan Singh, Gauravkumar Patel, Pooja Gangwani, Michael J ForsterUniversity of North Texas Health Science Center at Fort Worth, TX, USABackground: Data suggests that brain-derived neurotropic factor (BDNF plays a neuroadaptive role in addiction. Whether serum BDNF levels are different in alcohol or psychostimulants as a function of craving is unknown. Here, we examined craving and serum BDNF levels in persons with alcohol versus psychostimulant dependence. Our goals were to explore BDNF as an objective biomarker for 1 craving 2 abstinence, and 3 years of chronic substance use.Methods: An exploratory, cross-sectional study was designed. Men and women between 20–65 years old with alcohol, cocaine, or methamphetamine dependence were eligible. A craving questionnaire was used to measure alcohol, cocaine and methamphetamine cravings. Serum levels of BDNF were measured using enzyme linked immunoassay. Analysis of variance, chi-square, and correlations were performed using a 95% confidence interval and a significance level of P < 0.05.Results: We found a significant difference in the mean craving score among alcohol, cocaine and methamphetamine dependent subjects. There were no significant influences of race, gender, psychiatric disorder or psychotropic medication on serum BDNF levels. We found that among psychostimulant users BDNF levels were significantly higher in men than in women when the number of abstinent days was statistically controlled. Further, a significant correlation between serum BDNF levels and the number of abstinent days since last psychostimulant use was found.Conclusion: These data suggest that BDNF may be a biomarker of abstinence in psychostimulant dependent subjects and inform clinicians about treatment initiatives. The results are interpreted with caution due to small sample size and lack of a control group.Keywords: BDNF, alcohol, cocaine, methamphetamine, craving

  18. Observed parenting behaviors interact with a polymorphism of the brain-derived neurotrophic factor gene to predict the emergence of oppositional defiant and callous-unemotional behaviors at age 3 years.

    Science.gov (United States)

    Willoughby, Michael T; Mills-Koonce, Roger; Propper, Cathi B; Waschbusch, Daniel A

    2013-11-01

    Using the Durham Child Health and Development Study, this study (N = 171) tested whether observed parenting behaviors in infancy (6 and 12 months) and toddlerhood/preschool (24 and 36 months) interacted with a child polymorphism of the brain-derived neurotrophic factor gene to predict oppositional defiant disorder (ODD) and callous-unemotional (CU) behaviors at age 3 years. Child genotype interacted with observed harsh and intrusive (but not sensitive) parenting to predict ODD and CU behaviors. Harsh-intrusive parenting was more strongly associated with ODD and CU for children with a methionine allele of the brain-derived neurotrophic factor gene. CU behaviors were uniquely predicted by harsh-intrusive parenting in infancy, whereas ODD behaviors were predicted by harsh-intrusive parenting in both infancy and toddlerhood/preschool. The results are discussed from the perspective of the contributions of caregiving behaviors as contributing to distinct aspects of early onset disruptive behavior.

  19. Investigation of brain-derived neurotrophic factor (BDNF) gene expression in hypothalamus of obese rats: Modulation by omega-3 fatty acids.

    Science.gov (United States)

    Abdel-Maksoud, Sahar M; Hassanein, Sally I; Gohar, Neveen A; Attia, Saad M M; Gad, Mohamed Z

    2017-10-01

    The aim of this study was investigating the effect of omega-3 fatty acids (ω-3 FAs) on brain-derived neurotrophic factor (BDNF) gene expression, using in vivo and in vitro models, to unravel the potential mechanisms of polyunsaturated fatty acids use in obesity. Twenty-nine Sprague-Dawley rats were divided into three groups; lean controls fed normal chow diet for 14 weeks, obese controls fed 60% of their diet as saturated fats for 14 weeks, and ω-3 FAs-treated rats fed 60% saturated fat diet for 14 weeks with concomitant oral administration of 400 mg/kg/day ω-3 FAs, mainly docosahexaenoic acid and EPA, from week 12 to week 14. For the in vitro experiment, hypothalamic cells from six obese rats were cultured in the presence of different concentrations of ω-3 FAs to determine its direct effect on BDNF expression. In vivo results showed that obesity has negative effect on BDNF gene expression in rat hypothalamus that was reversed by administration of ω-3 FAs. Obese rats showed hypercholesterolemia, hypertriglyceridemia, normoinsulinemia, hyperglycemia and hyperleptinemia. Treatment with ω-3 FAs showed significant decrease in serum total cholesterol and TAG. Also serum glucose level and HOMA index were decreased significantly. In vitro results demonstrated the increase in BDNF expression by ω-3 FAs in a dose-dependent manner. Obesity causes down-regulation of BDNF gene expression that can be reversed by ω-3 FAs treatment, making them an interesting treatment approach for obesity and metabolic disease.

  20. The relationship of Chlamydophila pneumoniae with schizophrenia: The role of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) in this relationship.

    Science.gov (United States)

    Kalayci, Fatma; Ozdemir, Armagan; Saribas, Suat; Yuksel, Pelin; Ergin, Sevgi; Kuskucu, Ali Mert; Poyraz, Cana Aksoy; Balcioglu, Ibrahim; Alpay, Nihat; Kurt, Aykut; Sezgin, Zeynep; Kocak, Banu Tufan; Icel, Rana Sucu; Can, Gunay; Tokman, Hrisi Bahar; Kocazeybek, Bekir

    Several pathogens have been suspected of playing a role in the pathogenesis of schizophrenia. Chronic inflammation has been proposed to occur as a result of persistent infection caused by Chlamydophila pneumoniae cells that reside in brain endothelial cells for many years. It was recently hypothesized that brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) may play prominent roles in the development of schizophrenia. NT-3 and BDNF levels have been suggested to change in response to various manifestations of infection. Therefore, we aimed to elucidate the roles of BDNF and NT3 in the schizophrenia-C. pneumoniae infection relationship. RT-PCR, immunofluorescence and ELISA methods were used. Fifty patients suffering from schizophrenia and 35 healthy individuals were included as the patient group (PG) and the healthy control group (HCG), respectively. We detected persistent infection in 14 of the 50 individuals in the PG and in 1 of the 35 individuals in the HCG. A significant difference was found between the two groups (p0.05). C. pneumoniae DNA was not detected in any group. A signif