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Sample records for neurotrophic factor inhibits

  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. Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures.

    Science.gov (United States)

    Rutherford, L C; DeWan, A; Lauer, H M; Turrigiano, G G

    1997-06-15

    The excitability of cortical circuits is modulated by interneurons that release the inhibitory neurotransmitter GABA. In primate and rodent visual cortex, activity deprivation leads to a decrease in the expression of GABA. This suggests that activity is able to adjust the strength of cortical inhibition, but this has not been demonstrated directly. In addition, the nature of the signal linking activity to GABA expression has not been determined. Activity is known to regulate the expression of the neurotrophin brain-derived neurotrophic factor (BDNF), and BDNF has been shown to influence the phenotype of GABAergic interneurons. We use a culture system from postnatal rat visual cortex to test the hypothesis that activity is regulating the strength of cortical inhibition through the regulation of BDNF. Cultures were double-labeled against GABA and the neuronal marker MAP2, and the percentage of neurons that were GABA-positive was determined. Blocking spontaneous activity in these cultures reversibly decreased the number of GABA-positive neurons without affecting neuronal survival. Voltage-clamp analysis of inhibitory currents demonstrated that activity blockade also decreased GABA-mediated inhibition onto pyramidal neurons and raised pyramidal neuron firing rates. All of these effects were prevented by incubation with BDNF during activity blockade, but not by neurotrophin 3 or nerve growth factor. Additionally, blockade of neurotrophin signaling mimicked the effects of activity blockade on GABA expression. These data suggest that activity regulates cortical inhibition through a BDNF-dependent mechanism and that this neurotrophin plays an important role in the control of cortical excitability.

  3. Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.

    Science.gov (United States)

    Gill, Raminder; Chang, Philip K-Y; Prenosil, George A; Deane, Emily C; McKinney, Rebecca A

    2013-12-01

    Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

  4. Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired-pulse measures of neuronal inhibition in adult rats.

    Science.gov (United States)

    Osehobo, P; Adams, B; Sazgar, M; Xu, Y; Racine, R J; Fahnestock, M

    1999-01-01

    Kindling is an animal model of human temporal lobe epilepsy in which excitability in limbic structures is permanently enhanced by repeated stimulations. Kindling also increases the expression of nerve growth factor, brain-derived neurotrophic factor, and brain-derived neurotrophic factor receptor messenger RNAs in both the hippocampus and cerebral cortex and causes structural changes in the hippocampus including hilar hypertrophy. We have recently shown that intraventricular nerve growth factor infusion enhances the development of kindling, whereas blocking nerve growth factor activity retards amygdaloid kindling. Furthermore, we have shown that nerve growth factor protects against kindling-induced hilar hypertrophy. The physiological role of brain-derived neurotrophic factor in kindling is not as clear. Acute injection of brain-derived neurotrophic factor increases neuronal excitability and causes seizures, whereas chronic brain-derived neurotrophic factor infusion in rats slows hippocampal kindling. In agreement with the latter, we show here that intrahilar brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling. In addition, we show that brain-derived neurotrophic factor, unlike nerve growth factor, does not protect against kindling-induced increases in hilar area. To test the hypothesis that brain-derived neurotrophic factor suppresses kindling by increasing inhibition above normal levels, we performed paired-pulse measures in the perforant path-dentate gyrus pathway. Brain-derived neurotrophic factor infused into the hippocampus had no effect on the stimulus intensity function (input/output curves); there was also no significant effect on paired-pulse inhibition. We then kindled the perforant path 10 days after the end of brain-derived neurotrophic factor treatment. Once again, kindling was retarded, showing that the brain-derived neurotrophic factor effect is long-lasting. These results indicate that prolonged in vivo infusion

  5. Brain-derived neurotrophic factor inhibits neuromuscular junction maturation in a cAMP-PKA-dependent way.

    Science.gov (United States)

    Song, Wei; Jin, Xiwan Albert

    2015-03-30

    The development of neuromuscular junction (NMJ) is initiated by motor axon's contact with the skeletal muscle cell that is followed by synaptic maturation. Previous studies showed that brain-derived neurotrophic factor (BDNF) enhanced motoneurons' survival and growth but significantly inhibited synaptogenesis. Here, we report that chronic application of BDNF resulted in inhibition in the maturation process both physiologically and morphologically. The response to BDNF was mediated by its cognate receptor TrkB as the effects were abolished by Trk receptor inhibitor K252a. Protein kinase A (PKA) inhibitor reversed the effects of BDNF in inhibiting NMJ maturation. These results indicate that BDNF suppresses NMJ maturation through cAMP-PKA signaling pathway. Together with the previous studies, these results suggest that BDNF suppresses NMJ formation and maturation despite its effects in enhancing neuronal survival and growth.

  6. 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-G1 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.

  7. Pro-brain-derived neurotrophic factor inhibits GABAergic neurotransmission by activating endocytosis and repression of GABAA receptors.

    Science.gov (United States)

    Riffault, Baptiste; Medina, Igor; Dumon, Camille; Thalman, Carine; Ferrand, Nadine; Friedel, Perrine; Gaiarsa, Jean-Luc; Porcher, Christophe

    2014-10-01

    GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABAARs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABAAR trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABAAR, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABAARs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABAARs at inhibitory synapses.

  8. Localization of Brain-Derived Neurotrophic Factor to Distinct Terminals of Mossy Fiber Axons Implies Regulation of Both Excitation and Feedforward Inhibition of CA3 Pyramidal Cells

    OpenAIRE

    Danzer, Steve C.; McNamara, James O.

    2004-01-01

    Hippocampal dentate granule cells directly excite and indirectly inhibit CA3 pyramidal cells via distinct presynaptic terminal specializations of their mossy fiber axons. This mossy fiber pathway contains the highest concentration of brain-derived neurotrophic factor (BDNF) in the CNS, yet whether BDNF is positioned to regulate the excitatory and/or inhibitory pathways is unknown. To localize BDNF, confocal microscopy of green fluorescent protein transgenic mice was combined with BDNF immunoh...

  9. Brain-derived neurotrophic factor-dependent cdk1 inhibition prevents G2/M progression in differentiating tetraploid neurons.

    Science.gov (United States)

    Ovejero-Benito, María C; Frade, José M

    2013-01-01

    Neurodegeneration is often associated with DNA synthesis in neurons, the latter usually remaining for a long time as tetraploid cells before dying by apoptosis. The molecular mechanism preventing G2/M transition in these neurons remains unknown, but it may be reminiscent of the mechanism that maintains tetraploid retinal ganglion cells (RGCs) in a G2-like state during normal development, thus preventing their death. Here we show that this latter process, known to depend on brain-derived neurotrophic factor (BDNF), requires the inhibition of cdk1 by TrkB. We demonstrate that a subpopulation of chick RGCs previously shown to become tetraploid co-expresses TrkB and cdk1 in vivo. By using an in vitro system that recapitulates differentiation and cell cycle re-entry of chick retinal neurons we show that BDNF, employed at concentrations specific for the TrkB receptor, reduces the expression of cdk1 in TrkB-positive, differentiating neurons. In this system, BDNF also inhibits the activity of both endogenous cdk1 and exogenously-expressed cdk1/cyclin B1 complex. This inhibition correlates with the phosphorylation of cdk1 at Tyr15, an effect that can be prevented with K252a, a tyrosine kinase inhibitor commonly used to prevent the activity of neurotrophins through their Trk receptors. The effect of BDNF on cdk1 activity is Tyr15-specific since BDNF cannot prevent the activity of a constitutively active form of cdk1 (Tyr15Phe) when expressed in differentiating retinal neurons. We also show that BDNF-dependent phosphorylation of cdk1 at Tyr15 could not be blocked with MK-1775, a Wee1-selective inhibitor, indicating that Tyr15 phosphorylation in cdk1 does not seem to occur through the canonical mechanism observed in proliferating cells. We conclude that the inhibition of both expression and activity of cdk1 through a BDNF-dependent mechanism contributes to the maintenance of tetraploid RGCs in a G2-like state.

  10. Brain-derived neurotrophic factor inhibits osmotic swelling of rat retinal glial (Müller) and bipolar cells by activation of basic fibroblast growth factor signaling.

    Science.gov (United States)

    Berk, B-A; Vogler, S; Pannicke, T; Kuhrt, H; Garcia, T B; Wiedemann, P; Reichenbach, A; Seeger, J; Bringmann, A

    2015-06-04

    Water accumulation in retinal glial (Müller) and neuronal cells resulting in cellular swelling contributes to the development of retinal edema and neurodegeneration. Intravitreal administration of neurotrophins such as brain-derived neurotrophic factor (BDNF) is known to promote survival of retinal neurons. Here, we show that exogenous BDNF inhibits the osmotic swelling of Müller cell somata induced by superfusion of rat retinal slices or freshly isolated cells with a hypoosmotic solution containing barium ions. BDNF also inhibited the osmotic swelling of bipolar cell somata in retinal slices, but failed to inhibit the osmotic soma swelling of freshly isolated bipolar cells. The inhibitory effect of BDNF on Müller cell swelling was mediated by activation of tropomyosin-related kinase B (TrkB) and transactivation of fibroblast growth factor receptors. Exogenous basic fibroblast growth factor (bFGF) fully inhibited the osmotic swelling of Müller cell somata while it partially inhibited the osmotic swelling of bipolar cell somata. Isolated Müller cells displayed immunoreactivity of truncated TrkB, but not full-length TrkB. Isolated rod bipolar cells displayed immunoreactivities of both TrkB isoforms. Data suggest that the neuroprotective effect of exogenous BDNF in the retina is in part mediated by prevention of the cytotoxic swelling of retinal glial and bipolar cells. While BDNF directly acts on Müller cells by activation of TrkB, BDNF indirectly acts on bipolar cells by inducing glial release of factors like bFGF that inhibit bipolar cell swelling.

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

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    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 weeks of STZ-induced diabetes, respectively, and that both remained elevated after 12 weeks of diabetes. The increase in nerve lipid peroxidation was completely prevented or reversed by treatment with the aldose reductase inhibitor, ICI 222155, or by insulin, but not by the neurotrophic factors, prosaptide TX14(A) or neurotrophin-3. The increase in nerve DNA oxidation was significantly prevented by insulin treatment. In contrast, up to 16 weeks of galactose feeding did not alter nerve lipid peroxidation or protein oxidation, despite evidence of ongoing nerve conduction deficits. These observations demonstrate that nerve oxidative damage develops early after the onset of insulin-deficient diabetes and that it is not induced by increased hexose metabolism by aldose reductase per se, but rather is a downstream consequence of flux through this enzyme. Furthermore, the beneficial effect of prosaptide TX14(A) and neurotrophin-3 on nerve function and structure in diabetic rats are not due to amelioration of increased lipid peroxidation. PMID:18555826

  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

    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...... regulator of chromaffin cell division.......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...

  13. Optimizing neurotrophic factor combinations for neurite outgrowth

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    Deister, C.; Schmidt, C. E.

    2006-06-01

    Most neurotrophic factors are members of one of three families: the neurotrophins, the glial cell-line derived neurotrophic factor family ligands (GFLs) and the neuropoietic cytokines. Each family activates distinct but overlapping cellular pathways. Several studies have shown additive or synergistic interactions between neurotrophic factors from different families, though generally only a single combination has been studied. Because of possible interactions between the neurotrophic factors, the optimum concentration of a factor in a mixture may differ from the optimum when applied individually. Additionally, the effect of combinations of neurotrophic factors from each of the three families on neurite extension is unclear. This study examines the effects of several combinations of the neurotrophin nerve growth factor (NGF), the GFL glial cell-line derived neurotrophic factor (GDNF) and the neuropoietic cytokine ciliary neurotrophic factor (CNTF) on neurite outgrowth from young rat dorsal root ganglion (DRG) explants. The combination of 50 ng ml-1 NGF and 10 ng ml-1 of each GDNF and CNTF induced the highest level of neurite outgrowth at a 752 ± 53% increase over untreated DRGs and increased the longest neurite length to 2031 ± 97 µm compared to 916 ± 64 µm for untreated DRGs. The optimum concentrations of the three factors applied in combination corresponded to the optimum concentration of each factor when applied individually. These results indicate that the efficacy of future therapies for nerve repair would be enhanced by the controlled release of a combination of neurotrophins, GFLs and neuropoietic cytokines at higher concentrations than used in previous conduit designs.

  14. A novel mechanism of hepatocellular carcinoma cell apoptosis induced by lupeol via Brain-Derived Neurotrophic Factor Inhibition and Glycogen Synthase Kinase 3 beta reactivation.

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    Zhang, Lingli; Tu, Yi; He, Wen; Peng, Yan; Qiu, Zhenpeng

    2015-09-05

    Lupeol is a naturally available triterpenoid with selective anticancerous potential on various human cancer cells. The present study shows that lupeol can inhibit cell proliferation of hepatocellular carcinoma (HCC) HCCLM3 cells in a time- and dose-dependent manner, through caspase-3 dependent activation and Poly ADP-Ribose Polymerase (PARP) cleavage. Lupeol-induced cell death is associated with a marked decrease in the protein expression of Brain-Derived Neurotrophic Factor (BDNF) and ser-9-phosphoryltion of Glycogen Synthase Kinase 3 Beta (GSK-3β), with concomitant suppression of Akt1, phosphatidyl inositol 3-kinase (PI3K), β-catenin, c-Myc and Cyclin D1 mRNA expression. Suppressing overexpression of BDNF by lupeol results in decreased protein expression of p-Akt and PI3K (p110α), as well as reactivation of GSK-3β function in HepG2 cells. Lupeol treatment also inhibits LiCl-induced activation of Wnt signaling pathway and exerts the in vitro anti-invasive activity in Huh-7 cells. LiCl-triggered high expression of β-catenin, c-Myc and Cyclin D1 protein is reduced followed by lupeol exposure. The findings suggest a mechanistic link between caspase dependent pathway, BDNF secretion and Akt/PI3K/GSK-3β in HCC cells. These results indicate that lupeol can suppress HCC cell proliferation by inhibiting BDNF secretion and phosphorylation of GSK-3β(Ser-9), cooperated with blockade of Akt/PI3K and Wnt signaling pathway.

  15. Neurotrophic factors in sponal pain transmission

    NARCIS (Netherlands)

    J.L.M. Jongen (Joost)

    2006-01-01

    textabstractHet doel van dit proefschrift was de betrokkenheid van Glial Cell Line-Derived Neurotrophic Factor (GDNF) bij spinale pijntransmissie te bestuderen. In Hoofdstuk 1 worden enkele recente ontwikkelen betreffende de organisatie van het nociceptieve systeem besproken, gevolgd door een besc

  16. Localization of brain-derived neurotrophic factor to distinct terminals of mossy fiber axons implies regulation of both excitation and feedforward inhibition of CA3 pyramidal cells.

    Science.gov (United States)

    Danzer, Steve C; McNamara, James O

    2004-12-15

    Hippocampal dentate granule cells directly excite and indirectly inhibit CA3 pyramidal cells via distinct presynaptic terminal specializations of their mossy fiber axons. This mossy fiber pathway contains the highest concentration of brain-derived neurotrophic factor (BDNF) in the CNS, yet whether BDNF is positioned to regulate the excitatory and/or inhibitory pathways is unknown. To localize BDNF, confocal microscopy of green fluorescent protein transgenic mice was combined with BDNF immunohistochemistry. Approximately half of presynaptic granule cell-CA3 pyramidal cell contacts were found to contain BDNF. Moreover, enhanced neuronal activity virtually doubled the percentage of BDNF-immunoreactive terminals contacting CA3 pyramidal cells. To our surprise, BDNF was also found in mossy fiber terminals contacting inhibitory neurons. These studies demonstrate that mossy fiber BDNF is poised to regulate both direct excitatory and indirect feedforward inhibitory inputs to CA3 pyramdal cells and reveal that seizure activity increases the pool of BDNF-expressing granule cell presynaptic terminals contacting CA3 pyramidal cells.

  17. Inhibition of TRPA1 channel activity in sensory neurons by the glial cell line-derived neurotrophic factor family member, artemin

    Directory of Open Access Journals (Sweden)

    Wang Shenglan

    2011-05-01

    Full Text Available Abstract Background The transient receptor potential (TRP channel subtype A1 (TRPA1 is known to be expressed on sensory neurons and respond to changes in temperature, pH and local application of certain noxious chemicals such as allyl isothiocyanate (AITC. Artemin is a neuronal survival and differentiation factor and belongs to the glial cell line-derived neurotrophic factor (GDNF family. Both TRPA1 and artemin have been reported to be involved in pathological pain initiation and maintenance. In the present study, using whole-cell patch clamp recording technique, in situ hybridization and behavioral analyses, we examined the functional interaction between TRPA1 and artemin. Results We found that 85.8 ± 1.9% of TRPA1-expressing neurons also expressed GDNF family receptor alpha 3 (GFR α3, and 87.5 ± 4.1% of GFRα3-expressing neurons were TRPA1-positive. In whole-cell patch clamp analysis, a short-term treatment of 100 ng/ml artemin significantly suppressed the AITC-induced TRPA1 currents. A concentration-response curve of AITC resulting from the effect of artemin showed that this inhibition did not change EC50 but did lower the AITC-induced maximum response. In addition, pre-treatment of artemin significantly suppressed the number of paw lifts induced by intraplantar injection of AITC, as well as the formalin-induced pain behaviors. Conclusions These findings that a short-term application of artemin inhibits the TRPA1 channel's activity and the sequential pain behaviors suggest a role of artemin in regulation of sensory neurons.

  18. Oligomeric amyloid-{beta} inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning.

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    Zheng, Zhaoqing; Sabirzhanov, Boris; Keifer, Joyce

    2010-11-01

    Amyloid-β (Aβ) peptide is thought to have a significant role in the progressive memory loss observed in patients with Alzheimer disease and inhibits synaptic plasticity in animal models of learning. We previously demonstrated that brain-derived neurotrophic factor (BDNF) is critical for synaptic AMPA receptor delivery in an in vitro model of eyeblink classical conditioning. Here, we report that acquisition of conditioned responses was significantly attenuated by bath application of oligomeric (200 nm), but not fibrillar, Aβ peptide. Western blotting revealed that BDNF protein expression during conditioning is significantly reduced by treatment with oligomeric Aβ, as were phosphorylation levels of cAMP-response element-binding protein (CREB), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV), and ERK. However, levels of PKA and PKCζ/λ were unaffected, as was PDK-1. Protein localization studies using confocal imaging indicate that oligomeric Aβ, but not fibrillar or scrambled forms, suppresses colocalization of GluR1 and GluR4 AMPA receptor subunits with synaptophysin, indicating that trafficking of these subunits to synapses during the conditioning procedure is blocked. In contrast, coapplication of BDNF with oligomeric Aβ significantly reversed these findings. Interestingly, a tolloid-like metalloproteinase in turtle, tTLLs (turtle tolloid-like protein), which normally processes the precursor proBDNF into mature BDNF, was found to degrade oligomeric Aβ into small fragments. These data suggest that an Aβ-induced reduction in BDNF, perhaps due to interference in the proteolytic conversion of proBDNF to BDNF, results in inhibition of synaptic AMPA receptor delivery and suppression of the acquisition of conditioning.

  19. 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...

  20. 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...... reproducibility. Female gender is associated with higher whole blood BDNF concentrations whereas age, thrombocyte count and BDNF Val66Met polymorphism were un-associated....

  1. Glial Cell Line-Derived Neurotrophic Factor Family Members Reduce Microglial Activation via Inhibiting p38MAPKs-Mediated Inflammatory Responses

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    Uta Rickert

    2014-01-01

    Full Text Available Previous studies have shown that glial cell line-derived neurotrophic factor (GDNF family ligands (GFL are potent survival factors for dopaminergic neurons and motoneurons with therapeutic potential for Parkinson’s disease. However, little is known about direct influences of the GFL on microglia function, which are known to express part of the GDNF receptor system. Using RT-PCR and immunohistochemistrym we investigated the expression of the GDNF family receptor alpha 1 (GFR alpha and the coreceptor transmembrane receptor tyrosine kinase (RET in rat microglia in vitro as well as the effect of GFL on the expression of proinflammatory molecules in LPS activated microglia. We could show that GFL are able to regulate microglia functions and suggest that part of the well known neuroprotective action may be related to the suppression of microglial activation. We further elucidated the functional significance and pathophysiological implications of these findings and demonstrate that microglia are target cells of members of the GFL (GDNF and the structurally related neurotrophic factors neurturin (NRTN, artemin (ARTN, and persephin (PSPN.

  2. Neurotrophic factor - Characterization and partial purification

    Science.gov (United States)

    Popiela, H.; Ellis, S.

    1981-01-01

    Recent evidence suggests that neurotrophic activity is required for the normal proliferation and development of muscle cells. The present paper reports a study of the purification and characterization of a neurotrophic factor (NTF) from adult chicken ischiatic-peroneal nerves using two independent quantitative in vitro assay systems. The assays were performed by the measurement of the incorporation of tritiated thymidine or the sizes of single-cell clones by chick muscle cells grown in culture. The greatest amount of neutrotrophic activity is found to be extracted at a pH of 8; aqueous suspensions of the activity are stable to long-term storage at room temperature. The specific activity of the substance is doubled upon precipitation with ammonium sulfate or after gel filtration, and increase 4 to 5 fold after salt gradient elution from DEAE cellulose columns. The active fraction obtained after gel filtration and rechromatography on DEAE cellulose exhibits a 7 to 10-fold increase in specific activity. Electrophoresis of the most highly purified material yields a greatly concentrated band at around 80,000 daltons. Although NTF is purified almost 10-fold as indicated by the increase in specific activity, the maximum activity of the partially purified material is greatly reduced, possibly due to a requirement for a cofactor for the expression of maximum activity.

  3. 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.

  4. Neurotrophic factors in tension-type headache

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    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.

  5. [The research advance of brain derived neurotrophic factor].

    Science.gov (United States)

    Liu, Z; Chen, J

    2000-12-01

    Recent research advances in neuroscience show that neurotrophic factors are proteins that affect selectively various kinds of neurons of CNS and PNS. Brain derived neurotrophic factor (BDNF) is another neurotrophic factor that was first reported by Barde, a German chemist, thirty years later after the nerve growth factor had been found out. BDNF plays an important role in the growth, development, differentiation, maintenance and regeneration of various types of neurons in the CNS and has potential application to the treatment of brain injury and neurodegenerative diseases such as Alzheimer's disease, Parkinson's syndrome, Huntington's chorea and amyotrophic lateral sclerosis. In this paper, the structure, function and potential clinical application of BDNF were reviewed.

  6. 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

  7. Brain-derived Neurotrophic Factor in Megakaryocytes.

    Science.gov (United States)

    Chacón-Fernández, Pedro; Säuberli, Katharina; Colzani, Maria; Moreau, Thomas; Ghevaert, Cedric; Barde, Yves-Alain

    2016-05-06

    The biosynthesis of endogenous brain-derived neurotrophic factor (BDNF) has thus far been examined in neurons where it is expressed at very low levels, in an activity-dependent fashion. In humans, BDNF has long been known to accumulate in circulating platelets, at levels far higher than in the brain. During the process of blood coagulation, BDNF is released from platelets, which has led to its extensive use as a readily accessible biomarker, under the assumption that serum levels may somehow reflect brain levels. To identify the cellular origin of BDNF in platelets, we established primary cultures of megakaryocytes, the progenitors of platelets, and we found that human and rat megakaryocytes express the BDNF gene. Surprisingly, the pattern of mRNA transcripts is similar to neurons. In the presence of thapsigargin and external calcium, the levels of the mRNA species leading to efficient BDNF translation rapidly increase. Under these conditions, pro-BDNF, the obligatory precursor of biologically active BDNF, becomes readily detectable. Megakaryocytes store BDNF in α-granules, with more than 80% of them also containing platelet factor 4. By contrast, BDNF is undetectable in mouse megakaryocytes, in line with the absence of BDNF in mouse serum. These findings suggest that alterations of BDNF levels in human serum as reported in studies dealing with depression or physical exercise may primarily reflect changes occurring in megakaryocytes and platelets, including the ability of the latter to retain and release BDNF.

  8. Oligodendroglia and neurotrophic factors in neurodegeneration

    Institute of Scientific and Technical Information of China (English)

    Andrew N.Bankston; Mariana D.Mandler; Yue Feng

    2013-01-01

    Myelination by oligodendroglial cells (OLs) enables the propagation of action potentials along neuronal axons,which is essential for rapid information flow in the central nervous system.Besides saltatory conduction,the myelin sheath also protects axons against inflammatory and oxidative insults.Loss of myelin results in axonal damage and ultimately neuronal loss in demyelinating disorders.However,accumulating evidence indicates that OLs also provide support to neurons via mechanisms beyond the insulating function of myelin.More importantly,an increasing volume of reports indicates defects of OLs in numerous neurodegenerative diseases,sometimes even preceding neuronal loss in pre-symptomatic episodes,suggesting that OL pathology may be an important mechanism contributing to the initiation and/or progression of neurodegeneration.This review focuses on the emerging picture of neuronal support by OLs in the pathogenesis of neurodegenerative disorders through diverse molecular and cellular mechanisms,including direct neuron-myelin interaction,metabolic support by OLs,and neurotrophic factors produced by and/or acting on OLs.

  9. Neurotrophic factors and the pathophysiology of schizophrenic psychoses.

    Science.gov (United States)

    Durany, Nuria; Thome, Johannes

    2004-09-01

    The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.

  10. Dexmedetomidine ameliorates intracerebral hemorrhage-induced memory impairment by inhibiting apoptosis and enhancing brain-derived neurotrophic factor expression in the rat hippocampus.

    Science.gov (United States)

    Hwang, Lakkyong; Choi, In-Young; Kim, Sung-Eun; Ko, Il-Gyu; Shin, Mal-Soon; Kim, Chang-Ju; Kim, Sang-Hoon; Jin, Jun-Jang; Chung, Jun-Young; Yi, Jae-Woo

    2013-05-01

    Intracerebral hemorrhage (ICH) is a severe type of stroke causing neurological dysfunction with a high mortality rate. Dexmedetomidine is an agonist for α2‑adrenoreceptors with sedative, anxiolytic, analgesic and anesthetic effects. In the present study, we investigated the effects of dexmedetomidine on short‑term and spatial learning memory, as well as its effects on apoptosis following the induction of ICH in rats. A rat model of IHC was created by an injection of collagenase into the hippocampus using a stereotaxic instrument. Dexmedetomidine was administered intraperitoneally daily for 14 consecutive days, commencing 1 day after the induction of ICH. The step‑down avoidance test for short‑term memory and the radial 8‑arm maze test for spatial learning memory were conducted. Terminal deoxynucleotidyl transferase‑mediated dUTP nick end-labeling (TUNEL) assay, immunohistochemistry for caspase‑3, and western blot analysis for Bcl‑2, Bax, Bid and caspase-3 expression were performed for the detection of apoptosis in the hippocampus. Western blot analysis for the brain‑derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) was also performed for the detection of cell survival in the hippocampus. The induction of ICH deteriorated short‑term and spatial learning memory, increased apoptosis and suppressed BDNF and TrkB expression in the hippocampus. Treatment with dexmedetomidine ameliorated the ICH‑induced impairment of short‑term and spatial learning memory by suppressing apoptosis and enhancing BDNF and TrkB expression. In the normal rats, dexmedetomidine exerted no significant effects on memory function and apoptosis. The present results suggest the possibility that dexmedetomidine may be used as a therapeutic agent for the conservation of memory function in stroke patients.

  11. Hippocampal neurogenesis, neurotrophic factors and depression: possible therapeutic targets?

    Science.gov (United States)

    Serafini, Gianluca; Hayley, Shawn; Pompili, Maurizio; Dwivedi, Yogesh; Brahmachari, Goutam; Girardi, Paolo; Amore, Mario

    2014-01-01

    Major depression is one of the leading causes of disability and psychosocial impairment worldwide. Although many advances have been made in the neurobiology of this complex disorder, the pathophysiological mechanisms are still unclear. Among the proposed theories, impaired neuroplasticity and hippocampal neurogenesis have received considerable attention. The possible association between hippocampal neurogenesis, neurotrophic factors, major depression, and antidepressant responses was critically analyzed using a comprehensive search of articles/book chapters in English language between 1980 and 2014. One common emerging theme was that chronic stress and major depression are associated with structural brain changes such as a loss of dendritic spines and synapses, as well as reduced dendritic arborisation, together with diminished glial cells in the hippocampus. Both central monoamines and neurotrophic factors were associated with a modulation of hippocampal progenitor proliferation and cell survival. Accordingly, antidepressants are generally suggested to reverse stress-induced structural changes augmenting dendritic arborisation and synaptogenesis. Such antidepressant consequences are supposed to stem from their stimulatory effects on neurotrophic factors, and possibly modulation of glial cells. Of course, accumulating evidence also suggested that glutamatergic systems are implicated in not only basic neuroplastic processes, but also in the core features of depression. Hence, it is critical that antidepressant strategies focus on links between the various neurotransmitter systems, neurotrophic processes of hippocampal neurogenesis, and neurotrophic factors with regards to depressive symptomology. The identification of novel alternative antidepressant medications that target these systems is discussed in this review.

  12. Inhibition of CRMP2 phosphorylation repairs CNS by regulating neurotrophic and inhibitory responses.

    Science.gov (United States)

    Nagai, Jun; Owada, Kazuki; Kitamura, Yoshiteru; Goshima, Yoshio; Ohshima, Toshio

    2016-03-01

    Central nervous system (CNS) regeneration is restricted by both the lack of neurotrophic responses and the presence of inhibitory factors. As of yet, a common mediator of these two pathways has not been identified. Microtubule dynamics is responsible for several key processes after CNS injuries: intracellular trafficking of receptors for neurotrophic factors, axonal retraction by inhibitory factors, and secondary tissue damages by inflammation and scarring. Kinases regulating microtubule organization, such as Cdk5 or GSK3β, may play pivotal roles during CNS recovery, but the molecular mechanisms remain to be elucidated. Collapsin response mediator protein 2 (CRMP2) stabilizes cytoskeletal polymerization, while CRMP2 phosphorylation by Cdk5 and GSK3β loses its affinity for cytoskeleton proteins, leading to the inhibition of axonal growth. Here, we characterized CRMP2 phosphorylation as the first crucial factor regulating neurotrophic and inhibitory responses after spinal cord injury (SCI). We found that pharmacological inhibition of GSK3β enhanced brain-derived neurotrophic factor (BDNF)-induced axonal growth response in cultured dorsal root ganglion (DRG) neurons. DRG neurons from CRMP2 knock-in (Crmp2KI/KI) mice, where CRMP2 phosphorylation was eliminated, showed elevated sensitivity to BDNF as well. Additionally, cultured Crmp2KI/KI neurons exhibited suppressed axonal growth inhibition by chondroitin sulfate proteoglycan (CSPG). These data suggest a couple of new molecular insights: the BDNF/GSK3β/CRMP2 and CSPG/GSK3β/CRMP2 pathways. Next, we tested the significance of CRMP2 phosphorylation after CNS injury in vivo. The phosphorylation level of CRMP2 was enhanced in the injured spinal cord. Crmp2KI/KI mice exhibited prominent recovery of locomotive and nociceptive functions after SCI, which correlated with the enhanced axonal growth of the motor and sensory neurons. Neuroprotective effects against SCI, such as microtubule stabilization, reduced inflammation

  13. 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

    2011-01-01

    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 i

  14. Determinants of serum brain-derived neurotrophic factor

    NARCIS (Netherlands)

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

    2011-01-01

    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 i

  15. [Neurotrophic factors and their importance in attention deficit hyperactivity disorde].

    Science.gov (United States)

    Ramos-Quiroga, Josep A; Sánchez-Mora, Cristina; Corominas, Margarida; Martínez, Iris; Barrau, Víctor; Prats, Laura; Casas, Miguel; Ribasés, Marta

    2014-02-24

    The existing literature that reports findings linked with the involvement of neurotrophic factors in attention deficit hyperactivity disorder (ADHD) is reviewed. Neurotrophins, a family of neurotrophic factors, are a kind of proteins that are specific to the nervous system and play an essential role in neuron survival, differentiation and proliferation during the development of the central and peripheral nervous system. These molecules stimulate axonal growth and exert an influence on the connections with the target tissue in order to establish the synaptic connections. The study of neurotrophins in ADHD, a neurodevelopmental disorder, is of interest mainly due to the functions that these proteins perform in the central nervous system. Studies on animal, pharmacological and molecular genetic models yield evidence that relates neurotrophins with the disorder. This work reviews the results from the studies conducted to date on ADHD and neurotrophic factors, especially brain-derived neurotrophic factor (BDNF). Thus, although pharmacological studies suggest that the response to atomoxetine in adults with ADHD is not directly mediated by the effect on the BDNF, reductions in BDNF levels in the plasma of adult patients with ADHD have been reported. Further studies with broader samples and greater control of environmental factors that can regulate neurotrophin expression, such as diet, physical exercise and situations of social risk, are needed to be able to determine the role they play in the aetiology of ADHD.

  16. Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

    OpenAIRE

    Anita E Autry; Monteggia, Lisa M.

    2012-01-01

    Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Ret...

  17. Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite.

    Science.gov (United States)

    Byerly, Mardi S; Swanson, Roy D; Semsarzadeh, Nina N; McCulloh, Patrick S; Kwon, Kiwook; Aja, Susan; Moran, Timothy H; Wong, G William; Blackshaw, Seth

    2013-06-15

    Disruption of finely coordinated neuropeptide signals in the hypothalamus can result in altered food intake and body weight. We identified neuron-derived neurotrophic factor (NENF) as a novel secreted protein through a large-scale screen aimed at identifying novel secreted hypothalamic proteins that regulate food intake. We observed robust Nenf expression in hypothalamic nuclei known to regulate food intake, and its expression was altered under the diet-induced obese (DIO) condition relative to the fed state. Hypothalamic Nenf mRNA was regulated by brain-derived neurotrophic factor (BDNF) signaling, itself an important regulator of appetite. Delivery of purified recombinant BDNF into the lateral cerebral ventricle decreased hypothalamic Nenf expression, while pharmacological inhibition of trkB signaling increased Nenf mRNA expression. Furthermore, recombinant NENF administered via an intracerebroventricular cannula decreased food intake and body weight and increased hypothalamic Pomc and Mc4r mRNA expression. Importantly, the appetite-suppressing effect of NENF was abrogated in obese mice fed a high-fat diet, demonstrating a diet-dependent modulation of NENF function. We propose the existence of a regulatory circuit involving BDNF, NENF, and melanocortin signaling. Our study validates the power of using an integrated experimental and bioinformatic approach to identify novel CNS-derived proteins with appetite-modulating function and reveals NENF as an important central modulator of food intake.

  18. 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.

  19. Brain-derived neurotrophic factor and its clinical implications.

    Science.gov (United States)

    Bathina, Siresha; Das, Undurti N

    2015-12-10

    Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. It is widely expressed in the CNS, gut and other tissues. BDNF binds to its high affinity receptor TrkB (tyrosine kinase B) and activates signal transduction cascades (IRS1/2, PI3K, Akt), crucial for CREB and CBP production, that encode proteins involved in β cell survival. BDNF and insulin-like growth factor-1 have similar downstream signaling mechanisms incorporating both p-CAMK and MAPK that increase the expression of pro-survival genes. Brain-derived neurotrophic factor regulates glucose and energy metabolism and prevents exhaustion of β cells. Decreased levels of BDNF are associated with neurodegenerative diseases with neuronal loss, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease. Thus, BDNF may be useful in the prevention and management of several diseases including diabetes mellitus.

  20. Neonatal Levels of Neurotrophic Factors and Risk of Autism Spectrum Disorders

    DEFF Research Database (Denmark)

    W. Abdallah, Morsi; L. Mortensen, Erik; Greaves-Lord, Kirstin

    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....

  1. 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.

  2. Brain-derived neurotrophic factor and neuropsychiatric disorders.

    Science.gov (United States)

    Autry, Anita E; Monteggia, Lisa M

    2012-04-01

    Brain derived neurotrophic factor (BDNF) is the most prevalent growth factor in the central nervous system (CNS). It is essential for the development of the CNS and for neuronal plasticity. Because BDNF plays a crucial role in development and plasticity of the brain, it is widely implicated in psychiatric diseases. This review provides a summary of clinical and preclinical evidence for the involvement of this ubiquitous growth factor in major depressive disorder, schizophrenia, addiction, Rett syndrome, as well as other psychiatric and neurodevelopmental diseases. In addition, the review includes a discussion of the role of BDNF in the mechanism of action of pharmacological therapies currently used to treat these diseases, such antidepressants and antipsychotics. The review also covers a critique of experimental therapies such as BDNF mimetics and discusses the value of BDNF as a target for future drug development.

  3. Secretion of nerve growth factor, brain-derived neurotrophic factor, and glial cell-line derived neurotrophic factor in co-culture of four cell types in cerebrospinal fluid-containing medium

    Institute of Scientific and Technical Information of China (English)

    Sanjiang Feng; Minghua Zhuang; Rui Wu

    2012-01-01

    The present study co-cultured human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells in complete culture medium- containing cerebrospinal fluid. Enzyme linked immunosorbent assay was used to detect nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor secretion in the supernatant of co-cultured cells. Results showed that the number of all cell types reached a peak at 7–10 days, and the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor peaked at 9 days. Levels of secreted nerve growth factor were four-fold higher than brain-derived neurotrophic factor, which was three-fold higher than glial cell line-derived neurotrophic factor. Increasing concentrations of cerebrospinal fluid (10%, 20% and 30%) in the growth medium caused a decrease of neurotrophic factor secretion. Results indicated co-culture of human embryonic olfactory ensheathing cells, human Schwann cells, human amniotic epithelial cells and human vascular endothelial cells improved the expression of nerve growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor. The reduction of cerebrospinal fluid extravasation at the transplant site after spinal cord injury is beneficial for the survival and secretion of neurotrophic factors from transplanted cells.

  4. 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...

  5. Brain-Derived Neurotrophic Factor: Three Ligands, Many Actions.

    Science.gov (United States)

    Hempstead, Barbara L

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of a family of neurotrophins which include nerve growth factor, neurotrophin 3, and neurotrophin 4. Studies over the last three decades have identified mature BDNF as a key regulator of neuronal differentiation, structure, and function; actions mediated by the TrkB receptor. More recently identified isoforms which are translated from the bdnf gene, including the uncleaved precursor, pro-BDNF, and the cleaved prodomain, have been found to elicit opposing functions in neurons through the activation of distinct receptors. This work emphasizes the critical roles for all three isoforms of BDNF in modulating neuronal activity that impact complex human behaviors including memory, anxiety, depression, and hyperphagia.

  6. Progesterone, brain-derived neurotrophic factor and neuroprotection.

    Science.gov (United States)

    Singh, M; Su, C

    2013-06-03

    While the effects of progesterone in the CNS, like those of estrogen, have generally been considered within the context of reproductive function, growing evidence supports its importance in regulating non-reproductive functions including cognition and affect. In addition, progesterone has well-described protective effects against numerous insults in a variety of cell models, animal models and in humans. While ongoing research in several laboratories continues to shed light on the mechanism(s) by which progesterone and its related progestins exert their effects in the CNS, our understanding is still incomplete. Among the key mediators of progesterone's beneficial effects is the family of growth factors called neurotrophins. Here, we review the mechanisms by which progesterone regulates one important member of the neurotrophin family, brain-derived neurotrophic factor (BDNF), and provides support for its pivotal role in the protective program elicited by progesterone in the brain.

  7. Glial cell line-derived neurotrophic factor influences proliferation of osteoblastic cells.

    Science.gov (United States)

    Gale, Zoe; Cooper, Paul R; Scheven, Ben A

    2012-02-01

    Little is known about the role of neurotrophic growth factors in bone metabolism. This study investigated the short-term effects of glial cell line-derived neurotrophic factor (GDNF) on calvarial-derived MC3T3-E1 osteoblasts. MC3T3-E1 expressed GDNF as well as its canonical receptors, GFRα1 and RET. Addition of recombinant GDNF to cultures in serum-containing medium modestly inhibited cell growth at high concentrations; however, under serum-free culture conditions GDNF dose-dependently increased cell proliferation. GDNF effects on cell growth were inversely correlated with its effect on alkaline phosphatase (AlP) activity showing a significant dose-dependent inhibition of relative AlP activity with increasing concentrations of GDNF in serum-free culture medium. Live/dead and lactate dehydrogenase assays demonstrated that GDNF did not significantly affect cell death or survival under serum-containing and serum-free conditions. The effect of GDNF on cell growth was abolished in the presence of inhibitors to GFRα1 and RET indicating that GDNF stimulated calvarial osteoblasts via its canonical receptors. Finally, this study found that GDNF synergistically increased tumor necrosis factor-α (TNF-α)-stimulated MC3T3-E1 cell growth suggesting that GDNF interacted with TNF-α-induced signaling in osteoblastic cells. In conclusion, this study provides evidence for a direct, receptor-mediated effect of GDNF on osteoblasts highlighting a novel role for GDNF in bone physiology.

  8. Pleiotrophin promotes microglia proliferation and secretion of neurotrophic factors by activating extracellular signal-regulated kinase 1/2 pathway.

    Science.gov (United States)

    Miao, Jiayin; Ding, Minghui; Zhang, Aiwu; Xiao, Zijian; Qi, Weiwei; Luo, Ning; Di, Wei; Tao, Yuqian; Fang, Yannan

    2012-12-01

    Pleiotrophin (PTN) is an effective neuroprotective factor and its expression is strikingly increased in microglia after ischemia/reperfusion injury. However, whether PTN could provide neurotrophic support to neurons by regulating microglia function is not clear. In this study, we demonstrated that the expression of PTN was induced in microglia after oxygen-glucose deprivation/reperfusion. PTN promoted the proliferation of microglia by enhancing the G1 to S phase transition. PTN also stimulated the secretion of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and nerve growth factor (NGF) in microglia, but did not upregulate the expression of proinflammatory factors such as TNF-α, IL-1β and iNOS. Mechanistically, we found that PTN increased the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in microglia in both concentration-dependent and time-dependent manners. In addition, ERK1/2 inhibitor U0126 abolished the proliferation and G1 to S phase transition of microglia stimulated by PTN, and inhibited the production of BDNF, CNTF and NGF induced by PTN. In conclusion, our results demonstrated that PTN-ERK1/2 pathway plays important role in regulating microglia growth and secretion of neurotrophic factors. These findings provide new insight into the neuroprotective role of PTN and suggest that PTN is a new target for therapeutic intervention of stroke.

  9. Transfection of the glial cell line-derived neurotrophic factor gene promotes neuronal differentiation

    Institute of Scientific and Technical Information of China (English)

    Jie Du; Xiaoqing Gao; Li Deng; Nengbin Chang; Huailin Xiong; Yu Zheng

    2014-01-01

    Glial cell line-derived neurotrophic factor recombinant adenovirus vector-transfected bone marrow mesenchymal stem cells were induced to differentiate into neuron-like cells using inductive medium containing retinoic acid and epidermal growth factor. Cell viability, micro-tubule-associated protein 2-positive cell ratio, and the expression levels of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43 protein in the su-pernatant were signiifcantly higher in glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells compared with empty virus plasmid-transfected bone marrow mes-enchymal stem cells. Furthermore, microtubule-associated protein 2, glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43 mRNA levels in cell pellets were statistically higher in glial cell line-derived neurotrophic factor/bone marrow mesen-chymal stem cells compared with empty virus plasmid-transfected bone marrow mesenchymal stem cells. These results suggest that glial cell line-derived neurotrophic factor/bone marrow mesenchymal stem cells have a higher rate of induction into neuron-like cells, and this enhanced differentiation into neuron-like cells may be associated with up-regulated expression of glial cell line-derived neurotrophic factor, nerve growth factor and growth-associated protein-43.

  10. 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...

  11. 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

  12. Neuronal plasticity and neurotrophic factors in drug responses.

    Science.gov (United States)

    Castrén, E; Antila, H

    2017-08-01

    Neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and other members of the neurotrophin family, are central mediators of the activity-dependent plasticity through which environmental experiences, such as sensory information are translated into the structure and function of neuronal networks. Synthesis, release and action of BDNF is regulated by neuronal activity and BDNF in turn leads to trophic effects such as formation, stabilization and potentiation of synapses through its high-affinity TrkB receptors. Several clinically available drugs activate neurotrophin signaling and neuronal plasticity. In particular, antidepressant drugs rapidly activate TrkB signaling and gradually increase BDNF expression, and the behavioral effects of antidepressants are mediated by and dependent on BDNF signaling through TrkB at least in rodents. These findings indicate that antidepressants, widely used drugs, effectively act as TrkB activators. They further imply that neuronal plasticity is a central mechanism in the action of antidepressant drugs. Indeed, it was recently discovered that antidepressants reactivate a state of plasticity in the adult cerebral cortex that closely resembles the enhanced plasticity normally observed during postnatal critical periods. This state of induced plasticity, known as iPlasticity, allows environmental stimuli to beneficially reorganize networks abnormally wired during early life. iPlasticity has been observed in cortical as well as subcortical networks and is induced by several pharmacological and non-pharmacological treatments. iPlasticity is a new pharmacological principle where drug treatment and rehabilitation cooperate; the drug acts permissively to enhance plasticity and rehabilitation provides activity to guide the appropriate wiring of the plastic network. Optimization of iPlastic drug treatment with novel means of rehabilitation may help improve the efficacy of available drug treatments and expand the use of

  13. Role of brain-derived neurotrophic factor in Huntington's disease.

    Science.gov (United States)

    Zuccato, Chiara; Cattaneo, Elena

    2007-04-01

    Neurotrophic factors are essential contributors to the survival of peripheral and central nervous system (CNS) neurons, and demonstration of their reduced availability in diseased brains indicates that they play a role in various neurological disorders. This paper will concentrate on the role of brain-derived neurotrophic factor (BDNF) in the survival and activity of the neurons that die in Huntington's disease (HD) by reviewing the evidence indicating that it involves profound changes in BDNF levels and that attempts to restore these levels are therapeutically interesting. BDNF is a small dimeric protein that is widely expressed in adult mammalian brain and has been shown to promote the survival of all major neuronal types affected in Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, cortical BDNF production is required for the correct activity of the corticostriatal synapse and the survival of the GABA-ergic medium-sized spiny striatal neurons that die in HD. We will highlight the available data concerning changes in BDNF levels in HD cells, mice and human postmortem samples, describe the molecular evidence underlying this alteration, and review the data concerning the impact of the experimental manipulation of BDNF levels on HD progression. Such studies have revealed a major loss of BDNF protein in the striatum of HD patients which may contribute to the clinical manifestations of the disease. They have also opened up a molecular window into the underlying pathogenic mechanism and new therapeutic perspectives by raising the possibility that one of the mechanisms triggering the reduction in BDNF in HD may also affect the activity of many other neuronal proteins.

  14. Influence of endogenous ciliary neurotrophic factor on neural differentiation of adult rat hippocampal progenitors

    Institute of Scientific and Technical Information of China (English)

    Jun Ding; Zhili He; Juan Ruan; Ying Liu; Chengxin Gong; Shenggang Sun; Honghui Chen

    2013-01-01

    Ciliary neurotrophic factor is the only known neurotrophic factor that can promote differentiation of hippocampal neural progenitor cells to glial cells and neurons in adult rats. This process is similar to spontaneous differentiation. Therefore, ciliary neurotrophic factor may be involved in spontaneous differentiation of neural stem cells. To verify this hypothesis, the present study isolated neural progenitor cells from adult male rats and cultured them in vitro. Results showed that when neural progenitor cells were cultured in the absence of mitogen fibroblast growth factor-2 or epidermal growth factor, they underwent spontaneous differentiation into neurons and glial cells. Western blot and immunocytochemical staining showed that exogenous ciliary neurotrophic factor strongly induced adult hippocampal progenitor cells to differentiate into neurons and glial cells. Moreover, passage 4 adult hippocampal progenitor cells expressed high levels of endogenous ciliary neurotrophic factor, and a neutralizing antibody against ciliary neurotrophic factor prevented the spontaneous neuronal and glial differentiation of adult hippocampal progenitor cells. These results suggest that the spontaneous differentiation of adult hippocampal progenitor cells is mediated partially by endogenous ciliary neurotrophic factor.

  15. Regulation of ciliary neurotrophic factor receptor alpha in sciatic motor neurons following axotomy.

    Science.gov (United States)

    MacLennan, A J; Devlin, B K; Neitzel, K L; McLaurin, D L; Anderson, K J; Lee, N

    1999-01-01

    Spinal motor neurons are one of the few classes of neurons capable of regenerating axons following axotomy. Injury-induced expression of neurotrophic factors and corresponding receptors may play an important role in this rare ability. A wide variety of indirect data suggests that ciliary neurotrophic factor receptor alpha may critically contribute to the regeneration of injured spinal motor neurons. We used immunohistochemistry, in situ hybridization and retrograde tracing techniques to study the regulation of ciliary neurotrophic factor receptor alpha in axotomized sciatic motor neurons. Ciliary neurotrophic factor receptor alpha immunoreactivity, detected with two independent antisera, is increased in a subpopulation of caudal sciatic motor neuron soma one, two and six weeks after sciatic nerve transection and reattachment, while no changes are detected at one day and 15 weeks post-lesion. Ciliary neurotrophic factor receptor alpha messenger RNA levels are augmented in the same classes of neurons following an identical lesion, suggesting that increased synthesis contributes, at least in part, to the additional ciliary neurotrophic factor receptor alpha protein. Separating the proximal and distal nerve stumps with a plastic barrier does not noticeably affect the injury-induced change in ciliary neurotrophic factor receptor alpha regulation, thereby indicating that this injury response is not dependent on signals distal to the lesion traveling retrogradely through the nerve or signals generated by axonal growth through the distal nerve. The prolonged increases in ciliary neurotrophic factor receptor alpha protein and messenger RNA found in regenerating sciatic motor neurons contrast with the responses of non-regenerating central neurons, which are reported to display, at most, a short-lived increase in ciliary neurotrophic factor receptor alpha messenger RNA expression following injury. The present data are the first to demonstrate, in vivo, neuronal regulation of

  16. Brain-derived neurotrophic factor, food intake regulation, and obesity.

    Science.gov (United States)

    Rosas-Vargas, Haydeé; Martínez-Ezquerro, José Darío; Bienvenu, Thierry

    2011-08-01

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a fundamental role in development and plasticity of the central nervous system (CNS). It is currently recognized as a major participant in the regulation of food intake. Multiple studies have shown that different regulators of appetite such as leptin, insulin and pancreatic polypeptide (PP) potentially exert anorexigenic effects through BDNF. Low circulating levels of BDNF are associated with a higher risk of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Strict food restriction reduces BDNF and may trigger binge-eating episodes and weight gain. The existence of mutations that cause haploinsufficiency of BDNF as well as some genetic variants, notably the BDNF p.Val66Met polymorphism, are also associated with the development of obese phenotypes and hyperphagia. However, association of the Met allele with AN and BN, which have different phenotypic characteristics, shows clearly the existence of other relevant factors that regulate eating behavior. This may, in part, be explained by the epigenetic regulation of BDNF through mechanisms like DNA methylation and histone acetylation. Environmental factors, primarily during early development, are crucial to the establishment of these stable but reversible changes that alter the transcriptional expression and are transgenerationally heritable, with potential concomitant effects on the development of eating disorders and body weight control.

  17. S100B protein, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor in human milk.

    Directory of Open Access Journals (Sweden)

    Ruisong Li

    Full Text Available BACKGROUND: Human milk contains a wide variety of nutrients that contribute to the fulfillment of its functions, which include the regulation of newborn development. However, few studies have investigated the concentrations of S100B protein, brain-derived neurotrophic factor (BDNF, and glial cell line-derived neurotrophic factor (GDNF in human milk. The associations of the concentrations of S100B protein, BDNF, and GDNF with maternal factors are not well explored. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the concentrations of S100B protein, BDNF, and GDNF in human milk and characterize the maternal factors associated with their levels in human milk, human milk samples were collected at days 3, 10, 30, and 90 after parturition. Levels of S100B protein, BDNF, and GDNF, and their mRNAs in the samples were detected. Then, these concentrations were compared with lactation and other maternal factors. S100B protein levels in human milk samples collected at 3, 10, 30, and 90 d after parturition were 1249.79±398.10, 1345.05±539.16, 1481.83±573.30, and 1414.39±621.31 ng/L, respectively. On the other hand, the BDNF concentrations in human milk samples were 10.99±4.55, 13.01±5.88, 13.35±6.43, and 2.83±5.47 µg/L, while those of GDNF were 10.90±1.65, 11.38±1., 11.29±3.10, and 11.40±2.21 g/L for the same time periods. Maternal post-pregnancy body mass index was positively associated with S100B levels in human milk (r = 0.335, P = 0.030<0.05. In addition, there was a significant correlation between the levels of S100B protein and BDNF (z = 2.09, P = 0.037<0.05. Delivery modes were negatively associated with the concentration of GDNF in human milk. CONCLUSIONS: S100B protein, BDNF, and GDNF are present in all samples of human milk, and they may be responsible for the long term effects of breast feeding.

  18. 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

  19. Repetitive transcranial magnetic stimulation increases the corticospinal inhibition and the brain-derived neurotrophic factor in chronic myofascial pain syndrome: an explanatory double-blinded, randomized, sham-controlled trial.

    Science.gov (United States)

    Dall'Agnol, Letizzia; Medeiros, Liciane Fernandes; Torres, Iraci L S; Deitos, Alicia; Brietzke, Aline; Laste, Gabriela; de Souza, Andressa; Vieira, Júlia Lima; Fregni, Felipe; Caumo, Wolnei

    2014-08-01

    Chronic myofascial pain syndrome has been related to defective descending inhibitory systems. Twenty-four females aged 19 to 65 years with chronic myofascial pain syndrome were randomized to receive 10 sessions of repetitive transcranial magnetic stimulation (rTMS) (n = 12) at 10 Hz or a sham intervention (n = 12). We tested if pain (quantitative sensory testing), descending inhibitory systems (conditioned pain modulation [quantitative sensory testing + conditioned pain modulation]), cortical excitability (TMS parameters), and the brain-derived neurotrophic factor (BDNF) would be modified. There was a significant interaction (time vs group) regarding the main outcomes of the pain scores as indexed by the visual analog scale on pain (analysis of variance, P myofascial pain syndrome were mediated by top-down regulation mechanisms, enhancing the corticospinal inhibitory system possibly via BDNF secretion modulation. High-frequency rTMS analgesic effects were mediated by top-down regulation mechanisms enhancing the corticospinal inhibitory, and this effect involved an increase in BDNF secretion. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

  20. Brain-derived neurotrophic factor and substantia nigra dopaminergic neurons in Parkinson's disease

    Institute of Scientific and Technical Information of China (English)

    Haixia Ding; Meijiang Feng; Xinsheng Ding

    2008-01-01

    BACKGROUND:Parkinson's disease (PD) is a chronic, progressive neurodegenerative central nervous system disease which occurs in the substantia nigra-corpus striatum system. The main pathological feature of PD is selective dopaminergic neuronal loss with distinctive Lewy bodies in populations of surviving dopaminergic neurons. In the clinical and neuropathological diagnosis of PD, brain-derived neurotrophic factor mRNA expression in the substantia nigra pars compacta is reduced by 70%, and surviving dopaminergic neurons in the PD substantia nigra pars compacta express less brain-derived neurotrophic factor (BDNF) mRNA (20%) than their normal counterparts. In recent years, knowledge surrounding the relationship between neurotrophic factors and PD has increased, and detailed pathogenesis of the role of neurotrophic factors in PD becomes more important.

  1. Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review

    National Research Council Canada - National Science Library

    Cui, Huiru; Jin, Yi; Wang, Jijun; Weng, Xuchu; Li, Chunbo

    2012-01-01

    There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia...

  2. Effect of neurotrophic factor, MDP, on rats' nerve regeneration.

    Science.gov (United States)

    Fornazari, A A; Rezende, M R de; Mattar Jr, R; Taira, R I; Santos, G B dos; Paulos, R G

    2011-04-01

    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 MDP obtained better function, in the absence of any significant histological differences.

  3. Adenovirally Delivered Brain-derived Neurotrophic Factor to Rat Retina

    Institute of Scientific and Technical Information of China (English)

    Xu Hou; Dan Hu; Yannian Hui

    2004-01-01

    Purpose: To study the expression of brain-derived neurotrophic factor (BDNF) in the rat retina delivered by adenovirus.Methods: Adenovirus with BDNF gene was injected into the vitreous. Gene expression was detected by immunofluorescence staining, and quantitative analysis was performed after injury and transfection by Enzyme-linked immunosorbent assay (ELISA).Results: The positive cells can be seen on the 3rd day and last 4 weeks by immunofluorescence staining. Positive cells in the control group were fewer than those in the transfection group or the fluorescence intensity was lower at every time point. Quantitative analysis showed that the expression of BDNF groups was higher than that of the control group at every time point(P < 0.01 ), and that of the injured group without transfection was higher than that of the control group on the 3rd day and the 7th day (P < 0.01 ).Conclusion: Efficient and stable transfer of BDNF gene could be achieved by adenovirus delivery into the retina of rats. Injury can promote the expression of BDNF in early period.

  4. Protective Effects of Ciliary Neurotrophic Factor on Denervated Skeletal Muscle

    Institute of Scientific and Technical Information of China (English)

    黄仕龙; 王发斌; 洪光祥; 万圣祥; 康皓

    2002-01-01

    Summary: To study the effects of ciliary neurotrophic factor (CNTF) on denervated skeletal muscle atrophy and to find a new approach to ameliorate atrophy of denervated muscle, a model was estab lished by cutting the right sciatic nerve in 36 Wistar mice, with the left side serving as control. Then they were divided into two groups randomly. CNTF (1 U/ml) 0. 1 ml was injected into the right tib-ial muscle every day in experimental group, and saline was used into another group for comparison.The muscle wet weight, muscle total protein, Ca2+, physiological response and morphology were an alyzed on the 7th, 14th and 28th day after operation. Our results showed that compared to control group, there was a significant increase in muscle wet weight, total protein, Ca2+ , muscle fiber cross section area in CNTF group (P< 0. 05). CNTF could ameliorate the decrease of tetanic tension (PO), post-tetanic twitch potentiation (PTP), and the prolonged muscle relaxation time (RT)caused by denervation (P<0. 05). The motor end-plate areas 7 days and 14 days after denervation was similar (P>0. 05), but significantly larger 28 days after the denervation (P<0.05). Our re-sults suggest that CNTF exerts myotrophic effects by attenuating the morphological and functional changes associated with denervation of rat muscles and has protective effects on denervated muscle and motor end plate.

  5. DYNAMIC PLASTICITY: THE ROLE OF GLUCOCORTICOIDS, BRAIN-DERIVED NEUROTROPHIC FACTOR AND OTHER TROPHIC FACTORS

    OpenAIRE

    Gray, J. D.; MILNER, T. A.; MCEWEN, B. S.

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypo...

  6. Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

    OpenAIRE

    Magariños, A.M.; Li, C. J.; Toth, J. Gal; Bath, K.G.; Jing, D; Lee, F S; MCEWEN, B. S.

    2011-01-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the ...

  7. 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.

  8. Use of RNAi silencing to target preconditioned glial cell line-derived neurotrophic factor in neuronal apoptosis

    Institute of Scientific and Technical Information of China (English)

    Hongliang Guo; Zhongxin Xu; Xinhua Li; Jing Mang; Ying Xing; Jinting He; Guihua Xu; Shijun Yan; Lifeng Liu; Chunli Mei

    2011-01-01

    Several studies have suggested that exogenous glial cell line-derived neurotrophic factor may protect neurons from cerebral ischemic injury. However, the mechanisms underlying the neuroprotective effects of endogenous glial cell line-derived neurotrophic factor remain unclear. The present experiments sought to elucidate the influence of various conditioned media on neuronal apoptosis, using a normal culture medium for astrocytes, an astrocyte medium highly expressing glial cell line-derived neurotrophic factor, and an astrocyte medium in which glial cell line-derived neurotrophic factor expression was silenced using RNAi technology. The results confirmed that the use of RNAi silencing to target pretreated glial cell line-derived neurotrophic factor expression promoted neuronal apoptosis. In addition, oxygen and glucose deprivation preconditioning was found to upregulate glial cell line-derived neurotrophic factor expression, and significantly reduce neuronal apoptosis.

  9. 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.

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

    Science.gov (United States)

    Nie, Jing; Tian, Yong; Zhang, Yu; Lu, Yan-Liu; Li, Li-Sheng

    2016-01-01

    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. PMID:27994964

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

    Science.gov (United States)

    Nie, Jing; Tian, Yong; Zhang, Yu; Lu, Yan-Liu; Li, Li-Sheng; Shi, Jing-Shan

    2016-01-01

    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. 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. 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. 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.

  12. 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.

  13. Effect of propofol on brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus of aged rats with chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Gang Chen; Qiang Fu; Jiangbei Cao; Weidong Mi

    2012-01-01

    We intraperitoneally injected 10 and 50 mg/kg of propofol for 7 consecutive days to treat a rat model of chronic cerebral ischemia. A low-dose of propofol promoted the expression of brain-derived neurotrophic factor, tyrosine kinase receptor B, phosphorylated cAMP response element binding protein, and cAMP in the hippocampus of aged rats with chronic cerebral ischemia, but a high-dose of propofol inhibited their expression. Results indicated that the protective effect of propofol against cerebral ischemia in aged rats is related to changes in the expression of brain-derived neurotrophic factor and tyrosine kinase receptor B in the hippocampus, and that the cAMP-cAMP responsive element binding protein pathway is involved in the regulatory effect of propofol on brain-derived neurotrophic factor expression.

  14. Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes.

    Science.gov (United States)

    Xiao, Junhua; Wong, Agnes W; Willingham, Melanie M; van den Buuse, Maarten; Kilpatrick, Trevor J; Murray, Simon S

    2010-01-01

    The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain-derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes.

  15. Protective Action of Neurotrophic Factors and Estrogen against Oxidative Stress-Mediated Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Tadahiro Numakawa

    2011-01-01

    Full Text Available Oxidative stress is involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Low levels of reactive oxygen species (ROS and reactive nitrogen species (RNS are important for maintenance of neuronal function, though elevated levels lead to neuronal cell death. A complex series of events including excitotoxicity, Ca2+ overload, and mitochondrial dysfunction contributes to oxidative stress-mediated neurodegeneration. As expected, many antioxidants like phytochemicals and vitamins are known to reduce oxidative toxicity. Additionally, growing evidence indicates that neurotrophic factors such as brain-derived neurotrophic factor (BDNF and estrogens significantly prevent neuronal damage caused by oxidative stress. Here, we review and discuss recent studies addressing the protective mechanisms of neurotrophic factors and estrogen within this system.

  16. Serum brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 levels in children with attention-deficit/hyperactivity disorder.

    Science.gov (United States)

    Bilgiç, Ayhan; Toker, Aysun; Işık, Ümit; Kılınç, İbrahim

    2017-03-01

    It has been suggested that neurotrophins are involved in the etiopathogenesis of attention-deficit/hyperactivity disorder (ADHD). This study aimed to investigate whether there are differences in serum brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and neurotrophin-3 (NTF3) levels between children with ADHD and healthy controls. A total of 110 treatment-naive children with the combined presentation of ADHD and 44 healthy controls aged 8-18 years were enrolled in this study. The severity of ADHD symptoms was determined by scores on the Conners' Parent Rating Scale-Revised Short and Conners' Teacher Rating Scale-Revised Short. The severity of depression and anxiety symptoms of the children were evaluated by the self-report inventories. Serum levels of neurotrophins were measured using commercial enzyme-linked immunosorbent assay kits. The multivariate analysis of covariance (MANCOVA) revealed a significant main effect of groups in the levels of serum neurotrophins, an effect that was independent of age, sex, and the severity of the depression and anxiety. The analysis of covariance (ANCOVA) indicated that the mean serum GDNF and NTF3 levels of ADHD patients were significantly higher than that of controls. However, serum BDNF and NGF levels did not show any significant differences between groups. No correlations between the levels of serum neurotrophins and the severity of ADHD were observed. These results suggest that elevated serum GDNF and NTF3 levels may be related to ADHD in children.

  17. Aerobic exercise interacts with neurotrophic factors to predict cognitive functioning in adolescents.

    Science.gov (United States)

    Lee, Tatia M C; Wong, Mark Lawrence; Lau, Benson Wui-Man; Lee, Jada Chia-Di; Yau, Suk-Yu; So, Kwok-Fai

    2014-01-01

    Recent findings have suggested that aerobic exercise may have a positive effect on brain functioning, in addition to its well-recognized beneficial effects on human physiology. This study confirmed the cognitive effects of aerobic exercise on the human brain. It also examined the relationships between exercise and the serum levels of neurotrophic factors (BDNF, IGI-1, and VEGF). A total of 91 healthy teens who exercised regularly participated in this study. A between-group design was adopted to compare cognitive functioning subserved by the frontal and temporal brain regions and the serum levels of neurotrophic factors between 45 regular exercisers and 46 matched controls. The exercisers performed significantly better than the controls on the frontal and temporal functioning parameters measured. This beneficial cognitive effect was region-specific because no such positive cognitive effect on task-tapping occipital functioning was observed. With respect to the serum levels of the neurotrophic factors, a negative correlation between neurotrophic factors (BDNF and VEGF) with frontal and medial-temporal lobe function was revealed. Furthermore, the levels of BDNF and VEGF interacted with exercise status in predicting frontal and temporal lobe function. This is the first report of the interaction effects of exercise and neurotrophic factors on cognitive functioning. Herein, we report preliminary evidence of the beneficial effects of regular aerobic exercise in improving cognitive functions in teens. These beneficial effects are region-specific and are associated with the serum levels of neurotrophic factors. Our findings lay the path for future studies looking at ways to translate these beneficial effects to therapeutic strategies for adolescents.

  18. 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.

  19. 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.

  20. Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury

    Institute of Scientific and Technical Information of China (English)

    Qun Zhao; Zhi-yue Li; Ze-peng Zhang; Zhou-yun Mo; Shi-jie Chen; Si-yu Xiang; Qing-shan Zhang; Min Xue

    2015-01-01

    A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neuro-trophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site;their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the micro-spheres at 300-µm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implanta-tion, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve ifbers were observed and dis-tributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury.

  1. Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury

    Directory of Open Access Journals (Sweden)

    Qun Zhao

    2015-01-01

    Full Text Available A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the microspheres at 300-μm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury.

  2. Polylactic-co-glycolic acid microspheres containing three neurotrophic factors promote sciatic nerve repair after injury.

    Science.gov (United States)

    Zhao, Qun; Li, Zhi-Yue; Zhang, Ze-Peng; Mo, Zhou-Yun; Chen, Shi-Jie; Xiang, Si-Yu; Zhang, Qing-Shan; Xue, Min

    2015-09-01

    A variety of neurotrophic factors have been shown to repair the damaged peripheral nerve. However, in clinical practice, nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor are all peptides or proteins that may be rapidly deactivated at the focal injury site; their local effective concentration time following a single medication cannot meet the required time for spinal axons to regenerate and cross the glial scar. In this study, we produced polymer sustained-release microspheres based on the polylactic-co-glycolic acid copolymer; the microspheres at 300-μm diameter contained nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor. Six microspheres were longitudinally implanted into the sciatic nerve at the anastomosis site, serving as the experimental group; while the sciatic nerve in the control group was subjected to the end-to-end anastomosis using 10/0 suture thread. At 6 weeks after implantation, the lower limb activity, weight of triceps surae muscle, sciatic nerve conduction velocity and the maximum amplitude were obviously better in the experimental group than in the control group. Compared with the control group, more regenerating nerve fibers were observed and distributed in a dense and ordered manner with thicker myelin sheaths in the experimental group. More angiogenesis was also visible. Experimental findings indicate that polylactic-co-glycolic acid composite microspheres containing nerve growth factor, neurotrophin-3 and brain-derived neurotrophic factor can promote the restoration of sciatic nerve in rats after injury.

  3. Brain-derived neurotrophic factor enhances calcium regulatory mechanisms in human airway smooth muscle.

    Directory of Open Access Journals (Sweden)

    Amard J Abcejo

    Full Text Available Neurotrophins (NTs, which play an integral role in neuronal development and function, have been found in non-neuronal tissue (including lung, but their role is still under investigation. Recent reports show that NTs such as brain-derived neurotrophic factor (BDNF as well as NT receptors are expressed in human airway smooth muscle (ASM. However, their function is still under investigation. We hypothesized that NTs regulate ASM intracellular Ca(2+ ([Ca(2+](i by altered expression of Ca(2+ regulatory proteins. Human ASM cells isolated from lung samples incidental to patient surgery were incubated for 24 h (overnight in medium (control or 1 nM BDNF in the presence vs. absence of inhibitors of signaling cascades (MAP kinases; PI3/Akt; NFκB. Measurement of [Ca(2+](i responses to acetylcholine (ACh and histamine using the Ca(2+ indicator fluo-4 showed significantly greater responses following BDNF exposure: effects that were blunted by pathway inhibitors. Western analysis of whole cell lysates showed significantly higher expression of CD38, Orai1, STIM1, IP(3 and RyR receptors, and SERCA following BDNF exposure, effects inhibited by inhibitors of the above cascades. The functional significance of BDNF effects were verified by siRNA or pharmacological inhibition of proteins that were altered by this NT. Overall, these data demonstrate that NTs activate signaling pathways in human ASM that lead to enhanced [Ca(2+](i responses via increased regulatory protein expression, thus enhancing airway contractility.

  4. Absence of hippocampal mossy fiber sprouting in transgenic mice overexpressing brain-derived neurotrophic factor.

    Science.gov (United States)

    Qiao, X; Suri, C; Knusel, B; Noebels, J L

    2001-05-01

    Excess neuronal activity upregulates the expression of two neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in adult hippocampus. Nerve growth factor has been shown to contribute the induction of aberrant hippocampal mossy fiber sprouting in the inner molecular layer of the dentate gyrus, however the role of prolonged brain-derived neurotrophic factor exposure is uncertain. We examined the distribution and plasticity of mossy fibers in transgenic mice with developmental overexpression of brain-derived neurotrophic factor. Despite 2--3-fold elevated BDNF levels in the hippocampus sufficient to increase the intensity of neuropeptide Y immunoreactivity in interneurons, no visible changes in mossy fiber Timm staining patterns were observed in the inner molecular layer of adult mutant hippocampus compared to wild-type mice. In addition, no changes of the mRNA expression of two growth-associated proteins, GAP-43 and SCG-10 were found. These data suggest that early and persistent elevations of brain-derived neurotrophic factor in granule cells are not sufficient to elicit this pattern of axonal plasticity in the hippocampus.

  5. Gender specific associations of serum levels of brain-derived neurotrophic factor in anxiety

    NARCIS (Netherlands)

    Molendijk, Marc L.; Bus, Boudewijn A. A.; Spinhoven, Philip; Penninx, Brenda W. J. H.; Prickaerts, Jos; Voshaar, Richard C. Oude; Elzinga, Bernet M.

    2012-01-01

    Objectives. Whereas animal models indicate that brain-derived neurotrophic factor (BDNF) plays a role in anxiety-related behaviour, little is known about BDNF in patients with an anxiety disorder. We tested the hypothesis that serum BDNF levels are low in patients with an anxiety disorder as compare

  6. 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....

  7. Methodological considerations to determine the effect of exercise on brain-derived neurotrophic factor levels

    OpenAIRE

    Pareja Galeano, Helios; Alis, Rafael; Sanchís-Gomar, Fabián; Cabo, Helena; Cortell-Ballester, José; Gómez Cabrera, María del Carmen; Lucía Mulas, Alejandro; Viña, José

    2015-01-01

    Physical exercise up-regulates brain-derived neurotrophic factor (BDNF) in the brain and blood. However, there is yet no consensus about the adequate blood processing conditions to standardize its assessment. We aimed to find a reliable blood sample processing method to determine changes in BDNF due to exercise. 2.382 JCR (2015) Q2, 9/30 Medical laboratory technology UEM

  8. Differential Regulation of Brain-Derived Neurotrophic Factor Transcripts during the Consolidation of Fear Learning

    Science.gov (United States)

    Ressler, Kerry J.; Rattiner, Lisa M.; Davis, Michael

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated as a molecular mediator of learning and memory. The BDNF gene contains four differentially regulated promoters that generate four distinct mRNA transcripts, each containing a unique noncoding 5[prime]-exon and a common 3[prime]-coding exon. This study describes novel evidence for the…

  9. Chronic hyperoxia alters the expression of neurotrophic factors in the carotid body of neonatal rats.

    Science.gov (United States)

    Dmitrieff, Elizabeth F; Wilson, Julia T; Dunmire, Kyle B; Bavis, Ryan W

    2011-02-15

    Chronic exposure to hyperoxia alters the postnatal development and innervation of the rat carotid body. We hypothesized that this plasticity is related to changes in the expression of neurotrophic factors or related proteins. Rats were reared in 60% O(2) from 24 to 36h prior to birth until studied at 3d of age (P3). Protein levels for brain-derived neurotrophic factor (BDNF) were significantly reduced (-70%) in the P3 carotid body, while protein levels for its receptor, tyrosine kinase B, and for glial cell line-derived neurotrophic factor (GDNF) were unchanged. Transcript levels in the carotid body were downregulated for the GDNF receptor Ret (-34%) and the neuropeptide Vgf (-67%), upregulated for Cbln1 (+205%), and unchanged for Fgf2; protein levels were not quantified for these genes. Immunohistochemical analysis revealed that Vgf and Cbln1 proteins are expressed within the carotid body glomus cells. These data suggest that BDNF, and perhaps other neurotrophic factors, contribute to abnormal carotid body function following perinatal hyperoxia.

  10. Chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor promotes sciatic nerve repair

    Institute of Scientific and Technical Information of China (English)

    Yanru Zhang; Hui Zhang; Kaka Katiella; Wenhua Huang

    2014-01-01

    A chemically extracted acellular allogeneic nerve graft can reduce postoperative immune re-jection, similar to an autologous nerve graft, and can guide neural regeneration. However, it remains poorly understood whether a chemically extracted acellular allogeneic nerve graft combined with neurotrophic factors provides a good local environment for neural regenera-tion. This study investigated the repair of injured rat sciatic nerve using a chemically extracted acellular allogeneic nerve graft combined with ciliary neurotrophic factor. An autologous nerve anastomosis group and a chemical acellular allogeneic nerve bridging group were prepared as controls. At 8 weeks after repair, sciatic functional index, evoked potential amplitude of the soleus muscle, triceps wet weight recovery rate, total number of myelinated nerve fibers and myelin sheath thickness were measured. For these indices, values in the three groups showed the autologous nerve anastomosis group > chemically extracted acellular nerve graft + ciliary neurotrophic factor group > chemical acellular allogeneic nerve bridging group. These results suggest that chemically extracted acellular nerve grafts combined with ciliary neurotrophic factor can repair sciatic nerve defects, and that this repair is inferior to autologous nerve anasto-mosis, but superior to chemically extracted acellular allogeneic nerve bridging alone.

  11. 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 ...

  12. [Hematopoietic growth factor EPO has neuro-protective and neuro-trophic effects--review].

    Science.gov (United States)

    Zhou, Zhuo-Yan; Yang, Mo; Fok, Tai-Fai

    2005-04-01

    Erythropoietin (EPO) is an acidic glycoprotein that was first detected as a hematopoietic factor and its synthesis is triggered in response to cellular hypoxia-sensing. EPO binds to type I cytokine receptors, which associate with the non-receptor tyrosine kinase Jak2, and thereby activate Stat 5a/5b, Ras/MAPK, and PI3-K/Akt signaling pathways. The recent discovery shows that there is a specific EPO/EPO-receptor system in the central nervous system (CNS), independently of the haematopoietic system. Hypoxia and anemia can up-regulate EPO/EPOR expressions in the CNS. Further studies demonstrate that EPO has substantial neuro-protective effects and acts as a neurotrophic factor on central cholinergic neurons, influencing their differentiation and regeneration. EPO also exerts neuro-protective activities in different models of brain damage in vivo and in vitro, such as hypoxia, cerebral ischaemia and sub-arachnoid haemorrhage. EPO may also be involved in synaptic plasticity via the inhibition or stimulation of various neurotransmitters. Therefore, human recombinant EPO that activate its receptors in the central nervous system might be utilized in the future clinical practice involving neuroprotection and brain repair.

  13. 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.

  14. [Basic Research on Neurotrophic Factors and Its Application to Medical Uses].

    Science.gov (United States)

    Furukawa, Shoei

    2015-01-01

    The author has studied nerve growth factor (NGF) and its family of neurotrophic factors (neurotrophins) for over 40 years. During the first 20 years, my laboratory established a highly sensitive enzyme immunoassay for NGF and analyzed the regulatory mechanism of NGF synthesis in cultured primary cells. Fibroblast cells cultured from peripheral organs such as the heart and astrocytes from the brain produced a substantial amount of NGF in a growth-dependent manner. Furthermore, synthesis of NGF in these cells could be upregulated by catechol compounds including catecholamines. This observation might explain a physiological relation between the level of NGF mRNA and the density of innervation in the peripheral sympathetic nervous systems. Over the subsequent 20 years, my laboratory investigated the physiological functions of neurotrophic factors, including neurotrophins, during development or post-injury and found that brain-derived neurotrophic factor (BDNF) plays a role in the formation of the laminar structure of the cerebral cortex. In addition, my laboratory discovered that endogenous glial cell line-derived neurotrophic factor (GDNF) contributes to the amelioration of motor activity after spinal cord injury. Therefore we aimed to develop low-molecular weight compounds that generate neurotrophic factor-like intracellular signals to protect or ameliorate neurological/psychiatric diseases. 2-Decenoic acid derivatives and other similar molecules could protect or ameliorate in animal models of mood disorders such as depression and enhance recovery from spinal cord injury-induced motor paralysis. Compounds that can generate neurotrophin-like signals in neurons are expected to be developed as therapeutic drugs for certain neurological or psychiatric disorders.

  15. Protective effects of neurotrophic factor-secreting cells in a 6-OHDA rat model of Parkinson disease.

    Science.gov (United States)

    Sadan, Ofer; Bahat-Stromza, Merav; Barhum, Yael; Levy, Yossef S; Pisnevsky, Anat; Peretz, Hagit; Ilan, Avihay Bar; Bulvik, Shlomo; Shemesh, Noam; Krepel, Dana; Cohen, Yoram; Melamed, Eldad; Offen, Daniel

    2009-10-01

    Stem cell-based therapy is a promising treatment for neurodegenerative diseases. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells (MSC) into neurotrophic factors- secreting cells (NTF-SC), thus combining stem cell-based therapy with the NTF-based neuroprotection. These cells produce and secrete factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor. Conditioned medium of the NTF-SC that was applied to a neuroblastoma cell line (SH-SY5Y) 1 h before exposure to the neurotoxin 6-hydroxydopamine (6-OHDA) demonstrated marked protection. An efficacy study was conducted on the 6-OHDA-induced lesion, a rat model of Parkinson's disease. The cells, either MSC or NTF-SC, were transplanted on the day of 6-OHDA administration and amphetamine-induced rotations were measured as a primary behavior index. We demonstrated that when transplanted posterior to the 6-OHDA lesion, the NTF-SC ameliorated amphetamine-induced rotations by 45%. HPLC analysis demonstrated that 6-OHDA induced dopamine depletion to a level of 21% compared to the untreated striatum. NTF-SC inhibited dopamine depletion to a level of 72% of the contralateral striatum. Moreover, an MRI study conducted with iron-labeled cells, followed by histological verification, revealed that the engrafted cells migrated toward the lesion. In a histological assessment, we found that the cells induced regeneration in the damaged striatal dopaminergic nerve terminal network. We therefore conclude that the induced MSC have a therapeutic potential for neurodegenerative processes and diseases, both by the NTFs secretion and by the migratory trait toward the diseased tissue.

  16. Elevated expression of brain-derived neurotrophic factor facilitates visual imprinting in chicks.

    Science.gov (United States)

    Suzuki, Keiko; Maekawa, Fumihiko; Suzuki, Shingo; Nakamori, Tomoharu; Sugiyama, Hayato; Kanamatsu, Tomoyuki; Tanaka, Kohichi; Ohki-Hamazaki, Hiroko

    2012-12-01

    With the aim of elucidating the neural mechanisms of early learning, we studied the role of brain-derived neurotrophic factor (BDNF) in visual imprinting in birds. The telencephalic neural circuit connecting the visual Wulst and intermediate medial mesopallium is critical for imprinting, and the core region of the hyperpallium densocellulare (HDCo), situated at the center of this circuit, has a key role in regulating the activity of the circuit. We found that the number of BDNF mRNA-positive cells in the HDCo was elevated during the critical period, particularly at its onset, on the day of hatching (P0). After imprinting training on P1, BDNF mRNA-positive cells in the HDCo increased in number, and tyrosine phosphorylation of TrkB was observed. BDNF infusion into the HDCo at P1 induced imprinting, even with a weak training protocol that does not normally induce imprinting. In contrast, K252a, an antagonist of Trk, inhibited imprinting. Injection of BDNF at P7, after the critical period, did not elicit imprinting. These results suggest that BDNF promotes the induction of imprinting through TrkB exclusively during the critical period. © 2012 The Authors Journal of Neurochemistry © 2012 International Society for Neurochemistry.

  17. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

    Science.gov (United States)

    Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

    2011-03-23

    Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

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

    Science.gov (United States)

    Murphy, D D; Cole, N B; Segal, M

    1998-09-15

    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.

  19. Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis.

    Science.gov (United States)

    Makar, Tapas K; Trisler, David; Sura, Karna T; Sultana, Shireen; Patel, Niraj; Bever, Christopher T

    2008-07-15

    Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) which includes a neurodegenerative component. Brain derived neurotrophic factor (BDNF) is a neuroprotective agent which might be useful in preventing neurodegeneration but its application has been limited because the blood brain barrier restricts its access to the CNS. We have developed a novel delivery system for BDNF using transformed bone marrow stem cells (BMSC) and undertook studies of EAE to determine whether the delivery of BDNF could reduce inflammation and apoptosis. Mice receiving BDNF producing BMSC had reduced clinical impairment compared to control mice receiving BMSC that did not produce BDNF. Pathological examination of brain and spinal cord showed a reduction in inflammatory infiltrating cells in treated compared to control mice. Apoptosis was reduced in brain and spinal cord based on TUNEL and cleaved Caspase-3 staining. Consistent with the known mechanism of action of BDNF on apoptosis, Bcl-2 and Akt were increased in treated mice. Further studies suggested that these increases could be mediated by inhibition of both caspase dependent and caspase independent pathways. These results suggest that the BDNF delivered by the transformed bone marrow stem cells reduced clinical severity, inflammation and apoptosis in this model.

  20. Brain derived neurotrophic factor (BDNF contributes to the pain hypersensitivity following surgical incision in the rats

    Directory of Open Access Journals (Sweden)

    Zhang Jian-Yi

    2008-07-01

    Full Text Available Abstract Background The pathogenic role of brain derived neurotrophic factor (BDNF in the incisional pain is poorly understood. The present study explores the role of the BDNF in the incision-induced pain hypersensitivity. Methods A longitudinal incision was made in one plantar hind paw of isoflurane-anesthetized rats. Dorsal root ganglias (DRG and spinal cords were removed at various postoperative times (1–72 h. Expression pattern of BDNF was determined by immunohistochemistry and double-labeling immunofluorescence. Lidocaine-induced blockade of sciatic nerve function was used to determine the importance of afferent nerve activity on BDNF expression in the DRG and spinal cord after incision. BDNF antibody was administered intrathecally (IT or intraperitoneal (IP to modulate the spinal BDNF or peripheral BDNF after incision. Results After hind-paw incision, the BDNF was upregulated in the ipsilateral lumbar DRG and spinal cord whereas thoracic BDNF remained unchanged in response to incision. The upregulated BDNF was mainly expressed in the large-sized neurons in DRG and the neurons and the primary nerve terminals in the spinal cord. Sciatic nerve blockade prevented the increase of BDNF in the DRG and spinal cord. IT injection of BDNF antibody greatly inhibited the mechanical allodynia induced by incision whereas IP administration had only marginal effect. Conclusion The present study showed that incision induced the segmental upregulation of BDNF in the DRG and spinal cord through somatic afferent nerve transmission, and the upregulated BDNF contributed to the pain hypersensitivity induced by surgical incision.

  1. cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle.

    Science.gov (United States)

    Thompson, Michael A; Britt, Rodney D; Kuipers, Ine; Stewart, Alecia; Thu, James; Pandya, Hitesh C; MacFarlane, Peter; Pabelick, Christina M; Martin, Richard J; Prakash, Y S

    2015-10-01

    Moderate hyperoxic exposure in preterm infants contributes to subsequent airway dysfunction and to risk of developing recurrent wheeze and asthma. The regulatory mechanisms that can contribute to hyperoxia-induced airway dysfunction are still under investigation. Recent studies in mice show that hyperoxia increases brain-derived neurotrophic factor (BDNF), a growth factor that increases airway smooth muscle (ASM) proliferation and contractility. We assessed the mechanisms underlying effects of moderate hyperoxia (50% O2) on BDNF expression and secretion in developing human ASM. Hyperoxia increased BDNF secretion, but did not alter endogenous BDNF mRNA or intracellular protein levels. Exposure to hyperoxia significantly increased [Ca2+]i responses to histamine, an effect blunted by the BDNF chelator TrkB-Fc. Hyperoxia also increased ASM cAMP levels, associated with reduced PDE4 activity, but did not alter protein kinase A (PKA) activity or adenylyl cyclase mRNA levels. However, 50% O2 increased expression of Epac2, which is activated by cAMP and can regulate protein secretion. Silencing RNA studies indicated that Epac2, but not Epac1, is important for hyperoxia-induced BDNF secretion, while PKA inhibition did not influence BDNF secretion. In turn, BDNF had autocrine effects of enhancing ASM cAMP levels, an effect inhibited by TrkB and BDNF siRNAs. Together, these novel studies suggest that hyperoxia can modulate BDNF secretion, via cAMP-mediated Epac2 activation in ASM, resulting in a positive feedback effect of BDNF-mediated elevation in cAMP levels. The potential functional role of this pathway is to sustain BDNF secretion following hyperoxic stimulus, leading to enhanced ASM contractility and proliferation.

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

    OpenAIRE

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

    2015-01-01

    Background 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. Methods In this cross...

  3. Effects of Brain-Derived Neurotrophic Factor on Local Inflammation in Experimental Stroke of Rat

    OpenAIRE

    Yongjun Jiang; Ning Wei; Juehua Zhu; Tingting Lu; Zhaoyao Chen; Gelin Xu; Xinfeng Liu

    2010-01-01

    This study was aimed to investigate whether brain-derived neurotrophic factor (BDNF) can modulate local cerebral inflammation in ischemic stroke. Rats were subjected to ischemia by occluding the right middle cerebral artery (MCAO) for 2 hours. Rats were randomized as control, BDNF, and antibody groups. The local inflammation was evaluated on cellular, cytokine, and transcription factor levels with immunofluorescence, enzyme-linked immunosorbent assay, real-time qPCR, and electrophoretic mobil...

  4. TRPC3 Regulates Release of Brain-Derived Neurotrophic Factor From Human Airway Smooth Muscle

    OpenAIRE

    Vohra, Pawan K.; Thompson, Michael A.; Sathish, Venkatachalem; Kiel, Alexander; Jerde, Calvin; Pabelick, Christina M.; Singh, Brij B.; Prakash, Y. S.

    2013-01-01

    Exogenous brain-derived neurotrophic factor (BDNF) enhances Ca2+ signaling and cell proliferation in human airway smooth muscle (ASM), especially with inflammation. Human ASM also expresses BDNF, raising the potential for autocrine/paracrine effects. The mechanisms by which ASM BDNF secretion occurs are not known. Transient receptor potential channels (TRPCs) regulate a variety of intracellular processes including store-operated Ca2+ entry (SOCE; including in ASM) and secretion of factors suc...

  5. Brain-derived neurotrophic factor expression is higher in brain tissue from patients with refractory epilepsy than in normal controls

    Institute of Scientific and Technical Information of China (English)

    Yudan Lv; Jiqing Qiu; Zan Wang; Li Cui; Hongmei Meng; Weihong Lin

    2011-01-01

    The role of the brain-derived neurotrophic factor in epilepsy remains controversial. The present study utilized light and electron microscopy to investigate pathological and ultrastructural changes in brain tissue obtained from the seizure foci of 24 patients with temporal epilepsy. We found that epileptic tissue showed neuronal degeneration, glial cell proliferation, nuclear vacuolization, and neural cell tropism. Immunoelectron microscopy and immunohistochemistry showed that brain-derived neurotrophic factor was expressed at significantly higher levels in patients with refractory temporal epilepsy compared with normal controls, demonstrating that the pathological changes within seizure foci in patients with refractory epilepsy are associated with brain-derived neurotrophic factor expression alterations.

  6. The Role of Neurotrophic Factors Conjugated to Iron Oxide Nanoparticles in Peripheral Nerve Regeneration: In Vitro Studies

    Directory of Open Access Journals (Sweden)

    Ofra Ziv-Polat

    2014-01-01

    Full Text Available Local delivery of neurotrophic factors is a pillar of neural repair strategies in the peripheral nervous system. The main disadvantage of the free growth factors is their short half-life of few minutes. In order to prolong their activity, we have conjugated to iron oxide nanoparticles three neurotrophic factors: nerve growth factor (βNGF, glial cell-derived neurotrophic factor (GDNF, and basic fibroblast growth factor (FGF-2. Comparative stability studies of free versus conjugated factors revealed that the conjugated neurotrophic factors were significantly more stable in tissue cultures and in medium at 37°C. The biological effects of free versus conjugated neurotrophic factors were examined on organotypic dorsal root ganglion (DRG cultures performed in NVR-Gel, composed mainly of hyaluronic acid and laminin. Results revealed that the conjugated neurotrophic factors enhanced early nerve fiber sprouting compared to the corresponding free factors. The most meaningful result was that conjugated-GDNF, accelerated the onset and progression of myelin significantly earlier than the free GDNF and the other free and conjugated factors. This is probably due to the beneficial and long-acting effect that the stabilized conjugated-GDNF had on neurons and Schwann cells. These conclusive results make NVR-Gel enriched with conjugated-GDNF, a desirable scaffold for the reconstruction of severed peripheral nerve.

  7. Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson’s disease

    OpenAIRE

    2015-01-01

    Background The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson’s disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion re...

  8. The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation.

    Science.gov (United States)

    Linher-Melville, Katja; Li, Julang

    2013-02-01

    Neurotrophic factors were first identified to promote the growth, survival or differentiation of neurons and have also been associated with the early stages of ovarian folliculogenesis. More recently, their effects on the final stage of follicular development, including oocyte maturation and early embryonic development, have been reported. Glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are expressed in numerous peripheral tissues outside of the CNS, most notably the ovary, are now known to stimulate oocyte maturation in various species, also enhancing developmental competence. The mechanisms that underlie their actions in antral follicles, as well as the targets ultimately controlled by these factors, are beginning to emerge. GDNF, BDNF and NGF, alone or in combination, could be added to the media currently utilized for in vitro oocyte maturation, thereby potentially increasing the production and/or quality of early embryos.

  9. Upregulation of Neurotrophic Factors Selectively in Frontal Cortex in Response to Olfactory Discrimination Learning

    Directory of Open Access Journals (Sweden)

    Ari Naimark

    2007-01-01

    Full Text Available We have previously shown that olfactory discrimination learning is accompanied by several forms of long-term enhancement in synaptic connections between layer II pyramidal neurons selectively in the piriform cortex. This study sought to examine whether the previously demonstrated olfactory-learning-task-induced modifications are preceded by suitable changes in the expression of mRNA for neurotrophic factors and in which brain areas this occurs. Rats were trained to discriminate positive cues in pair of odors for a water reward. The relationship between the learning task and local levels of mRNA for brain-derived neurotrophic factor, tyrosine kinase B, nerve growth factor, and neurotrophin-3 in the frontal cortex, hippocampal subregions, and other regions were assessed 24 hours post olfactory learning. The olfactory discrimination learning activated production of endogenous neurotrophic factors and induced their signal transduction in the frontal cortex, but not in other brain areas. These findings suggest that different brain areas may be preferentially involved in different learning/memory tasks.

  10. Poxue Huayu and Tianjing Busui Decoction for cerebral hemorrhage Upregulation of neurotrophic factor expression**

    Institute of Scientific and Technical Information of China (English)

    Jixiang Ren; Xiangyu Zhou; Jian Wang; Jianjun Zhao; Pengguo Zhang

    2013-01-01

    This study established a rat model of cerebral hemorrhage by injecting autologous anticoagulated blood. Rat models were intragastrical y administered 5, 10, 20 g/kg Poxue Huayu and Tianjing Bu-sui Decoction, supplemented with Hirudo, raw rhubarb, raw Pol en Typhae, gadfly, Fructrs Tricho-santhis, Radix Notoginseng, Rhizoma Acori Talarinowi , and glue of tortoise plastron, once a day, for 14 consecutive days. Results demonstrated that brain water content significantly reduced in rats with cerebral hemorrhage, and intracerebral hematoma volume markedly reduced after treatment. Immunohistochemical staining revealed that brain-derived neurotrophic factor, tyrosine kinase B and vascular endothelial growth factor expression noticeably increased around the surrounding hematoma. Reverse transcription-PCR revealed that brain-derived neurotrophic factor and tyrosine kinase B mRNA expression significantly increased around the surrounding hematoma. Neurologic impairment obviously reduced. These results indicated that Poxue Huayu and Tianjing Busui De-coction exert therapeutic effects on cerebral hemorrhage by upregulating the expression of brain-derived neurotrophic factor.

  11. Shuganjieyu capsule increases neurotrophic factor expression in a rat model of depression

    Institute of Scientific and Technical Information of China (English)

    Jinhua Fu; Yingjin Zhang; Renrong Wu; Yingjun Zheng; Xianghui Zhang; Mei Yang; Jingping Zhao; Yong Liu

    2014-01-01

    Shuganjieyu capsule has been approved for clinical treatment by the State Food and Drug Ad-ministration of China since 2008. In the clinic, Shuganjieyu capsule is often used to treat mild to moderate depression. In the rat model of depression established in this study, Shuganjieyu capsule was administered intragastrically daily before stress. Behavioral results conifrmed that depressive symptoms lessened after treatment with high-dose (150 mg/kg) Shuganjieyu capsule. Immunohistochemistry results showed that high-dose Shuganjieyu capsule signiifcantly increased phosphorylation levels of phosphorylation cyclic adenosine monophosphate response element binding protein and brain-derived neurotrophic factor expression in the medial prefrontal cortex and hippocampal CA3 area. Overall, our results suggest that in rats, Shuganjieyu capsule effec-tively reverses depressive-like behaviors by increasing expression levels of neurotrophic factors in the brain.

  12. Gastrodin promotes the secretion of brain-derived neurotrophic factor in the injured spinal cord

    Institute of Scientific and Technical Information of China (English)

    Changwei Song; Shiqiang Fang; Gang Lv; Xifan Mei

    2013-01-01

    Gastrodin, an active component of tall gastrodia tuber, is widely used in the treatment of dizziness, paralysis, epilepsy, stroke and dementia, and exhibits a neuroprotective effect. A rat model of spinal cord injury was established using Allen's method, and gastrodin was administered via the subarachnoid cavity and by intraperitoneal injection for 7 days. Results show that gastrodin promoted the secretion of brain-derived neurotrophic factor in rats with spinal cord injury. After gastrodin treatment, the maximum angle of the inclined plane test, and the Basso, Beattie and Bresnahan scores increased. Moreover, gastrodin improved neural tissue recovery in the injured spinal cord. These results demonstrate that gastrodin promotes the secretion of brain-derived neurotrophic factor, contributes to the recovery of neurological function, and protects neural cells against injury.

  13. Assembly of neuronal connectivity by neurotrophic factors and leucine-rich repeat proteins

    Directory of Open Access Journals (Sweden)

    Fernanda Ledda

    2016-08-01

    Full Text Available Proper function of the nervous system critically relies on sophisticated neuronal networks interconnected in a highly specific pattern. The architecture of these connections arises from sequential developmental steps such as axonal growth and guidance, dendrite development, target determination, synapse formation and plasticity. Leucine-rich repeat (LRR transmembrane proteins have been involved in cell-type specific signaling pathways that underlie these developmental processes. The members of this superfamily of proteins execute their functions acting as trans-synaptic cell adhesion molecules involved in target specificity and synapse formation or working in cis as cell-intrinsic modulators of neurotrophic factor receptor trafficking and signaling. In this review, we will focus on novel physiological mechanisms through which LRR proteins regulate neurotrophic factor receptor signaling, highlighting the importance of these modulatory events for proper axonal extension and guidance, tissue innervation and dendrite morphogenesis. Additionally, we discuss few examples linking this set of LRR proteins to neurodevelopmental and psychiatric disorders.

  14. Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment.

    Science.gov (United States)

    Castrén, Eero; Rantamäki, Tomi

    2010-01-01

    Brain-derived neurotrophic factor (BDNF) is a critical mediator of activity-dependent neuronal plasticity in the cerebral cortex. Deficits in neurotrophic factors have been proposed to underlie mood disorders. However, recent evidence suggests that mood disorders may be produced by abnormalities in the adaptation of neural networks to environmental conditions. Antidepressants may act by enhancing neuronal plasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. Recent observations in the visual cortex directly support this idea. According to the network hypothesis of depression, changes in the levels of neurotrophins including BDNF may not directly produce depression or an antidepressant effect, but neurotrophins may act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment. This hypothesis suggests that antidepressant drugs should not be used alone but should always be combined with rehabilitation to guide the plastic networks within the brain.

  15. Acute strength exercise and the involvement of small or large muscle mass on plasma brain-derived neurotrophic factor levels

    Directory of Open Access Journals (Sweden)

    Paulo Roberto Correia

    2010-01-01

    Full Text Available OBJECTIVE: Blood neurotrophins, such as the brain-derived neurotrophic factor, are considered to be of great importance in mediating the benefits of physical exercise. In this study, the effect of acute strength exercise and the involvement of small versus large muscle mass on the levels of plasma brain-derived neurotrophic factor were evaluated in healthy individuals. METHODS: The concentric strengths of knee (large and elbow (small flexor and extensor muscles were measured on two separate days. Venous blood samples were obtained from 16 healthy subjects before and after exercise. RESULTS: The levels of brain-derived neurotrophic factor in the plasma did not significantly increase after both arm and leg exercise. There was no significant difference in the plasma levels of the brain-derived neurotrophic factor in the arms and legs. CONCLUSION: The present results demonstrate that acute strength exercise does not induce significant alterations in the levels of brain-derived neurotrophic factor plasma concentrations in healthy individuals. Considering that its levels may be affected by various factors, such as exercise, these findings suggest that the type of exercise program may be a decisive factor in altering peripheral brain-derived neurotrophic factor.

  16. Electroacupuncture-regulated neurotrophic factor mRNA expression in the substantia nigra of Parkinson’s disease rats

    Institute of Scientific and Technical Information of China (English)

    Shuju Wang; Jianqiao Fang; Jun Ma; Yanchun Wang; Shaorong Liang; Dan Zhou; Guojie Sun

    2013-01-01

    Acupuncture for the treatment of Parkinson's disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu (GV16) and Taichong (LR3) acupoints in rat models of Parkinson's disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson's disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson's disease. Thus, electroacupuncture may be useful in the treatment of Parkinson's disease.

  17. Electroacupuncture-regulated neurotrophic factor mRNA expression in the substantia nigra of Parkinson's disease rats.

    Science.gov (United States)

    Wang, Shuju; Fang, Jianqiao; Ma, Jun; Wang, Yanchun; Liang, Shaorong; Zhou, Dan; Sun, Guojie

    2013-02-25

    Acupuncture for the treatment of Parkinson's disease has a precise clinical outcome. This study investigated the effect of electroacupuncture at Fengfu (GV16) and Taichong (LR3) acupoints in rat models of Parkinson's disease induced by subcutaneous injection of rotenone into rat neck and back. Reverse transcription-PCR demonstrated that brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression was significantly increased in the substantia nigra of rat models of Parkinson's disease, and that abnormal behavior of rats was significantly improved following electroacupuncture treatment. These results indicated that electroacupuncture treatment upregulated brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor mRNA expression in the substantia nigra of rat models of Parkinson's disease. Thus, electroacupuncture may be useful in the treatment of Parkinson's disease.

  18. Mature and Precursor Brain-Derived Neurotrophic Factor Have Individual Roles in the Mouse Olfactory Bulb

    OpenAIRE

    Thomas Gerald Mast; Debra Ann Fadool

    2012-01-01

    BACKGROUND: Sensory deprivation induces dramatic morphological and neurochemical changes in the olfactory bulb (OB) that are largely restricted to glomerular and granule layer interneurons. Mitral cells, pyramidal-like neurons, are resistant to sensory-deprivation-induced changes and are associated with the precursor to brain-derived neurotrophic factor (proBDNF); here, we investigate its unknown function in the adult mouse OB. PRINCIPAL FINDINGS: As determined using brain-slice electrophysio...

  19. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor

    OpenAIRE

    Szuhany, Kristin L.; Bugatti, Matteo; Otto, Michael W

    2014-01-01

    Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1,111 participants) examining the effect of exercise on BDNF levels in three e...

  20. Brain-derived Neurotrophic Factor and Epilepsy—A Missing Link?

    OpenAIRE

    SCHARFMAN, HELEN E.

    2005-01-01

    It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, t...

  1. Unconventional neurotrophic factors CDNF and MANF: Structure, physiological functions and therapeutic potential.

    Science.gov (United States)

    Lindahl, Maria; Saarma, Mart; Lindholm, Päivi

    2017-01-01

    Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) promote the survival of midbrain dopaminergic neurons which degenerate in Parkinson's disease (PD). However, CDNF and MANF are structurally and functionally clearly distinct from the classical, target-derived neurotrophic factors (NTFs) that are solely secreted proteins. In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) and evidence suggests that MANF, and possibly CDNF, is important for the maintenance of ER homeostasis. MANF expression is particularly high in secretory tissues with extensive protein production and thus a high ER protein folding load. Deletion of MANF in mice results in a diabetic phenotype and the activation of unfolded protein response (UPR) in the pancreatic islets. However, information about the intracellular and extracellular mechanisms of MANF and CDNF action is still limited. Here we will discuss the structural motifs and physiological functions of CDNF and MANF as well as their therapeutic potential for the treatment of neurodegenerative diseases and diabetes. Currently available knockout models of MANF and CDNF in mice, zebrafish and fruit fly will increase information about the biology of these interesting proteins. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor.

    Science.gov (United States)

    Calabrese, Francesca; Guidotti, Gianluigi; Racagni, Giorgio; Riva, Marco A

    2013-12-01

    Aging is a physiological process characterized by a significant reduction of neuronal plasticity that might contribute to the functional defects observed in old subjects. Even if the neurobiological mechanisms that contribute to such impairment remain largely unknown, a role for neurotrophic molecules, such as the neurotrophin brain-derived neurotrophic factor (BDNF), has been postulated. On this basis, the purpose of this study was to provide a detailed investigation of the BDNF system, at transcriptional and translational levels, in the ventral and dorsal hippocampus and in the prefrontal cortex of middle-aged and old rats, compared with in adult animals. The expression of major players in BDNF regulation and response, including the transcription factors, calcium-responsive transcription factor, cyclic adenosine monophosphate (cAMP) responsive element-binding protein (CREB), and neuronal Per Arnt Sim (PAS) domain protein 4, and the high-affinity receptor tropomyosin receptor kinase B (TrkB), was also analyzed. Our results demonstrate that the BDNF system is affected at different levels in aged rats with global impairment including reduced transcription, impaired protein synthesis and processing, and decreased activation of the TrkB receptors. These modifications might contribute to the cognitive deficits associated with aging and suggest that pharmacological strategies aimed at restoring reduced neurotrophism might be useful to counteract age-related cognitive decline.

  3. Mature and precursor brain-derived neurotrophic factor have individual roles in the mouse olfactory bulb.

    Directory of Open Access Journals (Sweden)

    Thomas Gerald Mast

    Full Text Available BACKGROUND: Sensory deprivation induces dramatic morphological and neurochemical changes in the olfactory bulb (OB that are largely restricted to glomerular and granule layer interneurons. Mitral cells, pyramidal-like neurons, are resistant to sensory-deprivation-induced changes and are associated with the precursor to brain-derived neurotrophic factor (proBDNF; here, we investigate its unknown function in the adult mouse OB. PRINCIPAL FINDINGS: As determined using brain-slice electrophysiology in a whole-cell configuration, brain-derived neurotrophic factor (BDNF, but not proBDNF, increased mitral cell excitability. BDNF increased mitral cell action potential firing frequency and decreased interspike interval in response to current injection. In a separate set of experiments, intranasal delivery of neurotrophic factors to awake, adult mice was performed to induce sustained interneuron neurochemical changes. ProBDNF, but not BDNF, increased activated-caspase 3 and reduced tyrosine hydroxylase immunoreactivity in OB glomerular interneurons. In a parallel set of experiments, short-term sensory deprivation produced by unilateral naris occlusion generated an identical phenotype. CONCLUSIONS: Our results indicate that only mature BDNF increases mitral cell excitability whereas proBDNF remains ineffective. Our demonstration that proBDNF activates an apoptotic marker in vivo is the first for any proneurotrophin and establishes a role for proBDNF in a model of neuronal plasticity.

  4. Brain-derived neurotrophic factor and its receptors in Bergmann glia cells.

    Science.gov (United States)

    Poblete-Naredo, Irais; Guillem, Alain M; Juárez, Claudia; Zepeda, Rossana C; Ramírez, Leticia; Caba, Mario; Hernández-Kelly, Luisa C; Aguilera, José; López-Bayghen, Esther; Ortega, Arturo

    2011-12-01

    Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been extensively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stimulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. 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....

  6. 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

  7. Brain-derived neurotrophic factor mediates the suppression of alcohol self-administration by memantine.

    Science.gov (United States)

    Jeanblanc, Jérôme; Coune, Fabien; Botia, Béatrice; Naassila, Mickaël

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) within the striatum is part of a homeostatic pathway regulating alcohol consumption. Memantine, a non-competitive antagonist of N-methyl-D-aspartate receptors, induces expression of BDNF in several brain regions including the striatum. We hypothesized that memantine could decrease ethanol (EtOH) consumption via activation of the BNDF signalling pathway. Effects of memantine were evaluated in Long-Evans rats self-administering moderate or high amounts of EtOH 6, 30 and 54 hours after an acute injection (12.5 and 25 mg/kg). Motivation to consume alcohol was investigated through a progressive ratio paradigm. The possible role for BDNF in the memantine effect was tested by blockade of the TrkB receptor using the pharmacological agent K252a and by the BDNF scavenger TrkB-Fc. Candidate genes expression was also assessed by polymerase chain reaction array 4 and 28 hours after memantine injection. We found that memantine decreased EtOH self-administration and motivation to consume EtOH 6 and 30 hours post-injection. In addition, we found that inhibition or blockade of the BDNF signalling pathway prevented the early, but not the delayed decrease in EtOH consumption induced by memantine. Finally, Bdnf expression was differentially regulated between the early and delayed timepoints. These results demonstrate that an acute injection of memantine specifically reduces EtOH self-administration and motivation to consume EtOH for at least 30 hours. Moreover, we showed that BDNF was responsible for the early effect, but that the delayed effect was BDNF-independent.

  8. Glial cell line-derived neurotrophic factor induces cell proliferation in the mouse urogenital sinus.

    Science.gov (United States)

    Park, Hyun-Jung; Bolton, Eric C

    2015-02-01

    Glial cell line-derived neurotrophic factor (GDNF) is a TGFβ family member, and GDNF signals through a glycosyl-phosphatidylinositol-linked cell surface receptor (GFRα1) and RET receptor tyrosine kinase. GDNF signaling plays crucial roles in urogenital processes, ranging from cell fate decisions in germline progenitors to ureteric bud outgrowth and renal branching morphogenesis. Gene ablation studies in mice have revealed essential roles for GDNF signaling in urogenital development, although its role in prostate development is unclear. We investigated the functional role of GDNF signaling in the urogenital sinus (UGS) and the developing prostate of mice. GDNF, GFRα1, and RET show time-specific and cell-specific expression during prostate development in vivo. In the UGS, GDNF and GFRα1 are expressed in the urethral mesenchyme (UrM) and epithelium (UrE), whereas RET is restricted to the UrM. In each lobe of the developing prostate, GDNF and GFRα1 expression declines in the epithelium and becomes restricted to the stroma. Using a well-established organ culture system, we determined that exogenous GDNF increases proliferation of UrM and UrE cells, altering UGS morphology. With regard to mechanism, GDNF signaling in the UrM increased RET expression and phosphorylation of ERK1/2. Furthermore, inhibition of RET kinase activity or ERK kinases suppressed GDNF-induced proliferation of UrM cells but not UrE cells. We therefore propose that GDNF signaling in the UGS increases proliferation of UrM and UrE cells by different mechanisms, which are distinguished by the role of RET receptor tyrosine kinase and ERK kinase signaling, thus implicating GDNF signaling in prostate development and growth.

  9. Presynaptic modulation of spinal nociceptive transmission by glial cell line-derived neurotrophic factor (GDNF).

    Science.gov (United States)

    Salio, Chiara; Ferrini, Francesco; Muthuraju, Sangu; Merighi, Adalberto

    2014-10-01

    The role of glial cell line-derived neurotrophic factor (GDNF) in nociceptive pathways is still controversial, as both pronociceptive and antinociceptive actions have been reported. To elucidate this role in the mouse, we performed combined structural and functional studies in vivo and in acute spinal cord slices where C-fiber activation was mimicked by capsaicin challenge. Nociceptors and their terminals in superficial dorsal horn (SDH; laminae I-II) constitute two separate subpopulations: the peptidergic CGRP/somatostatin+ cells expressing GDNF and the nonpeptidergic IB4+ neurons expressing the GFRα1-RET GDNF receptor complex. Ultrastructurally the dorsal part of inner lamina II (LIIid) harbors a mix of glomeruli that either display GDNF/somatostatin (GIb)-IR or GFRα1/IB4 labeling (GIa). LIIid thus represents the preferential site for ligand-receptor interactions. Functionally, endogenous GDNF released from peptidergic CGRP/somatostatin+ nociceptors upon capsaicin stimulation exert a tonic inhibitory control on the glutamate excitatory drive of SDH neurons as measured after ERK1/2 phosphorylation assay. Real-time Ca(2+) imaging and patch-clamp experiments with bath-applied GDNF (100 nM) confirm the presynaptic inhibition of SDH neurons after stimulation of capsaicin-sensitive, nociceptive primary afferent fibers. Accordingly, the reduction of the capsaicin-evoked [Ca(2+)]i rise and of the frequency of mEPSCs in SDH neurons is specifically abolished after enzymatic ablation of GFRα1. Therefore, GDNF released from peptidergic CGRP/somatostatin+ nociceptors acutely depresses neuronal transmission in SDH signaling to nonpeptidergic IB4+ nociceptors at glomeruli in LIIid. These observations are of potential pharmacological interest as they highlight a novel modality of cross talk between nociceptors that may be relevant for discrimination of pain modalities.

  10. Developmental changes of TrkB signaling in response to exogenous brain-derived neurotrophic factor in primary cortical neurons.

    Science.gov (United States)

    Zhou, Xianju; Xiao, Hua; Wang, Hongbing

    2011-12-01

    Neocortical circuits are most sensitive to sensory experience during a critical period of early development. Previous studies implicate that brain-derived neurotrophic factor (BDNF) and GABAergic inhibition may control the timing of the critical period. By using an in vitro maturation model, we found that neurons at DIV (day in vitro) 7, around a period when functional synapses start to form and GABAergic inhibition emerges, displayed the most dynamic activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and CREB by exogenous BDNF. The BDNF-stimulated transcriptional up-regulation of CREB target genes was also the highest in DIV 7 neurons. The basal level of ERK1/2 and CREB activity, as well as the expression of CREB target genes, increased along with maturation, and neurons at DIV 13 and 22 displayed less dynamic responses to BDNF. Furthermore, we found that the developmentally regulated GABAergic inhibition correlated with the decline of BDNF-mediated signaling during maturation. BDNF stimulation along with suppression of GABAergic inhibition enhanced the activation of ERK1/2-CREB signaling and gene transcription in mature neurons. Conversely, BDNF stimulation along with enhancement of GABAergic inhibition reduced the overall induction of intracellular signaling in younger neurons. We propose that the less dynamic molecular changes may play a certain role in the loss of plasticity during maturation.

  11. Regulatory Mechanisms Involved in the Expression of Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor

    Science.gov (United States)

    1996-03-01

    Growth Factor Nerve growth factor (NGF), the prototypical neurotrophin, originally isolated by Levi -Montalcini and colleagues ( Levi -Montalcini, 1987; see...inclusion of NGF antibodies ( Levi -Montalcini, 1987). In addition, these neurons exhibit enhanced differentiation, as evidenced by extensive neurite...the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Neuron 6: 845-858, 1991. Hefti, F. Nerve growth factor

  12. Differential activation of dendritic cells by nerve growth factor and brain-derived neurotrophic factor.

    Science.gov (United States)

    Noga, O; Peiser, M; Altenähr, M; Knieling, H; Wanner, R; Hanf, G; Grosse, R; Suttorp, N

    2007-11-01

    Neurotrophins are involved in inflammatory reactions influencing several cells in health and disease including allergy and asthma. Dendritic cells (DCs) play a major role in the induction of inflammatory processes with an increasing role in allergic diseases as well. The aim of this study was to investigate the influence of neurotrophins on DC function. Monocyte-derived dendritic cells were generated from allergic and non-allergic donors. Neurotrophin receptors were demonstrated by western blotting, flow cytometry and fluorescence microscopy. Activation of small GTPases was evaluated by pull-down assays. DCs were incubated with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and supernatants were collected for measurement of IL-4, IL-6, IL-10, IL-12p70, TNF-alpha and TGF-beta. Receptor proteins were detectable by western blot, fluorescence activated cell sorting analysis and fluorescence microscopy. Signalling after neurotrophin stimulation occurred in a ligand-specific pattern. NGF led to decreased RhoA and increased Rac activation, while BDNF affected RhoA and Rac activity in a reciprocal fashion. Cells of allergics released a significantly increased amount of IL-6, while for healthy subjects a significantly higher amount of IL-10 was found. These data indicate that DCs are activated by the neurotrophins NGF and BDNF by different pathways in a receptor-dependant manner. These cells then may initiate inflammatory responses based on allergic sensitization releasing preferred cytokines inducing tolerance or a T-helper type 2 response.

  13. Alterations in BDNF (brain derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) serum levels in bipolar disorder: The role of lithium.

    Science.gov (United States)

    Tunca, Zeliha; Ozerdem, Aysegul; Ceylan, Deniz; Yalçın, Yaprak; Can, Güneş; Resmi, Halil; Akan, Pınar; Ergör, Gül; Aydemir, Omer; Cengisiz, Cengiz; Kerim, Doyuran

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) has been consistently reported to be decreased in mania or depression in bipolar disorders. Evidence suggests that Glial cell line-derived neurotrophic factor (GDNF) has a role in the pathogenesis of mood disorders. Whether GDNF and BDNF act in the same way across different episodes in bipolar disorders is unclear. BDNF and GDNF serum levels were measured simultaneously by enzyme-linked immunosorbent assay (ELISA) method in 96 patients diagnosed with bipolar disorder according to DSM-IV (37 euthymic, 33 manic, 26 depressed) in comparison to 61 healthy volunteers. SCID- I and SCID-non patient version were used for clinical evaluation of the patients and healthy volunteers respectively. Correlations between the two trophic factor levels, and medication dose, duration and serum levels of lithium or valproate were studied across different episodes of illness. Patients had significantly lower BDNF levels during mania and depression compared to euthymic patients and healthy controls. GDNF levels were not distinctive. However GDNF/BDNF ratio was higher in manic state compared to euthymia and healthy controls. Significant negative correlation was observed between BDNF and GDNF levels in euthymic patients. While BDNF levels correlated positively, GDNF levels correlated negatively with lithium levels. Regression analysis confirmed that lithium levels predicted only GDNF levels positively in mania, and negatively in euthymia. Small sample size in different episodes and drug-free patients was the limitation of thestudy. Current data suggests that lithium exerts its therapeutic action by an inverse effect on BDNF and GDNF levels, possibly by up-regulating BDNF and down-regulating GDNF to achieve euthymia. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Expression of brain derived-neurotrophic factor and granulocyte-colony stimulating factor in the urothelium: relation with voiding function

    OpenAIRE

    Yuk, Seung Mo; Shin, Ju Hyun; Song, Ki Hak; Na, Yong Gil; Lim, Jae Sung; Sul, Chong Koo

    2015-01-01

    Background We designed this experiment to elucidate the relationship between the expression of brain derived-neurotrophic factor (BDNF), the expression of granulocyte-colony stimulating factor (G-CSF), and the development of overactive bladder (OAB). In our previous study, the urothelium was observed to be more than a simple mechanosensory receptor and was found to be a potential therapeutic target for OAB. Moreover, neuregulin-1 and BDNF were found to be potential new biomarkers of OAB. Here...

  15. The Effect of Brain-derived Neurotrophic Factor on Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Chunyan SUN; Yu HU; Zhangbo CHU; Jing HUANG; Lu ZHANG

    2009-01-01

    To investigate the in vitro and in vivo proangiogenic effects of brain-derived ncurotrophic factor (BDNF),human umbilical vein endothelial cells (HUVECs) were isolated and cultured in primary culture.The effect of BDNF on the proliferation of HUVECs was examined by MTT assay.The effects of BDNF on HUVEC migration and tube formation were studied by modified Boyden chamber assay and tube formation assay,respectively.Matrigel plug assay and chorioaUantoic membrane assay were used to evaluate the effects of BDNF on angiogencsis in vivo.Our results showed that BDNF substantially stimulated the migration and tube formation of HUVECs in vitro,although it did not induce HUVEC proliferation.BDNF also induced angiogenesis both in matrigcl plug of mouse model and in chick chorioallantoic membrane.In conclusion,BDNF can promote angiogenesis both in vitro and in vivo,and may be a proangiogenic factor.

  16. Time Course of Behavioral Alteration and mRNA Levels of Neurotrophic Factor Following Stress Exposure in Mouse.

    Science.gov (United States)

    Hashikawa, Naoya; Ogawa, Takumi; Sakamoto, Yusuke; Ogawa, Mami; Matsuo, Yumi; Zamami, Yoshito; Hashikawa-Hobara, Narumi

    2015-08-01

    Stress is known to affect neurotrophic factor expression, which induces depression-like behavior. However, whether there are time-dependent changes in neurotrophic factor mRNA expression following stress remains unclear. In the present study, we tested whether chronic stress exposure induces long-term changes in depression-related behavior, serum corticosterone, and hippocampal proliferation as well as neurotrophic factor family mRNA levels, such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and ciliary neurotrophic factor (CNTF), in the mouse hippocampus. The mRNA level of neurotrophic factors (BDNF, NGF, NT-3, and CNTF) was measured using the real-time PCR. The serum corticosterone level was evaluated by enzyme-linked immunosorbent assay, and, for each subject, the hippocampal proliferation was examined by 5-bromo-2-deoxyuridine immunostaining. Mice exhibited depression-like behavior in the forced-swim test (FST) and decreased BDNF mRNA and hippocampal proliferation in the middle of the stress exposure. After 15 days of stress exposure, we observed increased immobility in the FST, serum corticosterone levels, and BDNF mRNA levels and degenerated hippocampal proliferation, maintained for at least 2 weeks. Anhedonia-like behavior in the sucrose preference test and NGF mRNA levels were decreased following 15 days of stress. NGF mRNA levels were significantly higher 1 week after stress exposure. The current data demonstrate that chronic stress exposure induces prolonged BDNF and NGF mRNA changes and increases corticosterone levels and depression-like behavior in the FST, but does not alter other neurotrophic factors or performance in the sucrose preference test.

  17. 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.

  18. Dynamic plasticity: the role of glucocorticoids, brain-derived neurotrophic factor and other trophic factors.

    Science.gov (United States)

    Gray, J D; Milner, T A; McEwen, B S

    2013-06-03

    Brain-derived neurotrophic factor (BDNF) is a secreted protein that has been linked to numerous aspects of plasticity in the central nervous system (CNS). Stress-induced remodeling of the hippocampus, prefrontal cortex and amygdala is coincident with changes in the levels of BDNF, which has been shown to act as a trophic factor facilitating the survival of existing and newly born neurons. Initially, hippocampal atrophy after chronic stress was associated with reduced BDNF, leading to the hypothesis that stress-related learning deficits resulted from suppressed hippocampal neurogenesis. However, recent evidence suggests that BDNF also plays a rapid and essential role in regulating synaptic plasticity, providing another mechanism through which BDNF can modulate learning and memory after a stressful event. Numerous reports have shown BDNF levels are highly dynamic in response to stress, and not only vary across brain regions but also fluctuate rapidly, both immediately after a stressor and over the course of a chronic stress paradigm. Yet, BDNF alone is not sufficient to effect many of the changes observed after stress. Glucocorticoids and other molecules have been shown to act in conjunction with BDNF to facilitate both the morphological and molecular changes that occur, particularly changes in spine density and gene expression. This review briefly summarizes the evidence supporting BDNF's role as a trophic factor modulating neuronal survival, and will primarily focus on the interactions between BDNF and other systems within the brain to facilitate synaptic plasticity. This growing body of evidence suggests a more nuanced role for BDNF in stress-related learning and memory, where it acts primarily as a facilitator of plasticity and is dependent upon the coactivation of glucocorticoids and other factors as the determinants of the final cellular response.

  19. Brain-derived neurotrophic factor modulates immune reaction in mice with peripheral nerve xenotransplantation

    Directory of Open Access Journals (Sweden)

    Yu X

    2016-03-01

    mice than that in the spleen of XT only mice (P<0.05. Serum levels of IL-6, TNF-α, interferon-γ, and IL-17 were decreased, while IL-4 and IL-10 were stimulated by BDNF following xenotransplantation. Conclusion: BDNF reduced NK cells but increased NKT cell accumulation in the spleen of xenotransplanted mice. BDNF modulated the number of splenic T cells and its subtype cells in the mice following xenotransplantation. These findings suggest that BDNF inhibits rejection of peripheral nerve following xenotransplantation by regulating innate as well as adaptive immune reaction. Keywords: peripheral nerve, xenotransplantation, brain-derived neurotrophic factor

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

    Science.gov (United States)

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

    2013-06-01

    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 astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

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

    Science.gov (United States)

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

    2010-12-01

    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 rat hearts and superior cervical ganglia, and were co-cultured, either in a random or localized way. Neurite growth from SNs toward CMs was assessed by immunohistochemistry for neurofilament M and α-actinin in response to neurotrophic factors-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF) and a chemical repellent, semaphorin 3A. As a result, GDNF as well as NGF and BDNF stimulated neurite growth. GDNF enhanced neurite outgrowth even under the NGF-depleted culture condition, excluding an indirect effect of GDNF via NGF. Quantification of mRNA and protein by real-time PCR and immunohistochemistry at different developmental stages revealed that GDNF is abundantly expressed in the hearts of embryos and neonates, but not in adult hearts. GDNF plays an important role in inducing cardiac sympathetic innervation at the early developmental stages. A possible role in (re)innervation of injured or transplanted or cultured and transplanted myocardium may deserve investigation.

  2. Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina.

    Science.gov (United States)

    Park, Hae-Young Lopilly; Kim, Jie Hyun; Sun Kim, Hwa; Park, Chan Kee

    2012-08-21

    As an alternative to a viral vector, the application of stem cells to transfer specific genes is under investigation in various organs. Using this strategy may provide more effective method to supply neurotrophic factor to the neurodegenerative diseases caused by neurotrophic factor deprivation. This study investigated the possibility and efficacy of stem cell-based delivery of the brain-derived neurotrophic factor (BDNF) gene to rat retina. Rat BDNF cDNA was transduced into rat bone marrow mesenchymal stem cells (rMSCs) using a retroviral vector. Its incorporation into the experimental rat retina and the expression of BDNF after intravitreal injection or subretinal injection were detected by real-time PCR, western blot analysis, and immunohistochemical staining. For the incorporated rMSCs, retinal-specific marker staining was performed to investigate the changes in morphology and the characteristics of the stem cells. Transduction of the rMSCs by retrovirus was effective, and the transduced rMSCs expressed high levels of the BDNF gene and protein. The subretinal injection of rMSCs produced rMSC migration and incorporation into the rat retina (about 15.7% incorporation rate), and retinal BDNF mRNA and protein expression was increased at 4 weeks after transplantation. When subretinal injection of rMSCs was applied to axotomized rat retina, it significantly increased the expression of BDNF until 4 weeks after transplantation. Some of the transplanted rMSCs exhibited morphological changes, but the retinal-specific marker stain was not sufficient to indicate whether neuronal differentiation had occurred. Using mesenchymal stem cells to deliver the BDNF gene to the retina may provide new treatment for glaucoma.

  3. Analysis of neurotrophic factors in limb and extraocular muscles of mouse model of amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Vahid M Harandi

    Full Text Available Amyotrophic lateral sclerosis (ALS is currently an incurable fatal motor neuron syndrome characterized by progressive weakness, muscle wasting and death ensuing 3-5 years after diagnosis. Neurotrophic factors (NTFs are known to be important in both nervous system development and maintenance. However, the attempt to translate the potential of NTFs into the therapeutic options remains limited despite substantial number of approaches, which have been tested clinically. Using quantitative RT-PCR (qRT-PCR technique, the present study investigated mRNA expression of four different NTFs: brain-derived neurotrophic factor (BDNF, neurotrophin-3 (NT-3, neurotrophin-4/5 (NT-4 and glial cell line-derived neurotrophic factor (GDNF in limb muscles and extraocular muscles (EOMs from SOD1G93A transgenic mice at early and terminal stages of ALS. General morphological examination revealed that muscle fibres were well preserved in both limb muscles and EOMs in early stage ALS mice. However, in terminal ALS mice, most muscle fibres were either atrophied or hypertrophied in limb muscles but unaffected in EOMs. qRT-PCR analysis showed that in early stage ALS mice, NT-4 was significantly down-regulated in limb muscles whereas NT-3 and GDNF were markedly up-regulated in EOMs. In terminal ALS mice, only GDNF was significantly up-regulated in limb muscles. We concluded that the early down-regulation of NT-4 in limb muscles is closely associated with muscle dystrophy and dysfunction at late stage, whereas the early up-regulations of GDNF and NT-3 in EOMs are closely associated with the relatively well-preserved muscle morphology at late stage. Collectively, the data suggested that comparing NTFs expression between limb muscles and EOMs from different stages of ALS animal models is a useful method in revealing the patho-physiology and progression of ALS, and eventually rescuing motor neuron in ALS patients.

  4. Repair of peripheral nerve defects with chemically extracted acellular nerve allografts loaded with neurotrophic factors-transfected bone marrow mesenchymal stem cells

    Institute of Scientific and Technical Information of China (English)

    Yan-ru Zhang; Ka Ka; Ge-chen Zhang; Hui Zhang; Yan Shang; Guo-qiang Zhao; Wen-hua Huang

    2015-01-01

    Chemically extracted acellular nerve allografts loaded with brain-derived neurotrophic fac-tor-transfected or ciliary neurotrophic factor-transfected bone marrow mesenchymal stem cells have been shown to repair sciatic nerve injury better than chemically extracted acellular nerve allografts alone, or chemically extracted acellular nerve allografts loaded with bone marrow mesenchymal stem cells. We hypothesized that these allografts compounded with both brain-derived neurotrophic factor- and ciliary neurotrophic factor-transfected bone marrow mesenchymal stem cells may demonstrate even better effects in the repair of peripheral nerve injury. We cultured bone marrow mesenchymal stem cells expressing brain-derived neuro-trophic factor and/or ciliary neurotrophic factor and used them to treat sciatic nerve injury in rats. We observed an increase in sciatic functional index, triceps wet weight recovery rate, myelin thickness, number of myelinated nerve ifbers, amplitude of motor-evoked potentials and nerve conduction velocity, and a shortened latency of motor-evoked potentials when al-lografts loaded with both neurotrophic factors were used, compared with allografts loaded with just one factor. Thus, the combination of both brain-derived neurotrophic factor and cili-ary neurotrophic factor-transfected bone marrow mesenchymal stem cells can greatly improve nerve injury.

  5. Adenovirus-mediated human brain-derived neurotrophic factor gene-modified bone marrow mesenchymal stem cell transplantation for spinal cord injury

    Institute of Scientific and Technical Information of China (English)

    Changsheng Wang; Jianhua Lin; Chaoyang Wu; Rongsheng Chen

    2011-01-01

    Rat bone marrow mesenchymal stem cells expressing brain-derived neurotrophic factor were successfully obtained using a gene transfection method, then intravenously transplanted into rats with spinal cord injury. At 1, 3, and 5 weeks after transplantation, the expression of ??brain-derived neurotrophic factor and neurofilament-200 was upregulated in the injured spinal cord, spinal cord injury was alleviated, and Basso-Beattie-Bresnahan scores of hindlimb motor function were significantly increased. This evidence suggested that intravenous transplantation of adenovirus- mediated brain-derived neurotrophic factor gene-modified rat bone marrow mesenchymal stem cells could play a dual role, simultaneously providing neural stem cells and neurotrophic factors.

  6. 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...

  7. 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...

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

    Indian Academy of Sciences (India)

    NATALYA P BONDAR; TATIANA I MERKULOVA

    2016-12-01

    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 reportsindicated the relationship between stress and BDNF to be much more complex, and the concept wassignificantly revised. In the present mini-review, we focus on the structure and regulation of the Bbnf geneas well as on the stress–BDNF interactions under early-life adverse conditions.

  9. 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...

  10. 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...

  11. Possible protective action of neurotrophic factors and natural compounds against common neurodegenerative diseases

    Institute of Scientific and Technical Information of China (English)

    Tadahiro Numakawa

    2014-01-01

    It has been suggested that altered levels/function of brain-derived neurotrophic factor (BDNF) play a role in the pathophysiology of neurodegenerative diseases including Alzheimer’s disease. BDNF positively contributes to neural survival and synapse maintenance via stimulating its high afifnity receptor TrkB, making upregulation of BDNF and/or activation of BDNF-related intracellular signaling an attractive approach to treating neurodegenerative diseases. In this short review, I brielfy introduce small natural compounds such as lfavonoids that successfully increase activation of the BDNF system and discuss their beneifcial effects against neurodegeneration.

  12. Circulating levels of brain-derived neurotrophic factor: correlation with mood, cognition and motor function.

    Science.gov (United States)

    Teixeira, Antonio Lucio; Barbosa, Izabela Guimarães; Diniz, Breno Satler; Kummer, Arthur

    2010-12-01

    Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the CNS, where it plays several pivotal roles in synaptic plasticity and neuronal survival. As a consequence, BDNF has become a key target in the physiopathology of several neurological and psychiatric diseases. Recent studies have consistently reported altered levels of BDNF in the circulation (i.e., serum or plasma) of patients with major depression, bipolar disorder, Alzheimer's disease, Huntington's disease and Parkinson's disease. Correlations between serum BDNF levels and affective, cognitive and motor symptoms have also been described. BDNF appears to be an unspecific biomarker of neuropsychiatric disorders characterized by neurodegenerative changes.

  13. [Brain-derived neurotrophic factor gene (BDNF) polymorphism among Moscow citizens].

    Science.gov (United States)

    Kokaeva, Z G; Kochetkova, T O; Afonchikova, E V; Kondratyeva, N S; Klimov, E A

    2013-12-01

    Recent studies showed that brain-derived neurotrophic factor (BDNF) can participate in pathogenesis of various CNS disorders, being connected with proliferation, differentiation, and survival of neurons. In present study, analysis of occurrence rate was performed for three single nucleotide polymorphisms (SNPs) located in BDNF gene (rs6267 (A/G) allele A-0.265; rs2049046 (A/T) allele A-0.407; rs11030107 (A/G) allele A-0.872) in randomized selection of Moscow citizens. Linkage disequilibrium of rs6165 and rs2049046 loci was shown. Differences in allele frequencies in studied selection and populations of other re- gions were discovered.

  14. Brain-derived neurotrophic factor and epilepsy--a missing link?

    Science.gov (United States)

    Scharfman, Helen E

    2005-01-01

    It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, that BDNF contributes to the development of temporal lobe epilepsy (TLE).

  15. 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.

  16. Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies.

    Science.gov (United States)

    Üçeyler, Nurcan; Riediger, Nadja; Kafke, Waldemar; Sommer, Claudia

    2015-01-01

    Pathophysiologically relevant alterations in cytokine and neurotrophic factor levels have been reported in neuropathy subtypes. We characterized gene expression profiles of pro- and anti-inflammatory cytokines and neurotrophic factors in nerve and skin samples of patients with neuropathies of different etiologies. We prospectively studied 133 patients with neuropathies and compared data between subtypes and with healthy controls. All patients underwent sural nerve and/or skin punch biopsy at the lateral thigh and lower leg; controls received skin punch biopsies. Gene expression of pro- and anti-inflammatory cytokines (IL-1β, IL-2, IL-6, TNF, IL-10), neurotrophic factors (BDNF, NGF, NT3, TrkA), and erythropoietin with the erythropoietin receptor (Epo, EpoR) was analyzed. Sural nerve gene expression of the investigated cytokines and neurotrophic factors did not differ between neuropathies of different etiologies; however, IL-6 (p neuropathies. Skin IL-6 and IL-10 gene expression was increased in patients compared to controls (p neuropathies compared to inflammatory neuropathies (p neuropathies was reduced compared to controls (NGF, NT3, Epo; p Neuropathies are associated with an increase in cytokine expression and a decrease in neurotrophic factor expression including nerve and skin.

  17. Postnatal roles of glial cell line-derived neurotrophic factor family members in nociceptors plasticity

    Institute of Scientific and Technical Information of China (English)

    Sacha A. Malin; Brian M. Davis

    2008-01-01

    The neurotrophin and glial cell line-derived neurotrophic factor (GDNF) family of growth factors have been extensively studied because of their proven ability to regulate development of the peripheral nervous system. The neurotrophin family,which includes nerve growth factor (NGF), NT-3, NT4/5 and BDNF, is also known for its ability to regulate the function of adult sensory neurons. Until recently, little was known concerning the role of the GNDF-family (that includes GDNF, artemin, neurturin and persephin) in adult sensory neuron function. Here we describe recent data that indicates that the GDNF family can regulate sensory neuron function, that some of its members are elevated in inflammatory pain models and that application of these growth factors produces pain in vivo. Finally we discuss how these two families of growth factors may converge on a single membrane receptor, TRPV 1, to produce long-lasting hyperalgesia.

  18. Glial cell derived neurotrophic factor induces spermatogonial stem cell marker genes in chicken mesenchymal stem cells.

    Science.gov (United States)

    Boozarpour, Sohrab; Matin, Maryam M; Momeni-Moghaddam, Madjid; Dehghani, Hesam; Mahdavi-Shahri, Naser; Sisakhtnezhad, Sajjad; Heirani-Tabasi, Asieh; Irfan-Maqsood, Muhammad; Bahrami, Ahmad Reza

    2016-06-01

    Mesenchymal stem cells (MSCs) are known with the potential of multi-lineage differentiation. Advances in differentiation technology have also resulted in the conversion of MSCs to other kinds of stem cells. MSCs are considered as a suitable source of cells for biotechnology purposes because they are abundant, easily accessible and well characterized cells. Nowadays small molecules are introduced as novel and efficient factors to differentiate stem cells. In this work, we examined the potential of glial cell derived neurotrophic factor (GDNF) for differentiating chicken MSCs toward spermatogonial stem cells. MSCs were isolated and characterized from chicken and cultured under treatment with all-trans retinoic acid (RA) or glial cell derived neurotrophic factor. Expression analysis of specific genes after 7days of RA treatment, as examined by RT-PCR, proved positive for some germ cell markers such as CVH, STRA8, PLZF and some genes involved in spermatogonial stem cell maintenance like BCL6b and c-KIT. On the other hand, GDNF could additionally induce expression of POU5F1, and NANOG as well as other genes which were induced after RA treatment. These data illustrated that GDNF is relatively more effective in diverting chicken MSCs towards Spermatogonial stem cell -like cells in chickens and suggests GDNF as a new agent to obtain transgenic poultry, nevertheless, exploitability of these cells should be verified by more experiments.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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 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.

  1. 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.

  2. Preferential Enhancement of Sensory and Motor Axon Regeneration by Combining Extracellular Matrix Components with Neurotrophic Factors

    Directory of Open Access Journals (Sweden)

    Daniel Santos

    2016-12-01

    Full Text Available After peripheral nerve injury, motor and sensory axons are able to regenerate but inaccuracy of target reinnervation leads to poor functional recovery. Extracellular matrix (ECM components and neurotrophic factors (NTFs exert their effect on different neuronal populations creating a suitable environment to promote axonal growth. Here, we assessed in vitro and in vivo the selective effects of combining different ECM components with NTFs on motor and sensory axons regeneration and target reinnervation. Organotypic cultures with collagen, laminin and nerve growth factor (NGF/neurotrophin-3 (NT3 or collagen, fibronectin and brain-derived neurotrophic factor (BDNF selectively enhanced sensory neurite outgrowth of DRG neurons and motor neurite outgrowth from spinal cord slices respectively. For in vivo studies, the rat sciatic nerve was transected and repaired with a silicone tube filled with a collagen and laminin matrix with NGF/NT3 encapsulated in poly(lactic-co-glycolic acid (PLGA microspheres (MP (LM + MP.NGF/NT3, or a collagen and fibronectin matrix with BDNF in PLGA MPs (FN + MP.BDNF. Retrograde labeling and functional tests showed that LM + MP.NGF/NT3 increased the number of regenerated sensory neurons and improved sensory functional recovery, whereas FN + MP.BDNF preferentially increased regenerated motoneurons and enhanced motor functional recovery. Therefore, combination of ECM molecules with NTFs may be a good approach to selectively enhance motor and sensory axons regeneration and promote appropriate target reinnervation.

  3. Effects of fibroblast growth factor and glial-derived neurotrophic factor on akinesia, F-DOPA uptake and dopamine cells in parkinsonian primates

    NARCIS (Netherlands)

    Fontan, A; Rojo, A; Pernaute, RS; Hernandez, [No Value; Lopez, [No Value; Castilla, C; Albisua, JS; Higueras, AP; Al-Rashid, [No Value; Rabano, A; Gonzalo, [No Value; Mena, MA; Cools, A; Eshuis, S; Maguire, P; Pruim, J; Leenders, K; de Yebenes, JG

    2002-01-01

    Parkinson's disease (PD) is a common neurodegenerative disorder that produces progressive disability despite symptomatic treatment. Several strategies, including stereotaxic brain lesions, deep brain stimulation, transplants of dopamine cells and administration of neurotrophic factors, have been pro

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

    Directory of Open Access Journals (Sweden)

    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

  5. 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...... and independently so in patients with type 2 diabetes. Brain-derived neurotrophic factor is expressed in non-neurogenic tissues, including skeletal muscle, and exercise increases BDNF levels not only in the brain and in plasma, but in skeletal muscle as well. Brain-derived neurotrophic factor mRNA and protein...... expression was increased in muscle cells that were electrically stimulated, and BDNF increased phosphorylation of AMP-activated protein kinase (AMPK) and acetyl coenzyme A carboxylase-beta (ACCbeta) and enhanced fatty oxidation both in vitro and ex vivo. These data identify BDNF as a contraction...

  6. 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.

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

    Institute of Scientific and Technical Information of China (English)

    Marianna Foldvari; Ding Wen Chen

    2016-01-01

    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 sufifcient 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 dis-cuss the challenges currently being faced in RGC-related therapy development with special considerations to the existence of multiple RGC subtypes and the lack of efifcient and representativein vitro models for rapid and reliable screening in the drug development process.

  8. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.

    Science.gov (United States)

    Stanga, Serena; Zanou, Nadège; Audouard, Emilie; Tasiaux, Bernadette; Contino, Sabrina; Vandermeulen, Gaëlle; René, Frédérique; Loeffler, Jean-Philippe; Clotman, Frédéric; Gailly, Philippe; Dewachter, Ilse; Octave, Jean-Noël; Kienlen-Campard, Pascal

    2016-05-01

    Besides its crucial role in the pathogenesis of Alzheimer's disease, the knowledge of amyloid precursor protein (APP) physiologic functions remains surprisingly scarce. Here, we show that APP regulates the transcription of the glial cell line-derived neurotrophic factor (GDNF). APP-dependent regulation of GDNF expression affects muscle strength, muscular trophy, and both neuronal and muscular differentiation fundamental for neuromuscular junction (NMJ) maturation in vivo In a nerve-muscle coculture model set up to modelize NMJ formation in vitro, silencing of muscular APP induces a 30% decrease in secreted GDNF levels and a 40% decrease in the total number of NMJs together with a significant reduction in the density of acetylcholine vesicles at the presynaptic site and in neuronal maturation. These defects are rescued by GDNF expression in muscle cells in the conditions where muscular APP has been previously silenced. Expression of GDNF in muscles of amyloid precursor protein null mice corrected the aberrant synaptic morphology of NMJs. Our findings highlight for the first time that APP-dependent GDNF expression drives the process of NMJ formation, providing new insights into the link between APP gene regulatory network and physiologic functions.-Stanga, S., Zanou, N., Audouard, E., Tasiaux, B., Contino, S., Vandermeulen, G., René, F., Loeffler, J.-P., Clotman, F., Gailly, P., Dewachter, I., Octave, J.-N., Kienlen-Campard, P. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.

  9. Conditional ablation of brain-derived neurotrophic factor-TrkB signaling impairs striatal neuron development.

    Science.gov (United States)

    Li, Yun; Yui, Daishi; Luikart, Bryan W; McKay, Renée M; Li, Yanjiao; Rubenstein, John L; Parada, Luis F

    2012-09-18

    Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), are associated with the physiology of the striatum and the loss of its normal functioning under pathological conditions. The role of BDNF and its downstream signaling in regulating the development of the striatum has not been fully investigated, however. Here we report that ablation of Bdnf in both the cortex and substantia nigra depletes BDNF in the striatum, and leads to impaired striatal development, severe motor deficits, and postnatal lethality. Furthermore, striatal-specific ablation of TrkB, the gene encoding the high-affinity receptor for BDNF, is sufficient to elicit an array of striatal developmental abnormalities, including decreased anatomical volume, smaller neuronal nucleus size, loss of dendritic spines, reduced enkephalin expression, diminished nigral dopaminergic projections, and severe deficits in striatal dopamine signaling through DARPP32. In addition, TrkB ablation in striatal neurons elicits a non-cell-autonomous reduction of tyrosine hydroxylase protein level in the axonal projections of substantia nigral dopaminergic neurons. Thus, our results establish an essential function for TrkB in regulating the development of striatal neurons.

  10. Focused ultrasound-enhanced intranasal brain delivery of brain-derived neurotrophic factor

    Science.gov (United States)

    Chen, Hong; Yang, Georgiana Zong Xin; Getachew, Hoheteberhan; Acosta, Camilo; Sierra Sánchez, Carlos; Konofagou, Elisa E.

    2016-06-01

    The objective of this study was to unveil the potential mechanism of focused ultrasound (FUS)-enhanced intranasal (IN) brain drug delivery and assess its feasibility in the delivery of therapeutic molecules. Delivery outcomes of fluorescently-labeled dextrans to mouse brains by IN administration either before or after FUS sonication were compared to evaluate whether FUS enhances IN delivery by active pumping or passive diffusion. Fluorescence imaging of brain slices found that IN administration followed by FUS sonication achieved significantly higher delivery than IN administration only, while pre-treatment by FUS sonication followed by IN administration was not significantly different from IN administration only. Brain-derived neurotrophic factor (BDNF), a promising neurotrophic factor for the treatment of many central nervous system diseases, was delivered by IN followed by FUS to demonstrate the feasibility of this technique and compared with the established FUS technique where drugs are injected intravenously. Immunohistochemistry staining of BDNF revealed that FUS-enhanced IN delivery achieved similar locally enhanced delivery as the established FUS technique. This study suggested that FUS enhances IN brain drug delivery by FUS-induced active pumping of the drug and demonstrated that FUS-enhanced IN delivery is a promising technique for noninvasive and localized delivery of therapeutic molecules to the brain.

  11. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced obesity.

    Science.gov (United States)

    Mwangi, Simon Musyoka; Nezami, Behtash Ghazi; Obukwelu, Blessing; Anitha, Mallappa; Marri, Smitha; Fu, Ping; Epperson, Monica F; Le, Ngoc-Anh; Shanmugam, Malathy; Sitaraman, Shanthi V; Tseng, Yu-Hua; Anania, Frank A; Srinivasan, Shanthi

    2014-03-01

    Obesity is a growing epidemic with limited effective treatments. The neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) was recently shown to enhance β-cell mass and improve glucose control in rodents. Its role in obesity is, however, not well characterized. In this study, we investigated the ability of GDNF to protect against high-fat diet (HFD)-induced obesity. GDNF transgenic (Tg) mice that overexpress GDNF under the control of the glial fibrillary acidic protein promoter and wild-type (WT) littermates were maintained on a HFD or regular rodent diet for 11 wk, and weight gain, energy expenditure, and insulin sensitivity were monitored. Differentiated mouse brown adipocytes and 3T3-L1 white adipocytes were used to study the effects of GDNF in vitro. Tg mice resisted the HFD-induced weight gain, insulin resistance, dyslipidemia, hyperleptinemia, and hepatic steatosis seen in WT mice despite similar food intake and activity levels. They exhibited significantly (PGDNF enhanced β-adrenergic-mediated cAMP release in brown adipocytes and suppressed lipid accumulation in differentiated 3T3L-1 cells through a p38MAPK signaling pathway. Our studies demonstrate a novel role for GDNF in the regulation of high-fat diet-induced obesity through increased energy expenditure. They show that GDNF and its receptor agonists may be potential targets for the treatment or prevention of obesity.

  12. 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.

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

    Science.gov (United States)

    Busanello, Anna; Bonini, Stefano; Quaranta, Luciano; Agnifili, Luca; Manni, Gianluca

    2017-01-01

    Purpose 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. Materials and Methods 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. Results 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). Conclusions BDNF and NGF serum levels are reduced in the early and moderate glaucoma stages, suggesting the possibility that

  14. Activity-Dependent Increase in Neurotrophic Factors Is Associated with an Enhanced Modulation of Spinal Reflexes after Spinal Cord Injury

    Science.gov (United States)

    Côté, Marie-Pascale; Azzam, Gregory A.; Lemay, Michel A.; Zhukareva, Victoria

    2011-01-01

    Abstract Activity-based therapies such as passive bicycling and step-training on a treadmill contribute to motor recovery after spinal cord injury (SCI), leading to a greater number of steps performed, improved gait kinematics, recovery of phase-dependent modulation of spinal reflexes, and prevention of decrease in muscle mass. Both tasks consist of alternating movements that rhythmically stretch and shorten hindlimb muscles. However, the paralyzed hindlimbs are passively moved by a motorized apparatus during bike-training, whereas locomotor movements during step-training are generated by spinal networks triggered by afferent feedback. Our objective was to compare the task-dependent effect of bike- and step-training after SCI on physiological measures of spinal cord plasticity in relation to changes in levels of neurotrophic factors. Thirty adult female Sprague-Dawley rats underwent complete spinal transection at a low thoracic level (T12). The rats were assigned to one of three groups: bike-training, step-training, or no training. The exercise regimen consisted of 15 min/d, 5 days/week, for 4 weeks, beginning 5 days after SCI. During a terminal experiment, H-reflexes were recorded from interosseus foot muscles following stimulation of the tibial nerve at 0.3, 5, or 10 Hz. The animals were sacrificed and the spinal cords were harvested for Western blot analysis of the expression of neurotrophic factors in the lumbar spinal cord. We provide evidence that bike- and step-training significantly increase the levels of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4 in the lumbar enlargement of SCI rats, whereas only step-training increased glial cell-derived neurotrophic factor (GDNF) levels. An increase in neurotrophic factor protein levels that positively correlated with the recovery of H-reflex frequency-dependent depression suggests a role for neurotrophic factors in reflex normalization. PMID:21083432

  15. Consequences of brain-derived neurotrophic factor withdrawal in CNS neurons and implications in disease.

    Science.gov (United States)

    Mariga, Abigail; Mitre, Mariela; Chao, Moses V

    2017-01-01

    Growth factor withdrawal has been studied across different species and has been shown to have dramatic consequences on cell survival. In the nervous system, withdrawal of nerve growth factor (NGF) from sympathetic and sensory neurons results in substantial neuronal cell death, signifying a requirement for NGF for the survival of neurons in the peripheral nervous system (PNS). In contrast to the PNS, withdrawal of central nervous system (CNS) enriched brain-derived neurotrophic factor (BDNF) has little effect on cell survival but is indispensible for synaptic plasticity. Given that most early events in neuropsychiatric disorders are marked by a loss of synapses, lack of BDNF may thus be an important part of a cascade of events that leads to neuronal degeneration. Here we review reports on the effects of BDNF withdrawal on CNS neurons and discuss the relevance of the loss in disease.

  16. 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

    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......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...... 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...

  17. Resveratrol Induces the Expression of Interleukin-10 and Brain-Derived Neurotrophic Factor in BV2 Microglia under Hypoxia

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Jung, Wonsug; Lee, Won Taek; Lee, Jong Eun

    2014-01-01

    Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury. PMID:25184950

  18. Resveratrol induces the expression of interleukin-10 and brain-derived neurotrophic factor in BV2 microglia under hypoxia.

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Jung, Wonsug; Lee, Won Taek; Lee, Jong Eun

    2014-09-02

    Microglia are the resident macrophages of the central nervous system (CNS) and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF) in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.

  19. Resveratrol Induces the Expression of Interleukin-10 and Brain-Derived Neurotrophic Factor in BV2 Microglia under Hypoxia

    Directory of Open Access Journals (Sweden)

    Juhyun Song

    2014-09-01

    Full Text Available Microglia are the resident macrophages of the central nervous system (CNS and play an important role in neuronal recovery by scavenging damaged neurons. However, overactivation of microglia leads to neuronal death that is associated with CNS disorders. Therefore, regulation of microglial activation has been suggested to be an important target for treatment of CNS diseases. In the present study, we investigated the beneficial effect of resveratrol, a natural phenol with antioxidant effects, in the microglial cell line, BV2, in a model of hypoxia injury. Resveratrol suppressed the mRNA expression of the pro-inflammatory molecule, tumor necrosis factor-α, and promoted the mRNA expression of the anti-inflammatory molecule, interleukin-10, in BV2 microglia under hypoxic conditions. In addition, resveratrol inhibited the activation of the transcription factor, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB, which is upstream in the control of inflammatory reactions in hypoxia-injured BV2 microglia. Moreover, resveratrol promoted the expression of brain-derived neurotrophic factor (BDNF in BV2 microglia under hypoxic stress. Overall, resveratrol may promote the beneficial function of microglia in ischemic brain injury.

  20. In vivo induction of glial cell proliferation and axonal outgrowth and myelination by brain-derived neurotrophic factor.

    NARCIS (Netherlands)

    Groot, D.M. de; Coenen, A.J.M.; Verhofstad, A.A.J.; Herp, F. van; Martens, G.J.M.

    2006-01-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of neuronal cell survival and differentiation factors but is thought to be involved in neuronal cell proliferation and myelination as well. To explore the role of BDNF in vivo, we employed the intermediate pituitary melanotr

  1. Hyperphagia, Severe Obesity, Impaired Cognitive Function, and Hyperactivity Associated With Functional Loss of One Copy of the Brain-Derived Neurotrophic Factor (BDNF) Gene

    OpenAIRE

    Gray, Juliette; Yeo, Giles S.H.; Cox, James J.; Morton, Jenny; Adlam, Anna-Lynne R.; Keogh, Julia M.; Yanovski, Jack A.; El Gharbawy, Areeg; Han, Joan C.; Tung, Y.C. Loraine; Hodges, John R.; Raymond, F Lucy; O’Rahilly, Stephen; Farooqi, I. Sadaf

    2006-01-01

    The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the...

  2. Brain-derived neurotrophic factor signaling rewrites the glucocorticoid transcriptome via glucocorticoid receptor phosphorylation.

    Science.gov (United States)

    Lambert, W Marcus; Xu, Chong-Feng; Neubert, Thomas A; Chao, Moses V; Garabedian, Michael J; Jeanneteau, Freddy D

    2013-09-01

    Abnormal glucocorticoid and neurotrophin signaling has been implicated in numerous psychiatric disorders. However, the impact of neurotrophic signaling on glucocorticoid receptor (GR)-dependent gene expression is not understood. We therefore examined the impact of brain-derived neurotrophic factor (BDNF) signaling on GR transcriptional regulatory function by gene expression profiling in primary rat cortical neurons stimulated with the selective GR agonist dexamethasone (Dex) and BDNF, alone or in combination. Simultaneous treatment with BDNF and Dex elicited a unique set of GR-responsive genes associated with neuronal growth and differentiation and also enhanced the induction of a large number of Dex-sensitive genes. BDNF via its receptor TrkB enhanced the transcriptional activity of a synthetic GR reporter, suggesting a direct effect of BDNF signaling on GR function. Indeed, BDNF treatment induces the phosphorylation of GR at serine 155 (S155) and serine 287 (S287). Expression of a nonphosphorylatable mutant (GR S155A/S287A) impaired the induction of a subset of BDNF- and Dex-regulated genes. Mechanistically, BDNF-induced GR phosphorylation increased GR occupancy and cofactor recruitment at the promoter of a BDNF-enhanced gene. GR phosphorylation in vivo is sensitive to changes in the levels of BDNF and TrkB as well as stress. Therefore, BDNF signaling specifies and amplifies the GR transcriptome through a coordinated GR phosphorylation-dependent detection mechanism.

  3. Effect of Oxcarbazepine on Serum Brain Derived Neurotrophic Factor in Bipolar Mania: An Exploratory Study.

    Science.gov (United States)

    Maiti, Rituparna; Mishra, Biswa Ranjan; Jowhar, Jaseem; Mohapatra, Debadatta; Parida, Sansita; Bisoi, Debasis

    2017-05-31

    In bipolar disorder, serum brain-derived neurotrophic factor (BDNF) level decreases leading to dysfunctions of critical neurotrophic, cellular plasticity and neuroprotective processes. The present study was conducted to evaluate the change in serum BDNF level with oxcarbazepine monotherapy in bipolar mania. The present study is a prospective, interventional, open label clinical study conducted on 25 patients of bipolar mania and 25 healthy controls. Detailed history, clinical evaluation including Young Mania Rating Scale (YMRS) scoring and serum BDNF were assessed at baseline for all 50 subjects. The bipolar patients were prescribed tablet oxcarbazepine and followed up after 4 weeks for clinical evaluation and re-estimation of serum BDNF and YMRS scoring. The serum BDNF level in bipolar manic patients were compared with healthy controls at baseline and results revealed that there is a significant reduction (p=0.002) in serum BDNF level in bipolar patients. At follow-up after 4 weeks, the mean change in serum BDNF in bipolar group who were on oxcarbazepine monotherapy was found statistically significant (p=0.02) in comparison to healthy controls. In bipolar group, the YMRS score and serum BDNF at baseline have an inverse relation(r=-0.59) whereas change of the YMRS score had a positive correlation (r=0.67) with the change of serum BDNF over 4 weeks. In bipolar mania serum BDNF level is low and it is found to be increased with short term monotherapy with oxcarbazepine.

  4. Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

    Science.gov (United States)

    Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

    2015-12-01

    Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

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

    Directory of Open Access Journals (Sweden)

    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

  6. Role of neurotrophic factor alterations in the neurodegenerative process in HIV associated neurocognitive disorders.

    Science.gov (United States)

    Fields, Jerel; Dumaop, Wilmar; Langford, T D; Rockenstein, Edward; Masliah, E

    2014-03-01

    Migration of HIV infected cells into the CNS is associated with a spectrum of neurological disorders, ranging from milder forms of HIV-associated neurocognitive disorders (HAND) to HIV-associated dementia (HAD). These neuro-psychiatric syndromes are related to the neurodegenerative pathology triggered by the release of HIV proteins and cytokine/chemokines from monocytes/macrophages into the CNS -a condition known as HIV encephalitis (HIVE). As a result of more effective combined anti-retroviral therapy patients with HIV are living longer and thus the frequency of HAND has increased considerably, resulting in an overlap between the neurodegenerative pathology associated with HIV and that related to aging. In fact, HIV infection is believed to hasten the aging process. The mechanisms through which HIV and aging lead to neurodegeneration include: abnormal calcium flux, excitotoxicity, signaling abnormalities, oxidative stress and autophagy defects. Moreover, recent studies have shown that defects in the processing and transport of neurotrophic factors such as fibroblast growth factors (FGFs), neural growth factor (NGF) and brain-derived growth factor (BDNF) might also play a role. Recent evidence implicates alterations in neurotrophins in the pathogenesis of neurodegeneration associated with HAND in the context of aging. Here, we report FGF overexpression curtails gp120-induced neurotoxicity in a double transgenic mouse model. Furthermore, our data show disparities in brain neurotrophic factor levels may be exacerbated in HIV patients over 50 years of age. In this review, we discuss the most recent findings on neurotrophins and HAND in the context of developing new therapies to combat HIV infection in the aging population.

  7. Furin mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation.

    Science.gov (United States)

    Chen, Yan; Zhang, Junjian; Deng, Min

    2015-01-01

    This study investigated the changes in brain-derived neurotrophic factor (BDNF) expression and the role of furin in BDNF maturation in reactive astrocytes from rats exposed to oxygen-glucose deprivation (OGD). Furin, a proprotein convertase, is upregulated and cleaves certain substrates during hypoxia in cancer cells. In addition, during hypoxia in the central nervous system, astrocytes become reactive and release BDNF to protect neurons. Maturation of BDNF in astrocytes requires furin-mediated endoproteolytic processing of the precursor protein pro-BDNF to BDNF. To expand our knowledge about the role of furin in BDNF maturation in astrocytes, these cells were exposed to OGD, and expression of furin and BDNF was detected by Western blot analysis. Changes in BDNF expression were observed when furin activity was inhibited by furin prosegment. We found that protein expression of BDNF and furin was upregulated, and this upregulation correlated with OGD stimulation. Furin inhibition reduced BDNF maturation and secretion. These results indicate that furin mediates the upregulation of BDNF in reactive astrocytes exposed to OGD and that furin may impact the biological effect of reactive astrocytes.

  8. Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors.

    Directory of Open Access Journals (Sweden)

    Jae-Sung Park

    Full Text Available Benefits of exercise on nerve regeneration and functional recovery have been reported in both central and peripheral nervous system disease models. However, underlying molecular mechanisms of enhanced regeneration and improved functional outcomes are less understood. We used a peripheral nerve regeneration model that has a good correlation between functional outcomes and number of motor axons that regenerate to evaluate the impact of treadmill exercise. In this model, the median nerve was transected and repaired while the ulnar nerve was transected and prevented from regeneration. Daily treadmill exercise resulted in faster recovery of the forelimb grip function as evaluated by grip power and inverted holding test. Daily exercise also resulted in better regeneration as evaluated by recovery of compound motor action potentials, higher number of axons in the median nerve and larger myofiber size in target muscles. Furthermore, these observations correlated with higher levels of neurotrophic factors, glial derived neurotrophic factor (GDNF, brain derived neurotrophic factor (BDNF and insulin-like growth factor-1 (IGF-1, in serum, nerve and muscle suggesting that increase in muscle derived neurotrophic factors may be responsible for improved regeneration.

  9. Inhibitory Effect of Memantine on Streptozotocin-Induced Insulin Receptor Dysfunction, Neuroinflammation, Amyloidogenesis, and Neurotrophic Factor Decline in Astrocytes.

    Science.gov (United States)

    Rajasekar, N; Nath, Chandishwar; Hanif, Kashif; Shukla, Rakesh

    2016-12-01

    Our earlier studies showed that insulin receptor (IR) dysfunction along with neuroinflammation and amyloidogenesis played a major role in streptozotocin (STZ)-induced toxicity in astrocytes. N-methyl-D-aspartate (NMDA) receptor antagonist-memantine shows beneficial effects in Alzheimer's disease (AD) pathology. However, the protective molecular and cellular mechanism of memantine in astrocytes is not properly understood. Therefore, the present study was undertaken to investigate the effect of memantine on insulin receptors, neurotrophic factors, neuroinflammation, and amyloidogenesis in STZ-treated astrocytes. STZ (100 μM) treatment for 24 h in astrocytes resulted significant decrease in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and insulin-degrading enzyme (IDE) expression in astrocytes. Treatment with memantine (1-10 μM) improved STZ-induced neurotrophic factor decline (BDNF, GDNF) along with IR dysfunction as evidenced by a significant increase in IR protein expression, phosphorylation of IRS-1, Akt, and GSK-3 α/β in astrocytes. Further, memantine attenuated STZ-induced amyloid precursor protein (APP), β-site APP-cleaving enzyme-1 and amyloid-β1-42 expression and restored IDE expression in astrocytes. In addition, memantine also displays protective effects against STZ-induced astrocyte activation showed by reduction of inflammatory markers, nuclear factor kappa-B translocation, glial fibrillary acidic protein, cyclooxygenase-2, tumor necrosis factor-α level, and oxidative-nitrostative stress. The results suggest that besides the NMDA receptor antagonisic activity, effect on astroglial IR and neurotrophic factor may also be an important factor in the beneficial effect of memantine in AD pathology. Graphical Abstract Novel neuroprotective mechanisms of memenatine in streptozotocin-induced toxicity in astrocytes.

  10. Brain-derived neurotrophic factor deficiency restricts proliferation of oligodendrocyte progenitors following cuprizone-induced demyelination.

    Science.gov (United States)

    Tsiperson, Vladislav; Huang, Yangyang; Bagayogo, Issa; Song, Yeri; VonDran, Melissa W; DiCicco-Bloom, Emanuel; Dreyfus, Cheryl F

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that through its neurotrophic tyrosine kinase, receptor, type 2 (TrkB) receptor, increases 5-bromo-2-deoxyuridine incorporation in oligodendrocyte progenitor cells (OPCs) in culture. Roles in vivo are less well understood; however, increases in numbers of OPCs are restricted in BDNF+/- mice following cuprizone-elicited demyelination. Here, we investigate whether these blunted increases in OPCs are associated with changes in proliferation. BDNF+/+ and BDNF+/- mice were fed cuprizone-containing or control feed. To assess effects on OPC numbers, platelet-derived growth factor receptor alpha (PDGFRα)+ or NG2+ cells were counted. To monitor DNA synthesis, 5-ethynyl-2'-deoxyuridine (EdU) was injected intraperitoneally and colocalized with PDGFRα+ cells. Alternatively, proliferating cell nuclear antigen (PCNA) was colocalized with PDGFRα or NG2. Labeling indices were determined in the BDNF+/+ and BDNF+/- animals. After 4 or 5 weeks of control feed, BDNF+/- mice exhibit similar numbers of OPCs compared with BDNF+/+ animals. The labeling indices for EdU and PCNA also were not significantly different, suggesting that neither the DNA synthesis phase (S phase) nor the proliferative pool size was different between genotypes. In contrast, when mice were challenged by cuprizone for 4 or 5 weeks, increases in OPCs observed in BDNF+/+ mice were reduced in the BDNF+/- mice. This difference in elevations in cell number was accompanied by decreases in EdU labeling and PCNA labeling without changes in cell death, indicating a reduction in the DNA synthesis and the proliferative pool. Therefore, levels of BDNF influence the proliferation of OPCs resulting from a demyelinating lesion.

  11. Parvalbumin immunoreactivity is enhanced by brain-derived neurotrophic factor in organotypic cultures of rat retina.

    Science.gov (United States)

    Rickman, D W

    1999-11-15

    The rodent retina undergoes considerable postnatal neurogenesis and phenotypic differentiation, and it is likely that diffusible neurotrophic factors contribute to this development and to the subsequent formation of functional retinal circuitry. Accordingly, perturbation of specific neurotrophin ligand-receptor interactions has provided valuable information as to the fundamental processes underlying this development. In the present studies we have built upon our previous observation that suppression of expression of trk(B), the high-affinity receptor for brain-derived neurotrophic factor (BDNF), in the postnatal rat retina results in the alteration of a specific interneuron in the rod pathway-the parvalbumin (PV)-immunoreactive AII amacrine cell. Here, we isolated retinas from newborn rats and maintained them in organotypic culture for up to 14 days (approximating the time of eye opening, in vivo) in the presence of individual neurotrophins [BDNF or nerve growth factor (NGF)]. We then examined histological sections of cultures for PV immunoreactivity. In control cultures, only sparse PV-immunostained cells were observed. In cultures supplemented with NGF, numerous lightly immunostained somata were present in the inner nuclear layer (INL) at the border of the inner plexiform layer (IPL). Many of these cells had rudimentary dendritic arborizations in the IPL. Cultures supplemented with BDNF displayed numerous well-immunostained somata at the INL/IPL border that gave rise to elaborate dendritic arborizations that approximated the morphology of mature AII amacrine cells in vivo. These observations indicate that neurotrophins have specific effects upon the neurochemical and, perhaps, morphological differentiation of an important interneuron in a specific functional retinal circuit.

  12. Glial cell line-derived neurotrophic factor (GDNF) as a novel candidate gene of anxiety.

    Science.gov (United States)

    Kotyuk, Eszter; Keszler, Gergely; Nemeth, Nora; Ronai, Zsolt; Sasvari-Szekely, Maria; Szekely, Anna

    2013-01-01

    Glial cell line-derived neurotrophic factor (GDNF) is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and drug abuse have also been published but little is known about any effects of these polymorphisms on mood characteristics such as anxiety and depression. Here we present an association study between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111) GDNF single nucleotide polymorphisms (SNPs) and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS) on 708 Caucasian young adults with no psychiatric history. Results of the allele-wise single marker association analyses provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p = 0.00070 and p = 0.00138 for rs3812047 and rs3096140, respectively), while no such result was obtained on depression scores. Haplotype analysis confirmed the role of these SNPs; mean anxiety scores raised according to the number of risk alleles present in the haplotypes (p = 0.00029). A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. In conclusion, this is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140) and individual variability of anxiety using self-report data from a non-clinical sample.

  13. Glial cell line-derived neurotrophic factor (GDNF as a novel candidate gene of anxiety.

    Directory of Open Access Journals (Sweden)

    Eszter Kotyuk

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF is a neurotrophic factor for dopaminergic neurons with promising therapeutic potential in Parkinson's disease. A few association analyses between GDNF gene polymorphisms and psychiatric disorders such as schizophrenia, attention deficit hyperactivity disorder and drug abuse have also been published but little is known about any effects of these polymorphisms on mood characteristics such as anxiety and depression. Here we present an association study between eight (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111 GDNF single nucleotide polymorphisms (SNPs and anxiety and depression scores measured by the Hospital Anxiety and Depression Scale (HADS on 708 Caucasian young adults with no psychiatric history. Results of the allele-wise single marker association analyses provided significant effects of two single nucleotide polymorphisms on anxiety scores following the Bonferroni correction for multiple testing (p = 0.00070 and p = 0.00138 for rs3812047 and rs3096140, respectively, while no such result was obtained on depression scores. Haplotype analysis confirmed the role of these SNPs; mean anxiety scores raised according to the number of risk alleles present in the haplotypes (p = 0.00029. A significant sex-gene interaction was also observed since the effect of the rs3812047 A allele as a risk factor of anxiety was more pronounced in males. In conclusion, this is the first demonstration of a significant association between the GDNF gene and mood characteristics demonstrated by the association of two SNPs of the GDNF gene (rs3812047 and rs3096140 and individual variability of anxiety using self-report data from a non-clinical sample.

  14. Chronic depression is associated with a pronounced decrease in serum brain-derived neurotrophic factor over time

    NARCIS (Netherlands)

    Bus, B. A. A.; Molendijk, M. L.; Tendolkar, I.; Penninx, B. W. J. H.; Prickaerts, J.; Elzinga, B. M.; Oude Voshaar, R. C.

    2015-01-01

    One of the leading neurobiological hypotheses on depression states that decreased expression of brain-derived neurotrophic factor (BDNF) contributes to depression. This is supported by consistent findings of low serum BDNF levels in depressed patients compared with non-depressed controls. Whereas it

  15. Comparative Analysis of the Effects of Neurotrophic Factors CDNF and GDNF in a Nonhuman Primate Model of Parkinson's Disease.

    Directory of Open Access Journals (Sweden)

    Enrique Garea-Rodríguez

    Full Text Available Cerebral dopamine neurotrophic factor (CDNF belongs to a newly discovered family of evolutionarily conserved neurotrophic factors. We demonstrate for the first time a therapeutic effect of CDNF in a unilateral 6-hydroxydopamine (6-OHDA lesion model of Parkinson's disease in marmoset monkeys. Furthermore, we tested the impact of high chronic doses of human recombinant CDNF on unlesioned monkeys and analyzed the amino acid sequence of marmoset CDNF. The severity of 6-OHDA lesions and treatment effects were monitored in vivo using 123I-FP-CIT (DaTSCAN SPECT. Quantitative analysis of 123I-FP-CIT SPECT showed a significant increase of dopamine transporter binding activity in lesioned animals treated with CDNF. Glial cell line-derived neurotrophic factor (GDNF, a well-characterized and potent neurotrophic factor for dopamine neurons, served as a control in a parallel comparison with CDNF. By contrast with CDNF, only single animals responded to the treatment with GDNF, but no statistical difference was observed in the GDNF group. However, increased numbers of tyrosine hydroxylase immunoreactive neurons, observed within the lesioned caudate nucleus of GDNF-treated animals, indicate a strong bioactive potential of GDNF.

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

    NARCIS (Netherlands)

    K. Miwa; J.K. Lee; Y. Takagishi; T. Opthof; X. Fu; I. Kodama

    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 ra

  17. 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

    2015-01-01

    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 sough

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

    Institute of Scientific and Technical Information of China (English)

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

    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, max-imum 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 neu-rotrophic factor or human umbilical cord blood stem cells. The damage to the ultrastructure of the optic nerve had also been reduced. These ifndings suggest that human umbilical cord blood stem cells and brain-derived neurotrophic factor effectively repair the injured optical nerve, im-prove biomechanical properties, and contribute to the recovery after injury.

  19. Association analysis of the brain-derived neurotrophic factor gene polymorphisms with early-onset schizophrenia in the Chinese population

    Institute of Scientific and Technical Information of China (English)

    易正辉

    2012-01-01

    Objective To investigate the relationship between the brain-derived neurotrophic factor (BDNF) gene Tag SNPs(rs 11030101 and rs6265) and early-onset schizophrenia in the Chinese Han population. Methods The tag single nucleotide polymorphisms (tag SNPs) rs11030101 and rs6265 in the BDNF gene were genotyped

  20. Ciliary Neurotrophic Factor Cell-Based Delivery Prevents Synaptic Impairment and Improves Memory in Mouse Models of Alzheimer's Disease

    NARCIS (Netherlands)

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

    2010-01-01

    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 whe

  1. Dopaminergic and brain-derived neurotrophic factor signalling in inbred mice exposed to a restricted feeding schedule

    NARCIS (Netherlands)

    Gelegen, C; van den Heuvel, J; Collier, D A; Campbell, I C; Oppelaar, H; Hessel, E; Kas, M J H

    2008-01-01

    Increased physical activity and decreased motivation to eat are common features in anorexia nervosa. We investigated the development of these features and the potential implication of brain-derived neurotrophic factor (BDNF) and dopaminergic signalling in their development in C57BL/6J and A/J inbred

  2. Developmental Thyroid Hormone Insufficiency Reduces Expression of Brain-Derived Neurotrophic Factor (BDNF) in Adults But Not in Neonates

    Science.gov (United States)

    Brain-derived neurotrophic factor (BDNF) is a neurotrophin critical for many developmental and physiological aspects of CNS function. Severe hypothyroidism in the early neonatal period results in developmental and cognitive impairments and reductions in mRNA and protein expressio...

  3. Aerobic Exercise Does Not Predict Brain Derived Neurotrophic Factor And Cortisol Alterations in Depressed Patients.

    Science.gov (United States)

    Lamego, Murilo Khede; de Souza Moura, Antonio Marcos; Paes, Flávia; Ferreira Rocha, Nuno Barbosa; de Sá Filho, Alberto Souza; Lattari, Eduardo; Rimes, Ridson; Manochio, João; Budde, Henning; Wegner, Mirko; Mura, Gioia; Arias-Carrión, Oscar; Yuan, Ti-Fei; Nardi, Antonio Egidio; Machado, Sergio

    2015-01-01

    The pathophysiology of depression is related to neurobiological changes that occur in the monoamine system, hypothalamic-pituitary-adrenal axis, neurogenesis system and the neuroimmune system. In recent years, there has been a growing interest in the research of the effects of exercise on brain function, with a special focus on its effects on brain-derived neurotrophic factor (BDNF), cortisol and other biomarkers. Thus, the aim of this study is to present a review investigating the acute and chronic effects of aerobic exercise on BDNF and cortisol levels in individuals with depression. It was not possible to establish an interaction between aerobic exercise and concentration of BDNF and cortisol, which may actually be the result of the divergence of methods, such as type of exercises, duration of the sessions, and prescribed intensity and frequency of sessions.

  4. Brain-derived neurotrophic factor and exercise in fibromyalgia syndrome patients: a mini review.

    Science.gov (United States)

    Nugraha, Boya; Karst, Matthias; Engeli, Stefan; Gutenbrunner, Christoph

    2012-09-01

    Fibromyalgia syndrome (FMS) is a common chronic pain condition characterized by chronic widespread pain and decreased pain threshold, with hyperalgesia and allodynia. Associated signs include fatigue, morning stiffness, non-restorative sleep, mood disturbance, depression, irritable bowel syndrome, and headache. In addition to the administration of drugs, psychological therapies treatment of FMS mainly consists of physical therapies. Although the precise pathogenesis of FMS remains elucidated, modern understanding conceptualizes FMS as central sensitization as a consequence of altered endogenous pain- and stress-response system and continuous nociceptive input. Altered brain-derived neurotrophic factor (BDNF) levels in FMS suggest that BDNF--well known for its effects on neuronal plasticity--is involved in this sensitization process. Exercise leads to changes in serum BDNF levels, too. This association highlights the importance of exercise in FMS and other chronic pain conditions.

  5. [BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF): NEUROBIOLOGY AND MARKER VALUE IN NEUROPSYCHIATRY].

    Science.gov (United States)

    Levada, O A; Cherednichenko, N V

    2015-01-01

    In this review current publications about neurobiology and marker value of brain derived neurotrophic factor (BDNF) in neuropsychiatry are analyzed. It is shown that BDNF is an important member of the family of neurotrophins which widely represented in various structures of the CNS. In prenatal period BDNF is involved in all stages of neuronal networks formation, and in the postnatal period its main role is maintaining the normal brain architectonics, involvement in the processes of neurogenesis and realization of neuroprotective functions. BDNF plays an important role in learning and memory organization, food and motor behavior. BDNF brain expression decreases with age, as well as in degenerative and vascular dementias, affective, anxiety, and behavioral disorders. The reducing of BDNF serum, level reflects the decreasing of its cerebral expression and could be used as a neurobiological marker of these pathological processes but the rising of its concentration could indicate the therapy effectiveness.

  6. Brain-derived neurotrophic factor in mood disorders and antidepressant treatments.

    Science.gov (United States)

    Castrén, Eero; Kojima, Masami

    2017-01-01

    Levels of brain-derived neurotrophic factor (BDNF) are reduced in the brain and serum of depressed patients and at least the reduction in serum levels is reversible upon successful treatment. These data, together with a wealth of reports using different animal models with depression-like behavior or manipulation of expression of BDNF or its receptor TrkB have implicated BDNF in the pathophysiology of depression as well as in the mechanism of action of antidepressant treatments. Recent findings have shown that posttranslational processing of BDNF gene product can yield different molecular entities that differently influence signaling through BNDF receptor TrkB and the pan-neurotrophin receptor p75(NTR). We will here review these data and discuss new insights into the possible pathophysiological roles of those new BDNF subtypes as well as recent findings on the role of BDNF mediated neuronal plasticity in mood disorders and their treatments.

  7. Gonadectomy affects brain derived neurotrophic factor in rats after chronic constriction nerve injury

    Institute of Scientific and Technical Information of China (English)

    Xin ZHAO; Xin WANG; Shu-yun ZHENG; Jian-guo XU

    2004-01-01

    AIM: To assess the effect of gonadectomy on brain derived neurotrophic factor (BDNF) expression in neuropathic pain. METHODS: Using chronic constriction injury (CCI) model, we detected BDNF mRNA in dorsal root ganglion and protein content in spinal cord by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay respectively. The time point we chose was post CCI operation d 0, 3, 7, 14, and 21.RESULTS: After CCI surgery, BDNF mRNA in ipsilateral DRGs was upregulated and reached its maximum on post operation d 7. BDNF protein level in ipsilateral spinal cord was also increased and reached its maximum on post operation d 14. The magnitude of this increase in gonadectomy (GDX) rats was significantly smaller than the GDX-sham rats at each time point. CONCLUSION: Gonadectomy reduced the BDNF increment after CCI surgery.Estrogen may affect nociceptive processing by its effect on BDNF.

  8. 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......, two controls were injected without GDNF, and two received no injection. At post-injection time points of 1, 2, 3, 6 hours (h), 1, 2, 4 or 7 days (d) eyes were enucleated and the ITV concentration of GDNF (cGDNF) was determined by enzyme-linked immunosorbent assay, and activity was tested using...... 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...

  9. Glial cell line-derived neurotrophic factor (GDNF therapy for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Shingo,Tetsuro

    2007-04-01

    Full Text Available Many studies using animals clarify that glial cell line-derived neurotrophic factor (GDNF has strong neuroprotective and neurorestorative effects on dopaminergic neurons. Several pilot studies clarified the validity of continuous intraputaminal GDNF infusion to patients with Parkinson's disease (PD, although a randomized controlled trial of GDNF therapy published in 2006 resulted in negative outcomes, and controversy remains about the efficacy and safety of the treatment. For a decade, our laboratory has investigated the efficacy and the most appropriate method of GDNF administration using animals, and consequently we have obtained some solid data that correspond to the results of clinical trials. In this review, we present an outline of our studies and other key studies related to GDNF, the current state of the research, problems to be overcome, and predictions regarding the use of GDNF therapy for PD in the future.

  10. 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...... were measured in 37 rapid cycling bipolar disorder patients and in 40 age- and gender matched healthy control subjects using enzyme-linked immunosorbent assay (ELISA). In a longitudinal design, repeated measurements of BDNF and NT-3 were evaluated in various affective states in bipolar disorder...

  11. 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...

  12. Serum brain-derived neurotrophic factor levels in different neurological diseases.

    Science.gov (United States)

    Ventriglia, Mariacarla; Zanardini, Roberta; Bonomini, Cristina; Zanetti, Orazio; Volpe, Daniele; Pasqualetti, Patrizio; Gennarelli, Massimo; Bocchio-Chiavetto, Luisella

    2013-01-01

    Consistent evidence indicates the involvement of the brain-derived neurotrophic factor (BDNF) in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In the present study, we compared serum BDNF in 624 subjects: 266 patients affected by AD, 28 by frontotemporal dementia (FTD), 40 by Lewy body dementia (LBD), 91 by vascular dementia (VAD), 30 by PD, and 169 controls. Our results evidenced lower BDNF serum levels in AD, FTD, LBD, and VAD patients (P benzodiazepines (P = 0.020). In conclusion, our results support the role of BDNF alterations in neurodegenerative mechanisms common to different forms of neurological disorders and underline the importance of including drug treatment in the analyses to avoid confounding effects.

  13. The brain derived neurotrophic factor and influences of stress in depression.

    Science.gov (United States)

    Kimpton, Jessica

    2012-09-01

    Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely expressed throughout the central nervous system (CNS). BDNF is involved in proliferation, differentiation, survival and death of neuronal and non-neuronal cells in the developing and adult CNS. The BDNF hypothesis of depression postulates that a reduction in BDNF is directly involved in the pathophysiology of depression, whilst anti-depressant mediated restoration of BDNF is responsible for the alleviation of the depressive state. This hypothesis is drawn from several studies implicating BDNF in depression and has received considerable support, which will be reviewed in this paper. This review will also discuss the implications of the functional Val66Met polymorphism of the gene encoding BDNF, which may reduce BDNF expression particularly when exposed to stress and thus may play a critical role in the pathogenesis of depression.

  14. Cell-based delivery of brain-derived neurotrophic factor in experimental allergic encephalomyelitis.

    Science.gov (United States)

    Makar, Tapas K; Nimmagadda, Vamshi K C; Trisler, David; Bever, Christopher T

    2014-08-01

    Brain-derived neurotrophic factor (BDNF) is a pleiotropic cytokine with neuroprotective properties that has been identified as a potential therapeutic agent for diseases of the central nervous system (CNS). The use of BDNF has been limited by a short serum half-life and poor penetration of the blood-brain barrier. To address this limitation we have explored cell-based approaches to delivery. We have used experimental allergic encephalomyelitis (EAE), an inflammatory disease of the CNS, as a model system. We engineered hematopoietic stem cells to produce BDNF to determine the feasibility and effectiveness of cell-based delivery of BDNF into the CNS in EAE. We review those studies here.

  15. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

    Science.gov (United States)

    Cunha, Carla; Angelucci, Andrea; D'Antoni, Angela; Dobrossy, Mate D; Dunnett, Stephen B; Berardi, Nicoletta; Brambilla, Riccardo

    2009-03-01

    In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

  16. Combination of Aβ clearance and neurotrophic factors as a potential treatment for Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Lian-Feng Lin; Min-Jing Liao; Xiao-Yan Xue; Wei Zhang; Li Yan; Liang Cai; Xiao-Wen Zhou

    2013-01-01

    There is no effective drug to treat Alzheimer's disease (AD),a neurodegenerative disease affecting an estimated 30 million people around the world.Strongly supported by preclinical and clinical studies,amyloid-beta (Aβ) may be a target for developing drugs against AD.Meanwhile,the fact that localized neuronal death/loss and synaptic impairment occur in AD should also be considered.Neuronal regeneration,which does not occur normally in the mammalian central nervous system,can be promoted by neurotrophic factors (NTFs).Evidence from clinical trials has shown that both Aβ clearance and NTFs are potentially effective in treating AD,thus a new approach combining Aβ clearance and administration of NTFs may be an effective therapeutic strategy.

  17. Reduced serum concentrations of nerve growth factor, but not brain-derived neurotrophic factor, in chronic cannabis abusers.

    Science.gov (United States)

    Angelucci, Francesco; Ricci, Valerio; Spalletta, Gianfranco; Pomponi, Massimiliano; Tonioni, Federico; Caltagirone, Carlo; Bria, Pietro

    2008-12-01

    Chronic cannabis use produces effects within the central nervous system (CNS) which include deficits in learning and attention tasks and decreased brain volume. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are proteins that serve as survival factors for CNS neurons. Deficits in the production and utilization of these proteins can lead to CNS dysfunctions including those associated with cannabis abuse. In this study we measured by enzyme-linked immunosorbent assay (ELISA) the NGF and BDNF serum levels in two groups of subjects: cannabis-dependent patients and healthy subjects. We found that NGF serum levels were significantly reduced in cannabis abusers as compared to healthy subjects. These findings indicate that NGF may have a role in the central action of cannabis and potentially in the neurotoxicity induced by this drug. These data also suggest that chronic cannabis consumption may be a risk factor for developing psychosis among drug users.

  18. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults

    OpenAIRE

    Azeredo,Lucas A.; Tatiana De Nardi; Levandowski, Mateus L.; Tractenberg,Saulo G.; Julia Kommers-Molina; Andrea Wieck; Tatiana Q. Irigaray; Irênio G. da Silva Filho; Rodrigo Grassi-Oliveira

    2017-01-01

    Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cogni...

  19. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

    Science.gov (United States)

    Magariños, A M; Li, C J; Gal Toth, J; Bath, K G; Jing, D; Lee, F S; McEwen, B S

    2011-03-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

  20. Effects of brain-derived neurotrophic factor on local inflammation in experimental stroke of rat.

    Science.gov (United States)

    Jiang, Yongjun; Wei, Ning; Zhu, Juehua; Lu, Tingting; Chen, Zhaoyao; Xu, Gelin; Liu, Xinfeng

    2010-01-01

    This study was aimed to investigate whether brain-derived neurotrophic factor (BDNF) can modulate local cerebral inflammation in ischemic stroke. Rats were subjected to ischemia by occluding the right middle cerebral artery (MCAO) for 2 hours. Rats were randomized as control, BDNF, and antibody groups. The local inflammation was evaluated on cellular, cytokine, and transcription factor levels with immunofluorescence, enzyme-linked immunosorbent assay, real-time qPCR, and electrophoretic mobility shift assay, respectively. Exogenous BDNF significantly improved motor-sensory, sensorimotor function, and vestibulomotor function, while BDNF did not decrease the infarct volume. Exogenous BDNF increased the number of both activated and phagocytotic microglia in brain. BDNF upregulated interleukin10 and its mRNA expression, while downregulated tumor necrosis factor α and its mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B. BDNF antibody, which blocked the activity of endogenous BDNF, showed the opposite effect of exogenous BDNF. Our data indicated that BDNF may modulate local inflammation in ischemic brain tissues on the cellular, cytokine, and transcription factor levels.

  1. Effects of Brain-Derived Neurotrophic Factor on Local Inflammation in Experimental Stroke of Rat

    Directory of Open Access Journals (Sweden)

    Yongjun Jiang

    2010-01-01

    Full Text Available This study was aimed to investigate whether brain-derived neurotrophic factor (BDNF can modulate local cerebral inflammation in ischemic stroke. Rats were subjected to ischemia by occluding the right middle cerebral artery (MCAO for 2 hours. Rats were randomized as control, BDNF, and antibody groups. The local inflammation was evaluated on cellular, cytokine, and transcription factor levels with immunofluorescence, enzyme-linked immunosorbent assay, real-time qPCR, and electrophoretic mobility shift assay, respectively. Exogenous BDNF significantly improved motor-sensory, sensorimotor function, and vestibulomotor function, while BDNF did not decrease the infarct volume. Exogenous BDNF increased the number of both activated and phagocytotic microglia in brain. BDNF upregulated interleukin10 and its mRNA expression, while downregulated tumor necrosis factor α and its mRNA expression. BDNF also increased DNA-binding activity of nuclear factor-kappa B. BDNF antibody, which blocked the activity of endogenous BDNF, showed the opposite effect of exogenous BDNF. Our data indicated that BDNF may modulate local inflammation in ischemic brain tissues on the cellular, cytokine, and transcription factor levels.

  2. 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.

  3. Fingolimod phosphate attenuates oligomeric amyloid β-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons.

    Directory of Open Access Journals (Sweden)

    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.

  4. Mature brain-derived neurotrophic factor and its receptor TrkB are upregulated in human glioma tissues.

    Science.gov (United States)

    Xiong, Jing; Zhou, L I; Lim, Yoon; Yang, Miao; Zhu, Yu-Hong; Li, Zhi-Wei; Fu, Deng-Li; Zhou, Xin-Fu

    2015-07-01

    There are two forms of brain-derived neurotrophic factor (BDNF), precursor of BDNF (proBDNF) and mature BDNF, which each exert opposing effects through two different transmembrane receptor signaling systems, consisting of p75 neurotrophin receptor (p75NTR) and tyrosine receptor kinase B (TrkB). Previous studies have demonstrated that proBDNF promotes cell death and inhibits the growth and migration of C6 glioma cells through p75NTR in vitro, while mature BDNF has opposite effects on C6 glioma cells. It is hypothesized that mature BDNF is essential in the development of malignancy in gliomas. However, histological data obtained in previous studies were unable distinguish mature BDNF from proBDNF due to the lack of specific antibodies. The present study investigated the expression of mature BDNF using a specific sheep monoclonal anti-mature BDNF antibody in 42 human glioma tissues of different grades and 10 control tissues. The correlation between mature BDNF and TrkB was analyzed. Mature BDNF expression was significantly increased in high-grade gliomas, and was positively correlated with the malignancy of the tumor and TrkB receptor expression. The present data have demonstrated that increased levels of mature BDNF contribute markedly to the development of malignancy of human gliomas through the primary BDNF receptor TrkB.

  5. Brain-derived neurotrophic factor as a regulator of systemic and brain energy metabolism and cardiovascular health.

    Science.gov (United States)

    Rothman, Sarah M; Griffioen, Kathleen J; Wan, Ruiqian; Mattson, Mark P

    2012-08-01

    Overweight sedentary individuals are at increased risk for cardiovascular disease, diabetes, and some neurological disorders. Beneficial effects of dietary energy restriction (DER) and exercise on brain structural plasticity and behaviors have been demonstrated in animal models of aging and acute (stroke and trauma) and chronic (Alzheimer's and Parkinson's diseases) neurological disorders. The findings described later, and evolutionary considerations, suggest brain-derived neurotrophic factor (BDNF) plays a critical role in the integration and optimization of behavioral and metabolic responses to environments with limited energy resources and intense competition. In particular, BDNF signaling mediates adaptive responses of the central, autonomic, and peripheral nervous systems from exercise and DER. In the hypothalamus, BDNF inhibits food intake and increases energy expenditure. By promoting synaptic plasticity and neurogenesis in the hippocampus, BDNF mediates exercise- and DER-induced improvements in cognitive function and neuroprotection. DER improves cardiovascular stress adaptation by a mechanism involving enhancement of brainstem cholinergic activity. Collectively, findings reviewed in this paper provide a rationale for targeting BDNF signaling for novel therapeutic interventions in a range of metabolic and neurological disorders.

  6. Brain-derived neurotrophic factor signalling mediates the antidepressant-like effect of piperine in chronically stressed mice.

    Science.gov (United States)

    Mao, Qing-Qiu; Huang, Zhen; Zhong, Xiao-Ming; Xian, Yan-Fang; Ip, Siu-Po

    2014-03-15

    Previous studies in our laboratory have demonstrated that piperine produced antidepressant-like action in various mouse models of behavioral despair. This study aimed to investigate the role of brain-derived neurotrophic factor (BDNF) signalling in the antidepressant-like effect of piperine in mice exposed to chronic unpredictable mild stress (CUMS). The results showed that CUMS caused depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test. It was also found that BDNF protein expression in the hippocampus and frontal cortex were significantly decreased in CUMS-treated mice. Chronic treatment of piperine at the dose of 10mg/kg significantly ameliorated behavioural deficits of CUMS-treated mice in the sucrose preference test and forced swim test. Piperine treatment also significantly decreased immobility time in the forced swim test in naive mice. In parallel, chronic piperine treatment significantly increased BDNF protein expression in the hippocampus and frontal cortex of both naive and CUMS-treated mice. In addition, inhibition of BDNF signalling by injection of K252a, an inhibitor of the BDNF receptor TrkB, significantly blocked the antidepressant-like effect of piperine in the sucrose preference test and forced swim test of CUMS-treated mice. Taken together, this study suggests that BDNF signalling is an essential mediator for the antidepressant-like effect of piperine.

  7. Recombinant human brain-derived neurotrophic factor prevents neuronal apoptosis in a novel in vitro model of subarachnoid hemorrhage.

    Science.gov (United States)

    Li, Mingchang; Wang, Yuefei; Wang, Wei; Zou, Changlin; Wang, Xin; Chen, Qianxue

    2017-01-01

    Subarachnoid hemorrhage (SAH) is a hemorrhagic stroke with high mortality and morbidity. An animal model for SAH was established by directly injecting a hemolysate into the subarachnoid space of rats or mice. However, the in vitro applications of the hemolysate SAH model have not been reported, and the mechanisms remain unclear. In this study, we established an in vitro SAH model by treating cortical pyramidal neurons with hemolysate. Using this model, we assessed the effects of recombinant human brain-derived neurotrophic factor (rhBDNF) on hemolysate-induced cell death and related mechanisms. Cortical neurons were treated with 10 ng/mL or 100 ng/mL rhBDNF prior to application of hemolysate. Hemolysate treatment markedly increased cell loss, triggered apoptosis, and promoted the expression of caspase-8, caspase-9, and cleaved caspase-3. rhBDNF significantly inhibited hemolysate-induced cell loss, neuronal apoptosis, and expression of caspase-8, caspase-9, and cleaved caspase-3. Our data revealed a previously unrecognized protective activity of rhBDNF against hemolysate-induced cell death, potentially via regulation of caspase-9-, caspase-8-, and cleaved caspase-3-related apoptosis. This study implicates that hemolysate-induced cortical neuron death represents an important in vitro model of SAH.

  8. Essential Role for Vav GEFs in Brain-derived Neurotrophic Factor (BDNF)-induced Dendritic Spine Growth and Synapse Plasticity

    OpenAIRE

    Hale, Carly F.; Dietz, Karen C.; Varela, Juan A.; Wood, Cody B.; Zirlin, Benjamin C.; Leah S. Leverich; Greene, Robert W.; Cowan, Christopher W.

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) and its cognate receptor, TrkB, regulate a wide range of cellular processes, including dendritic spine formation and functional synapse plasticity. However, the signaling mechanisms that link BDNF-activated TrkB to F-actin remodeling enzymes and dendritic spine morphological plasticity remain poorly understood. We report here that BDNF/TrkB signaling in neurons activates the Vav family of Rac/RhoA guanine nucleotide exchange factors (GEFs) through a no...

  9. Quantitative analysis of cerebrospinal fluid brain derived neurotrophic factor in the patients with multiple sclerosis.

    Science.gov (United States)

    Mashayekhi, Farhad; Salehi, Zivar; Jamalzadeh, Hamid Reza

    2012-01-01

    Multiple sclerosis (MS) is the most common cause ofnontraumatic neurological disability in Europe and North America. Growth factor expression could participate in the repair process of the demyelinating disease. Among growth factors, brain derived neurotrophic factors (BDNF) has been demonstrated to play an important role in neuronal and axonal survival. In the central nervous system (CNS), neurons are the main source of BDNF. Another potential source are activated astrocytes, which are present in inflamed areas in the CNS as shown in MS. In this study, total protein concentration (TPC) and BDNF levels in the cerebrospinal fluid (CSF) samples from the patients with MS (n = 48) and control subjects (n = 53) were measured using a Bio-Rad protein assay and enzyme linked immunosorbent assay (ELISA). No significant change in the CSF TPC of patients with MS was seen as compared to normal CSF. The presence of BDNF in the CSF samples was shown by Western blot. Using ELISA, it was shown that the level of BDNF in the MS CSF is higher than in normal CSF. It is concluded that BDNF is a constant component of human CSF. Moreover, it could be implicated in the pathophysiology of MS.

  10. Brain-derived neurotrophic factor as a drug target for CNS disorders.

    Science.gov (United States)

    Pezet, Sophie; Malcangio, Marzia

    2004-10-01

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of trophic factors. BDNF is widely and abundantly expressed in the CNS and is available to some peripheral nervous system neurons that uptake the neurotrophin produced by peripheral tissues. BDNF promotes survival and differentiation of certain neuronal populations during development. In adulthood, BDNF can modulate neuronal synaptic strength and has been implicated in hippocampal mechanisms of learning and memory and spinal mechanisms for pain. Several CNS disorders are associated with a decrease in trophic support. As BDNF and its high affinity receptor are abundant throughout the whole CNS, and BDNF is a potent neuroprotective agent, this trophic factor is a good candidate for therapeutic treatment of some of CNS disorders. This review aims to correlate the features of some CNS disorders (Parkinson's disease, Alzheimer's disease, depression, epilepsy and chronic pain) to changes in BDNF expression in the brain. The cellular and molecular mechanism by which BDNF might be a therapeutic strategy are critically examined.

  11. Brain-derived neurotrophic factor mediates activity-dependent dendritic growth in nonpyramidal neocortical interneurons in developing organotypic cultures.

    Science.gov (United States)

    Jin, Xiaoming; Hu, Hang; Mathers, Peter H; Agmon, Ariel

    2003-07-02

    Brain-derived neurotrophic factor (BDNF) promotes postnatal maturation of GABAergic inhibition in the cerebral and cerebellar cortices, and its expression and release are enhanced by neuronal activity, suggesting that it acts in a feedback manner to maintain a balance between excitation and inhibition during development. BDNF promotes differentiation of cerebellar, hippocampal, and neostriatal inhibitory neurons, but its effects on the dendritic development of neocortical inhibitory interneurons remain unknown. Here, we show that BDNF mediates depolarization-induced dendritic growth and branching in neocortical interneurons. To visualize inhibitory interneurons, we biolistically transfected organotypic cortical slice cultures from neonatal mice with green fluorescent protein (GFP) driven by the glutamic acid decarboxylase (GAD)67 promoter. Nearly all GAD67-GFP-expressing neurons were nonpyramidal, many contained GABA, and some expressed markers of neurochemically defined GABAergic subtypes, indicating that GAD67-GFP-expressing neurons were GABAergic. We traced dendritic trees from confocal images of the same GAD67-GFP-expressing neurons before and after a 5 d growth period, and quantified the change in total dendritic length (TDL) and total dendritic branch points (TDBPs) for each neuron. GAD67-GFP-expressing neurons growing in control medium exhibited a 20% increase in TDL, but in 200 ng/ml BDNF or 10 mm KCl, this increase nearly doubled and was accompanied by a significant increase in TDBPs. Blocking action potentials with TTX did not prevent the BDNF-induced growth, but antibodies against BDNF blocked the growth-promoting effect of KCl. We conclude that BDNF, released by neocortical pyramidal neurons in response to depolarization, enhances dendritic growth and branching in nearby inhibitory interneurons.

  12. Dipeptide Mimetic of the Brain-derived Neurotrophic Factor Prevents Impairments of Neurogenesis in Stressed Mice.

    Science.gov (United States)

    Gudasheva, T A; Povarnina, P Yu; Seredenin, S B

    2017-02-01

    Brain-derived neurotrophic factor (BDNF) plays the central role in the mechanisms of regulation of neurogenesis and neuroplasticity. Impairment of these mechanisms is considered as one of the main etiological factors of depression. Dimeric dipeptide mimetic of BDNF loop 4 bis-(N-monosuccinyl-l-seryl-l-lysine) hexamethylenediamide (GSB-106) was synthesized at the V. V. Zakusov Research Institute of Pharmacology. In vivo experiments revealed significant antidepressant properties of GSB-106 in doses of 0.1-10 mg/kg (intraperitoneally and orally). Effects of GSB-106 on hippocampal neurogenesis were studied in mice subjected to chronic predator stress. Proliferative activity in the subgranular zone of the dental gyrus was assessed immunohistochemically by Ki-67 expression (a marker of dividing cells). It was found that GSB-106 (10 mg/kg, intraperitoneally, 5 days) completely prevents neurogenesis disturbances in stressed mice. These findings suggest that GSB-106 is a promising candidate for the development of antidepressant agents with BDNF-like mechanism of action.

  13. The Non-Survival Effects of Glial Cell Line-Derived Neurotrophic Factor on Neural Cells

    Directory of Open Access Journals (Sweden)

    Daniel Cortés

    2017-08-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF was first characterized as a survival-promoting molecule for dopaminergic neurons (DANs. Afterwards, other cells were also discovered to respond to GDNF not only as a survival factor but also as a protein supporting other cellular functions, such as proliferation, differentiation, maturation, neurite outgrowth and other phenomena that have been less studied than survival and are now more extendedly described here in this review article. During development, GDNF favors the commitment of neural precursors towards dopaminergic, motor, enteric and adrenal neurons; in addition, it enhances the axonal growth of some of these neurons. GDNF also induces the acquisition of a dopaminergic phenotype by increasing the expression of Tyrosine Hydroxylase (TH, Nurr1 and other proteins that confer this identity and promote further dendritic and electrical maturation. In motor neurons (MNs, GDNF not only promotes proliferation and maturation but also participates in regenerating damaged axons and modulates the neuromuscular junction (NMJ at both presynaptic and postsynaptic levels. Moreover, GDNF modulates the rate of neuroblastoma (NB and glioblastoma cancer cell proliferation. Additionally, the presence or absence of GDNF has been correlated with conditions such as depression, pain, muscular soreness, etc. Although, the precise role of GDNF is unknown, it extends beyond a survival effect. The understanding of the complete range of properties of this trophic molecule will allow us to investigate its broad mechanisms of action to accelerate and/or improve therapies for the aforementioned pathological conditions.

  14. 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.

  15. Novel systems for tailored neurotrophic factor release based on hydrogel and resorbable glass hollow fibers.

    Science.gov (United States)

    Novajra, G; Tonda-Turo, C; Vitale-Brovarone, C; Ciardelli, G; Geuna, S; Raimondo, S

    2014-03-01

    A novel system for the release of neurotrophic factor into a nerve guidance channel (NGC) based on resorbable phosphate glass hollow fibers (50P2O5-30CaO-9Na2O-3SiO2-3MgO-2.5K2O-2.5TiO2 mol%) in combination with a genipin-crosslinked agar/gelatin hydrogel (A/G_GP) is proposed. No negative effect on the growth of neonatal olfactory bulb ensheathing cell line (NOBEC) as well as on the expression of pro- and anti-apoptotic proteins was measured in vitro in the presence of fiber dissolution products in the culture medium. For the release studies, fluorescein isothiocyanate-dextran (FD-20), taken as growth factor model molecule, was solubilized in different media and introduced into the fiber lumen exploiting the capillary action. The fibers were filled with i) FD-20/phosphate buffered saline (PBS) solution, ii) FD-20/hydrogel solution before gelation and iii) hydrogel before gelation, subsequently lyophilized and then filled with the FD-20/PBS solution. The different strategies used for the loading of the FD-20 into the fibers resulted in different release kinetics. A slower release was observed with the use of A/G_GP hydrogel. At last, poly(ε-caprolactone) (PCL) nerve guides containing the hollow fibers and the hydrogel have been fabricated.

  16. Imipramine induces brain-derived neurotrophic factor mRNA expression in cultured astrocytes.

    Science.gov (United States)

    Takano, Katsura; Yamasaki, Hiroshi; Kawabe, Kenji; Moriyama, Mitsuaki; Nakamura, Yoichi

    2012-01-01

    Depression is one of the most prevalent and livelihood-threatening forms of mental illnesses and the neural circuitry underlying depression remains incompletely understood. Recent studies suggest that the neuronal plasticity involved with brain-derived neurotrophic factor (BDNF) plays an important role in the recovery from depression. Some antidepressants are reported to induce BDNF expression in vivo; however, the mechanisms have been considered solely in neurons and not fully elucidated. In the present study, we evaluated the effects of imipramine, a classic tricyclic antidepressant drug, on BDNF expression in cultured rat brain astrocytes. Imipramine dose-dependently increased BDNF mRNA expression in astrocytes. The imipramine-induced BDNF increase was suppressed with inhibitors for protein kinase A (PKA) or MEK/ERK. Moreover, imipramine exposure activated transcription factor cAMP response element binding protein (CREB) in a dose-dependent manner. These results suggested that imipramine induced BDNF expression through CREB activation via PKA and/or ERK pathways. Imipramine treatment in depression might exert antidepressant action through BDNF production from astrocytes, and glial BDNF expression might be a target of developing novel antidepressants.

  17. Brain-derived neurotrophic factor Val66Met polymorphism and early life adversity affect hippocampal volume.

    Science.gov (United States)

    Carballedo, Angela; Morris, Derek; Zill, Peter; Fahey, Ciara; Reinhold, Elena; Meisenzahl, Eva; Bondy, Brigitta; Gill, Michael; Möller, Hans-Jürgen; Frodl, Thomas

    2013-03-01

    The interaction between adverse life events during childhood and genetic factors is associated with a higher risk to develop major depressive disorder (MDD). One of the polymorphisms found to be associated with MDD is the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF). The aim of our two-center study was to determine how the BDNF Val66Met polymorphism and childhood adversity affect the volumetric measures of the hippocampus in healthy individuals and people with MDD. In this two-center study, 62 adult patients with MDD and 71 healthy matched controls underwent high-resolution magnetic resonance imaging. We used manual tracing of the bilateral hippocampal structure with help of the software BRAINS2, assessed childhood adversity using the Childhood Trauma Questionnaire and genotyped Val66Met BDNF SNP (rs6265). MDD patients had smaller hippocampal volumes, both in the left and right hemispheres (F = 5.4, P = 0.022). We also found a significant interaction between BDNF allele and history of childhood adversity (F = 6.1, P = 0.015): Met allele carriers in our samples showed significantly smaller hippocampal volumes when they did have a history of childhood adversity, both in patients and controls. Our results highlight how relevant stress-gene interactions are for hippocampal volume reductions. Subjects exposed to early life adversity developed smaller hippocampal volumes when they carry the Met-allele of the BDNF polymorphism.

  18. Repetitive acute intermittent hypoxia increases growth/neurotrophic factor expression in non-respiratory motor neurons.

    Science.gov (United States)

    Satriotomo, I; Nichols, N L; Dale, E A; Emery, A T; Dahlberg, J M; Mitchell, G S

    2016-05-13

    Repetitive acute intermittent hypoxia (rAIH) increases growth/trophic factor expression in respiratory motor neurons, thereby eliciting spinal respiratory motor plasticity and/or neuroprotection. Here we demonstrate that rAIH effects are not unique to respiratory motor neurons, but are also expressed in non-respiratory, spinal alpha motor neurons and upper motor neurons of the motor cortex. In specific, we used immunohistochemistry and immunofluorescence to assess growth/trophic factor protein expression in spinal sections from rats exposed to AIH three times per week for 10weeks (3×wAIH). 3×wAIH increased brain-derived neurotrophic factor (BDNF), its high-affinity receptor, tropomyosin receptor kinase B (TrkB), and phosphorylated TrkB (pTrkB) immunoreactivity in putative alpha motor neurons of spinal cervical 7 (C7) and lumbar 3 (L3) segments, as well as in upper motor neurons of the primary motor cortex (M1). 3×wAIH also increased immunoreactivity of vascular endothelial growth factor A (VEGFA), the high-affinity VEGFA receptor (VEGFR-2) and an important VEGF gene regulator, hypoxia-inducible factor-1α (HIF-1α). Thus, rAIH effects on growth/trophic factors are characteristic of non-respiratory as well as respiratory motor neurons. rAIH may be a useful tool in the treatment of disorders causing paralysis, such as spinal injury and motor neuron disease, as a pretreatment to enhance motor neuron survival during disease, or as preconditioning for cell-transplant therapies.

  19. 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.

  20. Cervical dorsal rhizotomy increases brain-derived neurotrophic factor and neurotrophin-3 expression in the ventral spinal cord.

    Science.gov (United States)

    Johnson, R A; Okragly, A J; Haak-Frendscho, M; Mitchell, G S

    2000-05-15

    Although neurotrophic factors have been implicated in several forms of neuroplasticity, little is known concerning their potential role in spinal plasticity. Cervical dorsal rhizotomy (CDR) enhances serotonin terminal density near (spinal) phrenic motoneurons and serotonin-dependent long-term facilitation of phrenic motor output (Kinkead et al., 1998). We tested the hypothesis that selected neurotrophic factors change in a manner consistent with an involvement in this model of spinal plasticity. Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophic factor (GDNF), and transforming growth factor-beta(1) (TGF-beta(1)) concentrations were measured (ELISA) in three regions of interest to respiratory control: (1) ventral cervical spinal segments associated with the phrenic motor nucleus (C3-C6), (2) ventral thoracic spinal segments associated with inspiratory intercostal motor output (T3-T6) and (3) the diaphragm. Tissues were harvested from rats 7 d after bilateral CDR and compared with sham-operated and unoperated control rats. CDR increased BDNF (110%; p = 0.002) and NT-3 (100%; p = 0.002) in the cervical and NT-3 in the thoracic spinal cord (98%; p = 0.009). GDNF and TGF-beta(1) were not altered by CDR in any tissue. Immunohistochemistry localized BDNF and NT-3 to motoneurons and interneurons of the ventral spinal cord. These studies provide novel, suggestive evidence that BDNF and NT-3, possibly through their trophic effects on serotonergic neurons and/or motoneurons, may underlie serotonin-dependent plasticity in (spinal) respiratory motor control after CDR.

  1. Potential therapeutic action of natural products from traditional Chinese medicine on Alzheimer's disease animal models targeting neurotrophic factors.

    Science.gov (United States)

    Wei, Shuyong

    2016-12-01

    Alzheimer's disease (AD) is a neurodegenerative disorder in which the death of brain cells leads to memory loss and cognitive decline. To reduce the death rate and improve the biological activity of neurocytes, neurotrophic factors (NTFs) exhibit therapeutic effect on AD. However, therapeutic application of exogenous NTFs in treatment of AD is largely limited due to short half-life, poor stability, etc. Various extracts of traditional Chinese medicine (TCM) have been shown to exhibit therapeutic effects on AD, and some of these effects are associated with regulation on the expression of nerve growth factor, brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) and their associated receptors. This article reviews the progress on promotion of Panax ginseng, Rehmannia glutinosa Libosch., Epimedium, Polygala tenuifolia Willd, and seven other TCMs on secretion of NTFs during AD, with a view to preparation development and clinical application of these TCMs on AD. © 2016 Société Française de Pharmacologie et de Thérapeutique.

  2. From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF

    Directory of Open Access Journals (Sweden)

    Claire Géral

    2013-02-01

    Full Text Available Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF, which is the most abundant neurotrophin in the mammalian central nervous system (CNS. Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  3. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Géral, Claire; Angelova, Angelina; Lesieur, Sylviane

    2013-02-08

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe the existing approaches for delivery of brain-derived neurotrophic factor (BDNF), which is the most abundant neurotrophin in the mammalian central nervous system (CNS). Biomimetic peptides of BDNF have emerged as a promising therapy against neurodegenerative disorders. Polymer-based carriers have provided sustained neurotrophin delivery, whereas lipid-based particles have contributed also to potentiation of the BDNF action. Nanotechnology offers new possibilities for the design of vehicles for neuroprotection and neuroregeneration. Recent developments in nanoscale carriers for encapsulation and transport of BDNF are highlighted.

  4. Curative effect of transplantation of mesenchymal stem cells transfected with recombinant lentiviral vectors carrying brain-derived neurotrophic factor gene on intracerebral hemorrhage in rats

    Institute of Scientific and Technical Information of China (English)

    任瑞芳

    2013-01-01

    Objective To observe the curative effect of transplantation of mesenchymal stem cells(MSCs) transfected with recombinant lentiviral vectors carrying brain-derived neurotrophic factor(BDNF) gene on intracerebral

  5. Meta-analysis and association of brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder.

    Science.gov (United States)

    Zai, Gwyneth; Zai, Clement C; Arnold, Paul D; Freeman, Natalie; Burroughs, Eliza; Kennedy, James L; Richter, Margaret A

    2015-04-01

    Obsessive-compulsive disorder (OCD) is a severe psychiatric condition with a clear genetic component (Nicolini et al., 2009) in which neurodevelopmental mechanisms may be etiologically important. Brain-derived neurotrophic factor (BDNF) is an interesting candidate for molecular analysis in OCD on the basis of potential functional relevance, positive association studies, and reported interaction between this gene and other neurotransmitters implicated in this disorder.

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

    OpenAIRE

    Kim, Youngil

    2015-01-01

    [Purpose] 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. [Methods] 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 ex...

  7. Effect of Yoga on Pain, Brain-Derived Neurotrophic Factor, and Serotonin in Premenopausal Women with Chronic Low Back Pain

    OpenAIRE

    Moseon Lee; Woongjoon Moon; Jaehee Kim

    2014-01-01

    Background. Serotonin and brain-derived neurotrophic factor (BDNF) are known to be modulators of nociception. However, pain-related connection between yoga and those neuromodulators has not been investigated. Therefore, we aimed to evaluate the effect of yoga on pain, BDNF, and serotonin. Methods. Premenopausal women with chronic low back pain practiced yoga three times a week for 12 weeks. At baseline and after 12 weeks, back pain intensity was measured using visual analogue scale (VAS), and...

  8. Brain derived neurotrophic factor and structural vascular disease in black Africans : the SABPA study / Alwyn Johannes Smith

    OpenAIRE

    Smith, Alwyn Johannes

    2014-01-01

    Motivation - Brain-derived neurotrophic factor (BDNF) is a protein complex, synthesised and secreted mainly by the central nervous system and is involved in neuronal maintenance. Research suggests that BDNF is implicated in various neurological and psychiatric diseases, while recent evidence suggests a role for the neurotrophin on the periphery as well. Indeed, the specific functional role of BDNF and its action mechanism in the cardiovascular system, especially in that of Africans, is ye...

  9. Effects of Music Aerobic Exercise on Depression and Brain-Derived Neurotrophic Factor Levels in Community Dwelling Women

    OpenAIRE

    Shu-Hui Yeh; Li-Wei Lin; Yu Kuan Chuang; Cheng-Ling Liu; Lu-Jen Tsai; Feng-Shiou Tsuei; Ming-Tsung Lee; Chiu-Yueh Hsiao; Kuender D. Yang

    2015-01-01

    A randomized clinical trial was utilized to compare the improvement of depression and brain-derived neurotrophic factor (BDNF) levels between community women with and without music aerobic exercise (MAE) for 12 weeks. The MAE group involved 47 eligible participants, whereas the comparison group had 59 participants. No significant differences were recorded in the demographic characteristics between the participants in the MAE group and the comparison group. Forty-one participants in the MAE gr...

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

    OpenAIRE

    Tamura Makoto; Tamura Naohiro; Ikeda Takamitsu; Koyama Ryuta; Ikegaya Yuji; Matsuki Norio; Yamada Maki K

    2009-01-01

    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 a...

  11. From Molecular to Nanotechnology Strategies for Delivery of Neurotrophins: Emphasis on Brain-Derived Neurotrophic Factor (BDNF)

    OpenAIRE

    Claire Géral; Angelina Angelova; Sylviane Lesieur

    2013-01-01

    Neurodegenerative diseases represent a major public health problem, but beneficial clinical treatment with neurotrophic factors has not been established yet. The therapeutic use of neurotrophins has been restrained by their instability and rapid degradation in biological medium. A variety of strategies has been proposed for the administration of these leading therapeutic candidates, which are essential for the development, survival and function of human neurons. In this review, we describe th...

  12. Plasma level of brain-derived neurotrophic factor and the related analysis in depressive patients with suicide attempt

    Institute of Scientific and Technical Information of China (English)

    操军

    2014-01-01

    Objective To explore the association between brainderived neurotrophic factor(BDNF)and suicidal behavior through analyzing and detecting the alteration of plasma BDNF level in depressive patients with suicide attempt.Methods Using enzyme-linked immunosorbent analysis(ELISA)to test the plasma level of BDNF in 27suicidal depressed patients,33 non-suicidal depressed patients and 30 normal controls.Meanwhile,the Hamilton Depression Scale(HAMD)and Beck

  13. Binding characteristics of brain-derived neurotrophic factor to its receptors on neurons from the chick embryo

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Tebar, A.; Barde, Y.A.

    1988-09-01

    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.

  14. EXPRESSING HUMAN MATURED BRAIN-DERIVED NEUROTROPHIC FACTOR GENE IN E. Coli AND DETERMINING ITS BIOACTIVITY

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective Expressing the human matured brain-derived neurotrophic factor (mBDNF) gene in E.Coli and determining its bioactivity. Methods The resulting gene of mBDNF was subcloned into the EcoRI-BamHI site of the expression vector plasmid pBV220. The ligation products were used to transform the competent E. Coli DH5α. The proteins of mBDNF were experessed by temperature inducing. The expression products were dealed with solubilizing inclusion bodies and refolding protein. It was introduced into the embryonic chicken DRG to test whether the expressed mBDNF is a biologically active protein. Results The recombinant plasmid pBV/mBDNF was successfully constructed. By temperature inducing,under the control of the bacteriophage λ PL promoter, the experessed mBDNF protein was a 14Kd non-fusion protein,which existed in E. Coli as inclusion bodies. The size of expressed mBDNF is identical to the prediction. Bioactivity of the products was proved that it could support the cell survival and neurite growth in the primary cultures of embryonic 8-day-old chicken DRG neurons as compared to control.Conclusion The mBDNF gene can be expressed bioactively in E. Coli.

  15. 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.

  16. Serum brain-derived neurotrophic factor (BDNF) levels in attention deficit-hyperactivity disorder (ADHD).

    Science.gov (United States)

    Scassellati, Catia; Zanardini, Roberta; Tiberti, Alessandra; Pezzani, Marco; Valenti, Vera; Effedri, Paola; Filippini, Elena; Conte, Stefano; Ottolini, Alberto; Gennarelli, Massimo; Bocchio-Chiavetto, Luisella

    2014-03-01

    It has been proposed that the neurotrophin brain-derived neurotrophic factor (BDNF) may be involved in attention deficit-hyperactivity disorder (ADHD) etiopathogenesis. Alterations in BDNF serum levels have been observed in childhood/adulthood neurodevelopmental pathologies, but no evidence is available for BDNF serum concentrations in ADHD. The study includes 45 drug-naïve ADHD children and 45 age-sex matched healthy subjects. Concentration of serum BDNF was determined by the ELISA method. BDNF serum levels in patients with ADHD were not different from those of controls (mean ± SD; ADHD: 39.33 ± 10.41 ng/ml; controls: 38.82 ± 8.29 ng/ml, t = -0.26, p = 0.80). Our findings indicate no alteration of serum BDNF levels in untreated patients with ADHD. A further stratification for cognitive, neuropsychological and psychopathological assessment in a larger sample could be useful to clarify the role of BDNF in the endophenotype characterization of ADHD.

  17. 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.

  18. The Pattern of Brain-Derived Neurotrophic Factor Gene Expression in the Hippocampus of Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Iraj Salehi

    2010-06-01

    Full Text Available Objective(sThe aim of this study was to evaluate the effects of regular exercise in preventing diabetes complication in the hippocampus of streptozotocin (STZ-induced diabetic rat.Materials and MethodsA total of 48 male wistar rats were divided into four groups (control, control exercise, diabetic and diabetic exercise. Diabetes was induced by injection of single dose of STZ. Exercise was performed for one hr every day, over a period of 8 weeks. The antioxidant enzymes (SOD, GPX, CAT and GR and oxidant indexes with brain-derived neurotrophic factor (BDNF protein and its mRNA and apoptosis were measured in hippocampus of rats. ResultsA significant decrease in antioxidant enzymes activities and increased malondialdehyde (MDA level were observed in diabetic rats (P= 0.004. In response to exercise, antioxidant enzymes activities increased (P= 0.004. In contrast, MDA level decreased in diabetic rats (P= 0.004. Induction of diabetes caused an increase of BDNF protein and its mRNA expression. In response to exercise, BDNF protein and its mRNA expression reduced in hippocampus of diabetic rats. ConclusionDiabetes induced oxidative stress and increased BDNF gene expression. Exercise ameliorated oxidative stress and decreased BDNF gene expression.

  19. Plasma brain derived neurotrophic factor (BDNF) and response to ketamine in treatment-resistant depression.

    Science.gov (United States)

    Haile, C N; Murrough, J W; Iosifescu, D V; Chang, L C; Al Jurdi, R K; Foulkes, A; Iqbal, S; Mahoney, J J; De La Garza, R; Charney, D S; Newton, T F; Mathew, S J

    2014-02-01

    Ketamine produces rapid antidepressant effects in treatment-resistant depression (TRD), but the magnitude of response varies considerably between individual patients. Brain-derived neurotrophic factor (BDNF) has been investigated as a biomarker of treatment response in depression and has been implicated in the mechanism of action of ketamine. We evaluated plasma BDNF and associations with symptoms in 22 patients with TRD enrolled in a randomized controlled trial of ketamine compared to an anaesthetic control (midazolam). Ketamine significantly increased plasma BDNF levels in responders compared to non-responders 240 min post-infusion, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores were negatively correlated with BDNF (r=-0.701, p = 0.008). Plasma BDNF levels at 240 min post-infusion were highly negatively associated with MADRS scores at 240 min (r = -0.897, p=.002), 24 h (r = -0.791, p = 0.038), 48 h (r = -0.944, p = 0.001) and 72 h (r = -0.977, p = 0.010). No associations with BDNF were found for patients receiving midazolam. These data support plasma BDNF as a peripheral biomarker relevant to ketamine antidepressant response.

  20. Pro-region engineering for improved yeast display and secretion of brain derived neurotrophic factor.

    Science.gov (United States)

    Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Puguh, Arthya; Chan, Jonah R; Shusta, Eric V

    2016-03-01

    Brain derived neurotrophic factor (BDNF) is a promising therapeutic candidate for a variety of neurological diseases. However, it is difficult to produce as a recombinant protein. In its native mammalian context, BDNF is first produced as a pro-protein with subsequent proteolytic removal of the pro-region to yield mature BDNF protein. Therefore, in an attempt to improve yeast as a host for heterologous BDNF production, the BDNF pro-region was first evaluated for its effects on BDNF surface display and secretion. Addition of the wild-type pro-region to yeast BDNF production constructs improved BDNF folding both as a surface-displayed and secreted protein in terms of binding its natural receptors TrkB and p75, but titers remained low. Looking to further enhance the chaperone-like functions provided by the pro-region, two rounds of directed evolution were performed, yielding mutated pro-regions that further improved the display and secretion properties of BDNF. Subsequent optimization of the protease recognition site was used to control whether the produced protein was in pro- or mature BDNF forms. Taken together, we have demonstrated an effective strategy for improving BDNF compatibility with yeast protein engineering and secretion platforms.

  1. TrkB-Mediated Neuroprotective and Antihypoxic Properties of Brain-Derived Neurotrophic Factor.

    Science.gov (United States)

    Vedunova, Maria V; Mishchenko, Tatiana A; Mitroshina, Elena V; Mukhina, Irina V

    2015-01-01

    The neuroprotective and antihypoxic effects of brain-derived neurotrophic factor (BDNF) on dissociated hippocampal cultures in a hypoxia model were investigated. These experiments demonstrate that 10 minutes of normobaric hypoxia increased the number of dead cells in primary culture, whereas a preventive application of BDNF increased the number of viable cells. Spontaneous bioelectrical and calcium activity in neural networks was analyzed using multielectrode arrays and functional intravital calcium imaging. The results indicate that BDNF affects the functional parameters of neuronal networks in dissociated hippocampal cultures over the 7-day posthypoxic period. In addition, the effects of k252a, an antagonist of tropomyosin-related kinase B (TrkB), on functional bioelectrical activity during and after acute hypoxia were investigated. It was shown that the protective effects of BDNF are associated with binding to the TrkB receptor. Finally, intravital fluorescent mRNA probes were used to study the role of NF-κB1 in the protective effects of BDNF. Our experiments revealed that BDNF application stimulates NF-κB1 mRNA synthesis in primary dissociated hippocampal cells under normal conditions but not in hypoxic state.

  2. Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.

    Science.gov (United States)

    Martínez-Moreno, Araceli; Rodríguez-Durán, Luis F; Escobar, Martha L

    2016-01-15

    Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace.

  3. Directed evolution of brain-derived neurotrophic factor for improved folding and expression in Saccharomyces cerevisiae.

    Science.gov (United States)

    Burns, Michael L; Malott, Thomas M; Metcalf, Kevin J; Hackel, Benjamin J; Chan, Jonah R; Shusta, Eric V

    2014-09-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in nervous system function and has therapeutic potential. Microbial production of BDNF has resulted in a low-fidelity protein product, often in the form of large, insoluble aggregates incapable of binding to cognate TrkB or p75 receptors. In this study, employing Saccharomyces cerevisiae display and secretion systems, it was found that BDNF was poorly expressed and partially inactive on the yeast surface and that BDNF was secreted at low levels in the form of disulfide-bonded aggregates. Thus, for the purpose of increasing the compatibility of yeast as an expression host for BDNF, directed-evolution approaches were employed to improve BDNF folding and expression levels. Yeast surface display was combined with two rounds of directed evolution employing random mutagenesis and shuffling to identify BDNF mutants that had 5-fold improvements in expression, 4-fold increases in specific TrkB binding activity, and restored p75 binding activity, both as displayed proteins and as secreted proteins. Secreted BDNF mutants were found largely in the form of soluble homodimers that could stimulate TrkB phosphorylation in transfected PC12 cells. Site-directed mutagenesis studies indicated that a particularly important mutational class involved the introduction of cysteines proximal to the native cysteines that participate in the BDNF cysteine knot architecture. Taken together, these findings show that yeast is now a viable alternative for both the production and the engineering of BDNF.

  4. A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor.

    Science.gov (United States)

    Szuhany, Kristin L; Bugatti, Matteo; Otto, Michael W

    2015-01-01

    Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). When analyzing results across paradigms, sex significantly moderated the effect of exercise on BDNF levels, such that studies with more women showed less BDNF change resulting from exercise. Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans, but indicates that the magnitude of these effects may be lower in females relative to males.

  5. Low-level laser therapy promotes dendrite growth via upregulating brain-derived neurotrophic factor expression

    Science.gov (United States)

    Meng, Chengbo; He, Zhiyong; Xing, Da

    2014-09-01

    Downregulation of brain-derived neurotrophic factor (BDNF) in the hippocampus occurs early in the progression of Alzheimer's disease (AD). Since BDNF plays a critical role in neuronal survival and dendrite growth, BDNF upregulation may contribute to rescue dendrite atrophy and cell loss in AD. Low-level laser therapy (LLLT) has been demonstrated to regulate neuronal function both in vitro and in vivo. In the present study, we found that LLLT rescued neurons loss and dendritic atrophy via the increase of both BDNF mRNA and protein expression. In addition, dendrite growth was improved after LLLT, characterized by upregulation of PSD95 expression, and the increase in length, branching, and spine density of dendrites in hippocampal neurons. Together, these studies suggest that upregulation of BDNF with LLLT can ameliorate Aβ-induced neurons loss and dendritic atrophy, thus identifying a novel pathway by which LLLT protects against Aβ-induced neurotoxicity. Our research may provide a feasible therapeutic approach to control the progression of Alzheimer's disease.

  6. Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons.

    Science.gov (United States)

    Burkhalter, Julia; Fiumelli, Hubert; Allaman, Igor; Chatton, Jean-Yves; Martin, Jean-Luc

    2003-09-10

    Brain-derived neurotrophic factor (BDNF) promotes the biochemical and morphological differentiation of selective populations of neurons during development. In this study we examined the energy requirements associated with the effects of BDNF on neuronal differentiation. Because glucose is the preferred energy substrate in the brain, the effect of BDNF on glucose utilization was investigated in developing cortical neurons via biochemical and imaging studies. Results revealed that BDNF increases glucose utilization and the expression of the neuronal glucose transporter GLUT3. Stimulation of glucose utilization by BDNF was shown to result from the activation of Na+/K+-ATPase via an increase in Na+ influx that is mediated, at least in part, by the stimulation of Na+-dependent amino acid transport. The increased Na+-dependent amino acid uptake by BDNF is followed by an enhancement of overall protein synthesis associated with the differentiation of cortical neurons. Together, these data demonstrate the ability of BDNF to stimulate glucose utilization in response to an enhanced energy demand resulting from increases in amino acid uptake and protein synthesis associated with the promotion of neuronal differentiation by BDNF.

  7. Brain-derived Neurotrophic Factor Promotes the Migration of Olfactory Ensheathing Cells Through TRPC Channels.

    Science.gov (United States)

    Wang, Ying; Teng, Hong-Lin; Gao, Yuan; Zhang, Fan; Ding, Yu-Qiang; Huang, Zhi-Hui

    2016-12-01

    Olfactory ensheathing cells (OECs) are a unique type of glial cells with axonal growth-promoting properties in the olfactory system. Organized migration of OECs is essential for neural regeneration and olfactory development. However, the molecular mechanism of OEC migration remains unclear. In the present study, we examined the effects of brain-derived neurotrophic factor (BDNF) on OEC migration. Initially, the "scratch" migration assay, the inverted coverslip and Boyden chamber migration assays showed that BDNF could promote the migration of primary cultured OECs. Furthermore, BDNF gradient attracted the migration of OECs in single-cell migration assays. Mechanistically, TrkB receptor expressed in OECs mediated BDNF-induced OEC migration, and BDNF triggered calcium signals in OECs. Finally, transient receptor potential cation channels (TRPCs) highly expressed in OECs were responsible for BDNF-induced calcium signals, and required for BDNF-induced OEC migration. Taken together, these results demonstrate that BDNF promotes the migration of cultured OECs and an unexpected finding is that TRPCs are required for BDNF-induced OEC migration. GLIA 2016;64:2154-2165.

  8. Serum brain-derived neurotrophic factor in patients with trauma psychopathology.

    Science.gov (United States)

    Hauck, Simone; Kapczinski, Flávio; Roesler, Rafael; de Moura Silveira, Erico; Magalhães, Pedro V; Kruel, Letícia Rosito Pinto; Schestatsky, Sidnei Samuel; Ceitlin, Lúcia Helena Freitas

    2010-04-16

    Brain-derived neurotrophic factor (BDNF) has an important role in learning, motivation and regulation of mood. The aim of this study was to investigate levels of serum BDNF in patients with trauma psychopathology (acute and post-traumatic stress disorder) when compared to age and gender matched controls. A consecutive sample of 34 patients was evaluated regarding socio-demographic and clinical variables by means of a standard protocol, Davidson Trauma Scale, Beck Depression Inventory, Clinical Global Impression and the Global Assessment of Functioning. BDNF serum levels were measured right after the intake interview. Patients had higher BDNF levels than controls. Those levels, however, were higher right after the traumatic event, decreasing over time. When two groups of patients (recent and remote trauma) were investigated in separate, the recent trauma group (less than 1year since the traumatic event) had higher BDNF than controls, but this effect was not detected in the remote trauma group. The recent and remote trauma groups had different BDNF levels. Those findings persisted, even controlling for symptom severity, use of psychotropic medication, and history of psychiatric disease. As far as we know this is the first report of elevated serum BDNF levels in patients with recent trauma. Based in animal models that implicate BDNF in memory formation and consolidation, higher BDNF in recent PTSD could be related to memory and learning disruption central in PTSD psychopathology. Copyright 2010 Elsevier Inc. All rights reserved.

  9. Expression of ciliary neurotrophic factor after induction of ocular hypertension in the retina of rats

    Institute of Scientific and Technical Information of China (English)

    WU Qiang; ZHANG Min; SONG Bei-wen; LU Bin; HU Ping

    2007-01-01

    Background Glaucoma is mainly characterized by the loss of retinal ganglion cells. Ciliary neurotrophic factor (CNTF) is believed to stimulate the regeneration of axons of retinal ganglion cells. The objective of our study was to detect the expression of CNTF in the retina of a rat glaucoma model with increased intraocular pressure (lOP).Methods The rat glaucoma model was set up by electrocoagulating at least three episcleral and limbal veins. The location and the expression level of CNTF were detected at 1, 3, 7, 14, and 28 days post-surgery by immunohistochemistry, semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), and Western blot analysis.Results The rat glaucoma model with chronic, moderately elevated lOP was successfully produced. A minimum expression of CNTF was found in the ganglion cell layer of the retinas of the control group, and temporally increased expression and intensity of CNTF were found in the experimental retinas.Conclusion The expression of endogenous CNTF in the rat retina was found altered after the induction of ocular hypertension.

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

    Science.gov (United States)

    Chen, Hao-Hao; Zhang, Ning; Li, Wei-Yun; Fang, Ma-Rong; Zhang, Hui; Fang, Yuan-Shu; Ding, Ming-Xing; Fu, Xiao-Yan

    2015-09-01

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Institute of Scientific and Technical Information of China (English)

    Hao-hao Chen; Ning Zhang; Wei-yun Li; Ma-rong Fang; Hui Zhang; Yuan-shu Fang; Ming-xing Ding; Xiao-yan Fu

    2015-01-01

    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. ABDNF 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 hippo-campus 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 ifeld test in these rats as well. These ifndings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.

  13. 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.

  14. Construction of eukaryotic expression vector with brain-derived neurotrophic factor receptor trkB gene

    Institute of Scientific and Technical Information of China (English)

    HUANG Tao; JIANG Xiao-dan; XU Zhong; YUAN Jun; DING Lian-shu; ZOU Yu-xi; XU Ru-xiang

    2005-01-01

    Objective: To construct an eukaryotic expression vector carrying rat brain-derived neurotrophic factor receptor trkB gene. Methods: Using the total RNA isolated from rat brain as template, the trkB gene was amplified by reverse-transcription-polymerase chain reaction (RT-PCR) with a pair of specific primers which contained the restrictive sites of EcoR I and BamH I. The amplified fragment of trkB gene was digested with EcoR I and BamH I, and then subcloned into cloning vector pMD18-T and expression vector pEGFP-C2 respectively. The recombinant plasmids were identified by restriction endonuclease enzyme analysis and PCR. Results: The amplified DNA fragment was about 1461 bp in length. Enzyme digestion and PCR analysis showed that the gene of trkB had been successfully cloned into vector pMD18-T and pEGFP-C2. Conclusions: The trkB gene of rat has been amplified and cloned into the eukaryotic expression vector pEGFP-C2.

  15. Serum concentrations of brain-derived neurotrophic factor and mental disorders in imprisoned women

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    Renata M. Dotta-Panichi

    2015-06-01

    Full Text Available Objective:Mental disorders and early trauma are highly prevalent in female inmates. Brain-derived neurotrophic factor (BDNF plays an important role in learning, memory processes, and mood regulation. The aim of this study was to evaluate the relationship between serum BDNF levels and mental disorders among imprisoned women as compared with age- and education-matched controls.Methods:A consecutively recruited sample of 18 female prisoners with mental disorders was assessed for sociodemographic, criminal, and clinical variables using standardized instruments, the Mini International Neuropsychiatric Interview Plus (MINI Plus, and serum BDNF levels.Results:High rates of childhood sexual abuse and posttraumatic stress disorder (PTSD were found in the group of forensic patients. Serum BDNF levels in the forensic group did not differ from those of healthy controls, and were significantly higher when compared with those of women with mental disorders hospitalized in a general hospital.Conclusion:Elevated serum BDNF levels were found in imprisoned women. The results of this study may suggest neurobiological mechanisms similar to those seen in previous clinical and preclinical studies showing the involvement of BDNF in the pathophysiology of PTSD.

  16. Anatomical evidence for transsynaptic influences of estrogen on brain-derived neurotrophic factor expression.

    Science.gov (United States)

    Blurton-Jones, M; Kuan, P N; Tuszynski, M H

    2004-01-12

    Several studies have demonstrated that estrogen modulates brain-derived neurotrophic factor (BDNF) mRNA and protein within the adult hippocampus and cortex. However, mechanisms underlying this regulation are unknown. Although an estrogen response element (ERE)-like sequence has been identified within the BDNF gene, such a classical mechanism of estrogen-induced transcriptional activation requires the colocalized expression of estrogen receptors within cells that produce BDNF. Developmental studies have demonstrated such a relationship, but to date no studies have examined colocalization of estrogen receptors and BDNF within the adult brain. By utilizing double-label immunohistochemistry for BDNF, estrogen receptor-alpha (ER-alpha), and estrogen receptor-beta (ER-beta), we found only sparse colocalization between ER-alpha and BDNF in the hypothalamus, amygdala, prelimbic cortex, and ventral hippocampus. Furthermore, ER-beta and BDNF do not colocalize in any brain region. Given the recent finding that cortical ER-beta is almost exclusively localized to parvalbumin-immunoreactive GABAergic neurons, we performed BDNF/parvalbumin double labeling and discovered that axons from cortical ER-beta-expressing inhibitory neurons terminate on BDNF-immunoreactive pyramidal cells. Collectively, these findings support a potential transsynaptic relationship between estrogen state and cortical BDNF: By directly modulating GABAergic interneurons, estrogen may indirectly influence the activity and expression of BDNF-producing cortical neurons.

  17. Serum Brain-Derived Neurotrophic Factor Levels in Different Neurological Diseases

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    Mariacarla Ventriglia

    2013-01-01

    Full Text Available Consistent evidence indicates the involvement of the brain-derived neurotrophic factor (BDNF in neurodegenerative disorders such as Alzheimer's disease (AD and Parkinson’s disease (PD. In the present study, we compared serum BDNF in 624 subjects: 266 patients affected by AD, 28 by frontotemporal dementia (FTD, 40 by Lewy body dementia (LBD, 91 by vascular dementia (VAD, 30 by PD, and 169 controls. Our results evidenced lower BDNF serum levels in AD, FTD, LBD, and VAD patients (P<0.001 and a higher BDNF concentration in patients affected by PD (P=0.045. Analyses of effects of pharmacological treatments suggested significantly higher BDNF serum levels in patients taking mood stabilizers/antiepileptics (P=0.009 and L-DOPA (P<0.001 and significant reductions in patients taking benzodiazepines (P=0.020. In conclusion, our results support the role of BDNF alterations in neurodegenerative mechanisms common to different forms of neurological disorders and underline the importance of including drug treatment in the analyses to avoid confounding effects.

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

    Institute of Scientific and Technical Information of China (English)

    De-guo Jiang; Shi-li Jin; Gong-ying Li; Qing-qing Li; Zhi-ruo Li; Hong-xia Ma; Chuan-jun Zhuo; Rong-huan Jiang; Min-jie Ye

    2016-01-01

    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 andin 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 signiifcant 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 ifndings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress.

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

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    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.

  20. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity.

    Science.gov (United States)

    Suri, D; Vaidya, V A

    2013-06-01

    Glucocorticoids serve as key stress response hormones that facilitate stress coping. However, sustained glucocorticoid exposure is associated with adverse consequences on the brain, in particular within the hippocampus. Chronic glucocorticoid exposure evokes neuronal cell damage and dendritic atrophy, reduces hippocampal neurogenesis and impairs synaptic plasticity. Glucocorticoids also alter expression and signaling of the neurotrophin, brain-derived neurotrophic factor (BDNF). Since BDNF is known to promote neuroplasticity, enhance cell survival, increase hippocampal neurogenesis and cellular excitability, it has been hypothesized that specific adverse effects of glucocorticoids may be mediated by attenuating BDNF expression and signaling. The purpose of this review is to summarize the current state of literature examining the influence of glucocorticoids on BDNF, and to address whether specific effects of glucocorticoids arise through perturbation of BDNF signaling. We integrate evidence of glucocorticoid regulation of BDNF at multiple levels, spanning from the well-documented glucocorticoid-induced changes in BDNF mRNA to studies examining alterations in BDNF receptor-mediated signaling. Further, we delineate potential lines of future investigation to address hitherto unexplored aspects of the influence of glucocorticoids on BDNF. Finally, we discuss the current understanding of the contribution of BDNF to the modulation of structural and functional plasticity by glucocorticoids, in particular in the context of the hippocampus. Understanding the mechanistic crosstalk between glucocorticoids and BDNF holds promise for the identification of potential therapeutic targets for disorders associated with the dysfunction of stress hormone pathways.

  1. Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.

    Science.gov (United States)

    Guiard, Bruno P; David, Denis J P; Deltheil, Thierry; Chenu, Franck; Le Maître, Erwan; Renoir, Thibault; Leroux-Nicollet, Isabelle; Sokoloff, Pierre; Lanfumey, Laurence; Hamon, Michel; Andrews, Anne M; Hen, René; Gardier, Alain M

    2008-02-01

    Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus. The zero net flux method of quantitative microdialysis revealed that BDNF +/- heterozygous mice have increased basal extracellular 5-HT levels in the hippocampus and decreased 5-HT reuptake capacity. In keeping with these results, the selective serotonin reuptake inhibitor paroxetine failed to increase hippocampal extracellular 5-HT levels in BDNF +/- mice while it produced robust effects in wild-type littermates. Using in-vitro autoradiography and synaptosome techniques, we investigated the causes of attenuated 5-HT reuptake in BDNF +/- mice. A significant decrease in [3H]citalopram-binding-site density in the CA3 subregion of the ventral hippocampus and a significant reduction in [3H]5-HT uptake in hippocampal synaptosomes, revealed mainly a decrease in SERT function. However, 5-HT1A autoreceptors were not desensitized in BDNF +/- mice. These results provide evidence that constitutive reductions in BDNF modulate SERT function reuptake in the hippocampus.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. Zinc-triggered induction of tissue plasminogen activator by brain-derived neurotrophic factor and metalloproteinases.

    Science.gov (United States)

    Hwang, Ih-Yeon; Sun, Eun-Sun; An, Ji Hak; Im, Hana; Lee, Sun-Ho; Lee, Joo-Yong; Han, Pyung-Lim; Koh, Jae-Young; Kim, Yang-Hee

    2011-09-01

    Tissue plasminogen activator (tPA) is necessary for hippocampal long-term potentiation. Synaptically released zinc also contributes to long-term potentiation, especially in the hippocampal CA3 region. Using cortical cultures, we examined whether zinc increased the concentration and/or activity of tPA. Two hours after a 10-min exposure to 300 μM zinc, expression of tPA and its substrate, plasminogen, were significantly increased, as was the proteolytic activity of tPA. In contrast, increasing extracellular or intracellular calcium levels did not affect the expression or secretion of tPA. Changing zinc influx or chelating intracellular zinc also failed to alter tPA/plasminogen induction by zinc, indicating that zinc acts extracellularly. Zinc-mediated extracellular activation of matrix metalloproteinase (MMP) underlies the up-regulation of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (Trk) signaling. Consistent with these findings, co-treatment with a neutralizing antibody against BDNF or specific inhibitors of MMPs or Trk largely reversed tPA/plasminogen induction by zinc. Treatment of cortical cultures with p-aminophenylmercuric acetate, an MMP activator, MMP-2, or BDNF alone induced tPA/plasminogen expression. BDNF mRNA and protein expression was also increased by zinc and mediated by MMPs. Thus, an extracellular zinc-dependent, MMP- and BDNF-mediated synaptic mechanism may regulate the levels and activity of tPA.

  5. The Effects of Acute Exercise on Memory and Brain-Derived Neurotrophic Factor (BDNF).

    Science.gov (United States)

    Etnier, Jennifer L; Wideman, Laurie; Labban, Jeffrey D; Piepmeier, Aaron T; Pendleton, Daniel M; Dvorak, Kelly K; Becofsky, Katie

    2016-08-01

    Acute exercise benefits cognition, and some evidence suggests that brain-derived neurotrophic factor (BDNF) plays a role in this effect. The purpose of this study was to explore the dose-response relationship between exercise intensity, memory, and BDNF. Young adults completed 3 exercise sessions at different intensities relative to ventilator threshold (Vt) (VO2max, Vt - 20%, Vt + 20%). For each session, participants exercised for approximately 30 min. Following exercise, they performed the Rey Auditory Verbal Learning Test (RAVLT) to assess short-term memory, learning, and long-term memory recall. Twenty-four hours later, they completed the RAVLT recognition trial, which provided another measure of long-term memory. Blood was drawn before exercise, immediately postexercise, and after the 30-min recall test. Results indicated that long-term memory as assessed after the 24-hr delay differed as a function of exercise intensity with the largest benefits observed following maximal intensity exercise. BDNF data showed a significant increase in response to exercise; however, there were no differences relative to exercise intensity and there were no significant associations between BDNF and memory. Future research is warranted so that we can better understand how to use exercise to benefit cognitive performance.

  6. Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra.

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    Parain, K; Murer, M G; Yan, Q; Faucheux, B; Agid, Y; Hirsch, E; Raisman-Vozari, R

    1999-02-25

    Several in vitro and in vivo studies have shown that brain-derived neurotrophic factor (BDNF) promotes survival of damaged mesencephalic dopaminergic neurons. Using a specific antibody directed against human recombinant BDNF, we studied the expression of the protein at the cellular level in the post-mortem mesencephalon of control subjects and patients with Parkinson's disease (PD). In control subjects, BDNF was expressed in all mesencephalic regions containing dopaminergic neurons, and in the substantia nigra pars compacta (SNpc) 65% of the melanized neurons expressed BDNF. In the PD SNpc, the total number of pigmented neurons containing BDNF was reduced to 9.6% of the corresponding control value. In contrast, the number of pigmented neurons non-immunoreactive for BDNF was reduced to 23.9% of the corresponding control value. This result appears to indicate that SNpc melanized neurons not expressing BDNF have a 2.5-fold greater probability of surviving than BDNF-positive melanized neurons. Furthermore, we found that in parkinsonian mesencephalon almost all dopaminergic neurons containing Lewy bodies were immunoreactive for BDNF. These findings demonstrate a reduced expression of BDNF in PD and suggest that BDNF protein expression does not protect melanized SNpc neurons from the degenerative process in this disease.

  7. The role of dorsal root ganglia activation and brain-derived neurotrophic factor in multiple sclerosis.

    Science.gov (United States)

    Zhu, Wenjun; Frost, Emma E; Begum, Farhana; Vora, Parvez; Au, Kelvin; Gong, Yuewen; MacNeil, Brian; Pillai, Prakash; Namaka, Mike

    2012-08-01

    Multiple sclerosis (MS) is characterized by focal destruction of the white matter of the brain and spinal cord. The exact mechanisms underlying the pathophysiology of the disease are unknown. Many studies have shown that MS is predominantly an autoimmune disease with an inflammatory phase followed by a demyelinating phase. Recent studies alongside current treatment strategies, including glatiramer acetate, have revealed a potential role for brain-derived neurotrophic factor (BDNF) in MS. However, the exact role of BDNF is not fully understood. We used the experimental autoimmune encephalomyelitis (EAE) model of MS in adolescent female Lewis rats to identify the role of BDNF in disease progression. Dorsal root ganglia (DRG) and spinal cords were harvested for protein and gene expression analysis every 3 days post-disease induction (pdi) up to 15 days. We show significant increases in BDNF protein and gene expression in the DRG of EAE animals at 12 dpi, which correlates with peak neurological disability. BDNF protein expression in the spinal cord was significantly increased at 12 dpi, and maintained at 15 dpi. However, there was no significant change in mRNA levels. We show evidence for the anterograde transport of BDNF protein from the DRG to the dorsal horn of the spinal cord via the dorsal roots. Increased levels of BDNF within the DRG and spinal cord in EAE may facilitate myelin repair and neuroprotection in the CNS. The anterograde transport of DRG-derived BDNF to the spinal cord may have potential implications in facilitating central myelin repair and neuroprotection.

  8. Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development.

    Science.gov (United States)

    Suzuki, Shingo; Kiyosue, Kazuyuki; Hazama, Shunsuke; Ogura, Akihiko; Kashihara, Megumi; Hara, Tomoko; Koshimizu, Hisatsugu; Kojima, Masami

    2007-06-13

    Brain-derived neurotrophic factor (BDNF) exerts multiple biological functions in the CNS. Although BDNF can control transcription and protein synthesis, it still remains open to question whether BDNF regulates lipid biosynthesis. Here we show that BDNF elicits cholesterol biosynthesis in cultured cortical and hippocampal neurons. Importantly, BDNF elicited cholesterol synthesis in neurons, but not in glial cells. Quantitative reverse transcriptase-PCR revealed that BDNF stimulated the transcription of enzymes in the cholesterol biosynthetic pathway. BDNF-induced cholesterol increases were blocked by specific inhibitors of cholesterol synthesis, mevastatin and zaragozic acid, suggesting that BDNF stimulates de novo synthesis of cholesterol rather than the incorporation of extracellular cholesterol. Because cholesterol is a major component of lipid rafts, we investigated whether BDNF would increase the cholesterol content in lipid rafts or nonraft membrane domains. Interestingly, the BDNF-mediated increase in cholesterol occurred in rafts, but not in nonrafts, suggesting that BDNF promotes the development of neuronal lipid rafts. Consistent with this notion, BDNF raised the level of the lipid raft marker protein caveolin-2 in rafts. Remarkably, BDNF increased the levels of presynaptic proteins in lipid rafts, but not in nonrafts. An electrophysiological study revealed that BDNF-dependent cholesterol biosynthesis plays an important role for the development of a readily releasable pool of synaptic vesicles. Together, these results suggest a novel role for BDNF in cholesterol metabolism and synapse development.

  9. Brain-derived neurotrophic factor and the course of experimental cerebral malaria.

    Science.gov (United States)

    Linares, María; Marín-García, Patricia; Pérez-Benavente, Susana; Sánchez-Nogueiro, Jesús; Puyet, Antonio; Bautista, José M; Diez, Amalia

    2013-01-15

    The role of neurotrophic factors on the integrity of the central nervous system (CNS) during cerebral malaria (CM) infection remains obscure, but the long-standing neurocognitive sequelae often observed in rescued children can be attributed in part to the modulation of neuronal survival and synaptic plasticity. To discriminate the contribution of key responses in the time-sequence of the pathogenic events that trigger the development of neurocognitive malaria syndrome we defined four stages (I-IV) of the neurological progression of CM in C57BL/6 mice infected with Plasmodium berghei ANKA. Upregulation of ICAM-1, VCAM-1, e-selectin and p-selectin expression was detected in all cerebral regions before parasitized red blood cells (pRBC) accumulation. As the severity of symptoms increased, BDNF mRNA progressively diminished in several brain regions, earliest in the thalamus-hypothalamus, cerebellum, brainstem and cortex, and correlated with a four-stage disease sequence. Immunohistochemical confocal microscopy revealed changes in the BDNF distribution pattern, suggesting altered axonal transport. During CM progression, molecular markers of neurological infection and inflammation in the parasite and the host, respectively, were accompanied by a switch in the brain constitutive proteasome to the immunoproteasome, which could impede normal protein turnover. In parallel with BDNF downregulation, NCAM expression also diminished with increased CM severity. Together, these data suggest that changes in BDNF availability could be involved in the pathogenesis of CM.

  10. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor.

    Science.gov (United States)

    Parkhurst, Christopher N; Yang, Guang; Ninan, Ipe; Savas, Jeffrey N; Yates, John R; Lafaille, Juan J; Hempstead, Barbara L; Littman, Dan R; Gan, Wen-Biao

    2013-12-19

    Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of synaptic plasticity. Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling.

  11. Brain-derived neurotrophic factor and glucocorticoids: reciprocal influence on the central nervous system.

    Science.gov (United States)

    Numakawa, T; Adachi, N; Richards, M; Chiba, S; Kunugi, H

    2013-06-03

    Brain-derived neurotrophic factor (BDNF) has multiple roles in the central nervous system (CNS), including maintaining cell survival and regulation of synaptic function. In CNS neurons, BDNF triggers activation of phospholipase Cγ (PLCγ), mitogen-activated protein/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide 3-kinase (PI3K)/Akt pathways, influencing neuronal cells beneficially through these intracellular signaling cascades. There is evidence to suggest that decreased BDNF expression or function is related to the pathophysiology of brain diseases including psychiatric disorders. Additionally, glucocorticoids, which are critical stress hormones, also influence neuronal function in the CNS, and are putatively involved in the onset of depression when levels are abnormally high. In animal models of depression, changes in glucocorticoid levels, expression of glucocorticoid receptor (GR), and alterations in BDNF signaling are observed. Interestingly, several studies using in vivo and in vitro systems suggest that glucocorticoids interact with BDNF to ultimately affect CNS function. In the present review, we provide an overview of recent evidence concerning the interaction between BDNF and glucocorticoids.

  12. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation.

    Science.gov (United States)

    Guo, Wei; Robbins, Meredith T; Wei, Feng; Zou, Shiping; Dubner, Ronald; Ren, Ke

    2006-01-04

    In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10-100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP(3), PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.

  13. Sex and stress hormone influences on the expression and activity of brain-derived neurotrophic factor.

    Science.gov (United States)

    Carbone, D L; Handa, R J

    2013-06-03

    The neurotrophin, brain-derived neurotrophic factor (BDNF), is recognized as a key component in the regulation of CNS ontogeny, homeostasis and adult neuroplasticity. The importance of BDNF in CNS development and function is well documented by numerous reports from animal studies linking abnormal BDNF signaling to metabolic disturbances and anxiety or depressive-like behavior. Despite the diverse roles for BDNF in nearly all aspects of CNS physiology, the regulation of BDNF expression, as well as our understanding of the signaling mechanisms associated with this neurotrophin, remains incomplete. However, links between sex hormones such as estradiol and testosterone, as well as endogenous and synthetic glucocorticoids (GCs), have emerged as important mediators of BDNF expression and function. Examples of such regulation include brain region-specific induction of Bdnf mRNA in response to estradiol. Additional studies have also documented regulation of the expression of the high-affinity BDNF receptor Tropomyosin-Related Kinase B by estradiol, thus implicating sex steroids not only in the regulation of BDNF expression, but also in mechanisms of signaling associated with it. In addition to gonadal steroids, further evidence also suggests functional interaction between BDNF and GCs, such as in the regulation of corticotrophin-releasing hormone and other important neuropeptides. In this review, we provide an overview of the roles played by selected sex or stress hormones in the regulation of BDNF expression and signaling in the CNS.

  14. Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis.

    Science.gov (United States)

    Javeri, Sita; Rodi, Michael; Tary-Lehmann, Magdalena; Lehmann, Paul V; Addicks, Klaus; Kuerten, Stefanie

    2010-11-01

    The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (-/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T(H)1/T(H)17 response was attenuated in BDNF (-/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (-/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.

  15. Effect of childhood maltreatment and brain-derived neurotrophic factor on brain morphology

    Science.gov (United States)

    Schmaal, Lianne; Jansen, Rick; Milaneschi, Yuri; Opmeer, Esther M.; Elzinga, Bernet M.; van der Wee, Nic J. A.; Veltman, Dick J.; Penninx, Brenda W. J. H.

    2016-01-01

    Childhood maltreatment (CM) has been associated with altered brain morphology, which may partly be due to a direct impact on neural growth, e.g. through the brain-derived neurotrophic factor (BDNF) pathway. Findings on CM, BDNF and brain volume are inconsistent and have never accounted for the entire BDNF pathway. We examined the effects of CM, BDNF (genotype, gene expression and protein level) and their interactions on hippocampus, amygdala and anterior cingulate cortex (ACC) morphology. Data were collected from patients with depression and/or an anxiety disorder and healthy subjects within the Netherlands Study of Depression and Anxiety (NESDA) (N = 289). CM was assessed using the Childhood Trauma Interview. BDNF Val66Met genotype, gene expression and serum protein levels were determined in blood and T1 MRI scans were acquired at 3T. Regional brain morphology was assessed using FreeSurfer. Covariate-adjusted linear regression analyses were performed. Amygdala volume was lower in maltreated individuals. This was more pronounced in maltreated met-allele carriers. The expected positive relationship between BDNF gene expression and volume of the amygdala is attenuated in maltreated subjects. Finally, decreased cortical thickness of the ACC was identified in maltreated subjects with the val/val genotype. CM was associated with altered brain morphology, partly in interaction with multiple levels of the BNDF pathway. Our results suggest that CM has different effects on brain morphology in met-carriers and val-homozygotes and that CM may disrupt the neuroprotective effect of BDNF. PMID:27405617

  16. Effect of Training Exercise on Urinary Brain-derived Neurotrophic Factor Levels and Cognitive Performances in Overweight and Obese Subjects: A Pilot Study.

    Science.gov (United States)

    Russo, Angelo; Buratta, Livia; Pippi, Roberto; Aiello, Cristina; Ranucci, Claudia; Reginato, Elisa; Santangelo, Valerio; DeFeo, Pierpaolo; Mazzeschi, Claudia

    2016-11-21

    Exercise-mediated, brain-derived neurotrophic factor induction benefits health and cognitive functions. The multifaceted interplay between physical activity, urinary brain-derived neurotrophic factor levels and cognitive functioning has been largely neglected in previous literature. In this pilot study, two bouts of training exercise (65% and 70% of heart rate reserve) influenced urinary brain-derived neurotrophic factor levels and cognitive performances in 12 overweight and obese participants. Percent heart rate reserve, expenditure energy, brain-derived neurotrophic factor urinary levels and cognitive performances were measured before and after the exercise. No significant variations in energy expenditure were observed, while differences of heart rate reserve between two groups were maintained. Both bouts of training exercise induced a similar reduction in urinary brain-derived neurotrophic factor levels. Only visuo-spatial working memory capacity at 65% of heart rate reserve showed a significant increase. These findings indicate a consistent effect of training exercise on urinary brain-derived neurotrophic factor levels and cognitive factors in overweight and obese participants.

  17. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men.

    Science.gov (United States)

    Cho, Su Youn; Roh, Hee Tae

    2016-04-01

    [Purpose] The aim of the present study was to investigate the effects of aerobic exercise training on the levels of peripheral brain-derived neurotrophic factor and eotaxin-1 in obese young men. [Subjects and Methods] The subjects included sixteen obese young men with a body mass index greater than 25 kg/m(2). They were randomly divided between control and exercise groups (n = 8 in each group). The exercise group performed treadmill exercise for 40 min, 3 times a week for 8 weeks at the intensity of 70% heart rate reserve. Blood collection was performed to examine the levels of serum glucose, plasma malonaldehyde, serum brain-derived neurotrophic factor, and plasma eotaxin-1 before and after the intervention (aerobic exercise training). [Results] Following the intervention, serum BDNF levels were significantly higher, while serum glucose, plasma MDA, and plasma eotaxin-1 levels were significantly lower than those prior to the intervention in the exercise group. [Conclusion] Aerobic exercise training can induce neurogenesis in obese individuals by increasing the levels of brain-derived neurotrophic factor and reducing the levels of eotaxin-1. Alleviation of oxidative stress is possibly responsible for such changes.

  18. 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 Taekwondo exercise training may increase cognitive functions (Stroop test). However the training did not statistically affect neurotrophic factors (BDNF, NGF, IGF-1) in undergraduate students.

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

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    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.

  20. TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle.

    Science.gov (United States)

    Vohra, Pawan K; Thompson, Michael A; Sathish, Venkatachalem; Kiel, Alexander; Jerde, Calvin; Pabelick, Christina M; Singh, Brij B; Prakash, Y S

    2013-12-01

    Exogenous brain-derived neurotrophic factor (BDNF) enhances Ca(2+) signaling and cell proliferation in human airway smooth muscle (ASM), especially with inflammation. Human ASM also expresses BDNF, raising the potential for autocrine/paracrine effects. The mechanisms by which ASM BDNF secretion occurs are not known. Transient receptor potential channels (TRPCs) regulate a variety of intracellular processes including store-operated Ca(2+) entry (SOCE; including in ASM) and secretion of factors such as cytokines. In human ASM, we tested the hypothesis that TRPC3 regulates BDNF secretion. At baseline, intracellular BDNF was present, and BDNF secretion was detectable by enzyme linked immunosorbent assay (ELISA) of cell supernatants or by real-time fluorescence imaging of cells transfected with GFP-BDNF vector. Exposure to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) (20ng/ml, 48h) or a mixture of allergens (ovalbumin, house dust mite, Alternaria, and Aspergillus extracts) significantly enhanced BDNF secretion and increased TRPC3 expression. TRPC3 knockdown (siRNA or inhibitor Pyr3; 10μM) blunted BDNF secretion, and prevented inflammation effects. Chelation of extracellular Ca(2+) (EGTA; 1mM) or intracellular Ca(2+) (BAPTA; 5μM) significantly reduced secreted BDNF, as did the knockdown of SOCE proteins STIM1 and Orai1 or plasma membrane caveolin-1. Functionally, secreted BDNF had autocrine effects suggested by phosphorylation of high-affinity tropomyosin-related kinase TrkB receptor, prevented by chelating extracellular BDNF with chimeric TrkB-Fc. These data emphasize the role of TRPC3 and Ca(2+) influx in the regulation of BDNF secretion by human ASM and the enhancing effects of inflammation. Given the BDNF effects on Ca(2+) and cell proliferation, BDNF secretion may contribute to altered airway structure and function in diseases such as asthma.

  1. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    Science.gov (United States)

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-02

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

  2. Cerebrolysin, a mixture of neurotrophic factors induces marked neuroprotection in spinal cord injury following intoxication of engineered nanoparticles from metals.

    Science.gov (United States)

    Menon, Preeti Kumaran; Muresanu, Dafin Fior; Sharma, Aruna; Mössler, Herbert; Sharma, Hari Shanker

    2012-02-01

    Spinal cord injury (SCI) is the world's most disastrous disease for which there is no effective treatment till today. Several studies suggest that nanoparticles could adversely influence the pathology of SCI and thereby alter the efficacy of many neuroprotective agents. Thus, there is an urgent need to find suitable therapeutic agents that could minimize cord pathology following trauma upon nanoparticle intoxication. Our laboratory has been engaged for the last 7 years in finding suitable therapeutic strategies that could equally reduce cord pathology in normal and in nanoparticle-treated animal models of SCI. We observed that engineered nanoparticles from metals e.g., aluminum (Al), silver (Ag) and copper (Cu) (50-60 nm) when administered in rats daily for 7 days (50 mg/kg, i.p.) resulted in exacerbation of cord pathology after trauma that correlated well with breakdown of the blood-spinal cord barrier (BSCB) to serum proteins. The entry of plasma proteins into the cord leads to edema formation and neuronal damage. Thus, future drugs should be designed in such a way to be effective even when the SCI is influenced by nanoparticles. Previous research suggests that a suitable combination of neurotrophic factors could induce marked neuroprotection in SCI in normal animals. Thus, we examined the effects of a new drug; cerebrolysin that is a mixture of different neurotrophic factors e.g., brain-derived neurotrophic factor (BDNF), glial cell line derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF) and other peptide fragments to treat normal or nanoparticle-treated rats after SCI. Our observations showed that cerebrolysin (2.5 ml/kg, i.v.) before SCI resulted in good neuroprotection in normal animals, whereas nanoparticle-treated rats required a higher dose of the drug (5.0 ml/kg, i.v.) to induce comparable neuroprotection in the cord after SCI. Cerebrolysin also reduced spinal cord water content, leakage of plasma proteins

  3. Effects of Yulangsan polysaccharide on monoamine neurotransmitters, adenylate cyclase activity and brain-derived neurotrophic factor expression in a mouse model of depression induced by unpredictable chronic mild stress

    Institute of Scientific and Technical Information of China (English)

    Shuang Liang; Renbin Huang; Xing Lin; Jianchun Huang; Zhongshi Huang; Huagang Liu

    2012-01-01

    The present study established a mouse model of depression induced by unpredictable chronic mild stress. The model mice were treated with Yulangsan polysaccharide (YLSPS; 150, 300 and 600 mg/kg) for 21 days, and compared with fluoxetine-treated and normal control groups. Enzyme-linked immunosorbent assay, radioimmunity and immunohistochemical staining showed that following treatment with YLSPS (300 and 600 mg/kg), monoamine neurotransmitter levels, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression were significantly elevated, and depression-like behaviors were improved. Open-field and novelty-suppressed feeding tests showed that mouse activity levels were increased and feeding latency was shortened following treatment. Our results indicate that YLSPS inhibits depression by upregulating monoamine neurotransmitters, prefrontal cortex adenylate cyclase activity and hippocampal brain-derived neurotrophic factor expression.

  4. Association of brain-derived neurotrophic factor and nerve growth factor gene polymorphisms with susceptibility to migraine

    Directory of Open Access Journals (Sweden)

    Coskun S

    2016-07-01

    Full Text Available Salih Coskun,1 Sefer Varol,2 Hasan H Ozdemir,2 Elif Agacayak,3 Birsen Aydın,4 Oktay Kapan,5 Mehmet Akif Camkurt,6 Saban Tunc,7 Mehmet Ugur Cevik2 1Department of Medical Genetics, 2Department of Neurology, 3Department of Obstetrics and Gynecology, Medical Faculty, Dicle University, Diyarbakır, Turkey; 4Department of Neurology, Diyarbakır Education and Research Hospital, Diyarbakır, Turkey; 5Department of Neurology, Elaziğ Education and Research Hospital, Elaziğ, Turkey; 6Department of Psychiatry, Afsin State Hospital, Kahramanmaras, Turkey; 7Laboratory of Molecular Genetics, Medical Faculty, Dicle University, Diyarbakır, Turkey Abstract: Migraine is one of the most common neurological diseases worldwide. Migraine pathophysiology is very complex. Genetic factors play a major role in migraine. Neurotrophic factors, such as brain-derived neurotrophic factor (BDNF and nerve growth factor (NGF, play an important role in central nervous system functioning, development, and modulation of pain. This study investigates whether polymorphisms in the BDNF and NGF genes are associated with migraine disease in a Turkish case–control population. Overall, 576 subjects were investigated (288 patients with migraine and 288 healthy controls for the following polymorphisms: rs6265(G/A, rs8192466(C/T, rs925946(G/T, rs2049046(A/T, and rs12273363(T/C in the BDNF gene, and rs6330(C/T, rs11466112(C/T, rs11102930(C/A, and rs4839435(G/A in the NGF gene using 5'-exonuclease allelic discrimination assays. We found no differences in frequency of the analyzed eight polymorphisms between migraine and control groups. However, the frequency of minor A alleles of rs6265 in BDNF gene was borderline significant in the patients compared with the healthy controls (P=0.049; odds ratios [ORs] [95% confidence intervals {CIs}] =0.723 [0.523–0.999]. Moreover, when the migraine patients were divided into two subgroups, migraine with aura (MA and migraine without aura (MO, the

  5. Developmental traumatic brain injury decreased brain derived neurotrophic factor expression late after injury.

    Science.gov (United States)

    Schober, Michelle Elena; Block, Benjamin; Requena, Daniela F; Hale, Merica A; Lane, Robert H

    2012-06-01

    Pediatric traumatic brain injury (TBI) is a major cause of acquired cognitive dysfunction in children. Hippocampal Brain Derived Neurotrophic Factor (BDNF) is important for normal cognition. Little is known about the effects of TBI on BDNF levels in the developing hippocampus. We used controlled cortical impact (CCI) in the 17 day old rat pup to test the hypothesis that CCI would first increase rat hippocampal BDNF mRNA/protein levels relative to SHAM and Naïve rats by post injury day (PID) 2 and then decrease BDNF mRNA/protein by PID14. Relative to SHAM, CCI did not change BDNF mRNA/protein levels in the injured hippocampus in the first 2 days after injury but did decrease BDNF protein at PID14. Surprisingly, BDNF mRNA decreased at PID 1, 3, 7 and 14, and BDNF protein decreased at PID 2, in SHAM and CCI hippocampi relative to Naïve. In conclusion, TBI decreased BDNF protein in the injured rat pup hippocampus 14 days after injury. BDNF mRNA levels decreased in both CCI and SHAM hippocampi relative to Naïve, suggesting that certain aspects of the experimental paradigm (such as craniotomy, anesthesia, and/or maternal separation) may decrease the expression of BDNF in the developing hippocampus. While BDNF is important for normal cognition, no inferences can be made regarding the cognitive impact of any of these factors. Such findings, however, suggest that meticulous attention to the experimental paradigm, and possible inclusion of a Naïve group, is warranted in studies of BDNF expression in the developing brain after TBI.

  6. Effects of the neurotrophic factor artemin on sensory afferent development and sensitivity

    Institute of Scientific and Technical Information of China (English)

    Shuying WANG; Christopher M. Elitt; Sacha A. Malin; Kathryn M. Albers

    2008-01-01

    Artemin is a neuronal survival and differentiation factor in the glial cell line-derived neurotrophic factor family. Its receptor GFRα3 is expressed by a subpopulation of nociceptor type sensory neurons in the dorsal root and trigeminal ganglia (DRG and TG). These neurons co-express the heat, capsaicin and proton-sensitive channel TRPV 1 and the cold and chemical-sensitive channel TRPA1. To further investigate the effects of artemin on sensory neurons, we isolated transgenic mice (ARTN-OE mice) that overexpress artemin in keratinocytes of the skin and tongue. Enhanced levels of artemin led to a 20% increase in the total number of DRG neurons and increases in the level of mRNA encoding TRPV1 and TRPAI. Calcium imaging showed that isolated sensory neurons from ARTN-OE mice were hypersensitive to the TRPV 1 agonist capsaicin and the TRPA1 agonist mustard oil. Behavioral testing of ARTN-OE mice also showed an increased sensitivity to heat, cold, capsaicin and mustard oil stimuli applied either to the skin or in the drinking water. Sensory neurons from wildtype mice also exhibited potentiated capsaicin responses following artemin addition to the media. In addition, injection of artemin into hindpaw skin produced transient thermal hyperalgesia. These findings indicate that artemin can modulate sensory function and that this regulation may occur through changes in channel gene expression. Because artemin mRNA expression is up-regulated in inflamed tissue and following nerve injury, it may have a significant role in cellular changes that underlie pain associated with pathological conditions. Manipulation of artemin expression may therefore offer a new pain treatment strategy.

  7. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain.

    Science.gov (United States)

    Trang, Tuan; Beggs, Simon; Salter, Michael W

    2011-02-01

    One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia-neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia-neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia-neuron interactions in the pathobiology of neuropathic pain.

  8. New function of the adaptor protein SH2B1 in brain-derived neurotrophic factor-induced neurite outgrowth.

    Directory of Open Access Journals (Sweden)

    Chien-Hung Shih

    Full Text Available Neurite outgrowth is an essential process for the establishment of the nervous system. Brain-derived neurotrophic factor (BDNF binds to its receptor TrkB and regulates axonal and dendritic morphology of neurons through signal transduction and gene expression. SH2B1 is a signaling adaptor protein that regulates cellular signaling in various physiological processes. The purpose of this study is to investigate the role of SH2B1 in the development of the central nervous system. In this study, we show that knocking down SH2B1 reduces neurite formation of cortical neurons whereas overexpression of SH2B1β promotes the development of hippocampal neurons. We further demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth and signaling using the established PC12 cells stably expressing TrkB, SH2B1β or SH2B1β mutants. Our data indicate that overexpressing SH2B1β enhances BDNF-induced MEK-ERK1/2, and PI3K-AKT signaling pathways. Inhibition of MEK-ERK1/2 and PI3K-AKT pathways by specific inhibitors suggest that these two pathways are required for SH2B1β-promoted BDNF-induced neurite outgrowth. Moreover, SH2B1β enhances BDNF-stimulated phosphorylation of signal transducer and activator of transcription 3 at serine 727. Finally, our data indicate that the SH2 domain and tyrosine phosphorylation of SH2B1β contribute to BDNF-induced signaling pathways and neurite outgrowth. Taken together, these findings demonstrate that SH2B1β promotes BDNF-induced neurite outgrowth through enhancing pathways involved MEK-ERK1/2 and PI3K-AKT.

  9. Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting.

    Science.gov (United States)

    Reibel, S; Vivien-Roels, B; Lê, B T; Larmet, Y; Carnahan, J; Marescaux, C; Depaulis, A

    2000-02-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal neuroplasticity. In particular, BDNF upregulation in the hippocampus by epileptic seizures suggests its involvement in the neuronal rearrangements accompanying epileptogenesis. We have shown previously that chronic infusion of BDNF in the hippocampus induces a long-term delay in hippocampal kindling progression. Although BDNF has been shown to enhance the excitability of this structure upon acute application, long-term transcriptional regulations leading to increased inhibition within the hippocampus may account for its suppressive effects on epileptogenesis. Therefore, the long-term consequences of a 7-day chronic intrahippocampal infusion of BDNF (12 microg/day) were investigated up to 2 weeks after the end of the infusion, on the expression of neurotransmitters contained in inhibitory hippocampal interneurons and which display anti-epileptic properties. Our results show that BDNF does not modify levels of immunostaining for glutamic acid decarboxylase, the rate-limiting enzyme for gamma-aminobutyric acid (GABA) synthesis, and somatostatin. Conversely, BDNF induces a long-lasting increase of neuropeptide Y (NPY) in the hippocampus, measured by immunohistochemistry and radioimmunoassay, outlasting the end of the infusion by at least 7 days. The distribution of BDNF-induced neuropeptide Y immunoreactivity is similar to the pattern observed in animals submitted to hippocampal kindling, with the exception of mossy fibres which only become immunoreactive following seizure activity. The enduring increase of neuropeptide Y expression induced by BDNF in the hippocampus suggests that this neurotrophin can trigger long-term genomic effects, which may contribute to the neuroplasticity of this structure, in particular during epileptogenesis.

  10. Postsynaptic action of brain-derived neurotrophic factor attenuates alpha7 nicotinic acetylcholine receptor-mediated responses in hippocampal interneurons.

    Science.gov (United States)

    Fernandes, Catarina C; Pinto-Duarte, António; Ribeiro, Joaquim Alexandre; Sebastião, Ana M

    2008-05-21

    Nicotinic mechanisms acting on the hippocampus influence attention, learning, and memory and constitute a significant therapeutic target for many neurodegenerative, neurological, and psychiatric disorders. Here, we report that brain-derived neurotrophic factor (BDNF) (1-100 ng/ml), a member of the neurotrophin gene family, rapidly decreases alpha7 nicotinic acetylcholine receptor responses in interneurons of the hippocampal CA1 stratum radiatum. Such effect is dependent on the activation of the TrkB receptor and involves the actin cytoskeleton; noteworthy, it is compromised when the extracellular levels of the endogenous neuromodulator adenosine are reduced with adenosine deaminase (1 U/ml) or when adenosine A(2A) receptors are blocked with SCH 58261 (2-(2-furanyl)-7-(2-phenylethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine) (100 nm). The intracellular application of U73122 (1-[6[[(17beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione) (5 mum), a broad-spectrum inhibitor of phospholipase C, or GF 109203X (bisindolylmaleimide I) (2 mum), a general inhibitor of protein kinase C isoforms, blocks BDNF-induced inhibition of alpha7 nicotinic acetylcholine receptor function. Moreover, in conditions of simultaneous intracellular dialysis of the fast Ca(2+) chelator BAPTA (10 mm) and removal of extracellular Ca(2+) ions, the inhibitory action of BDNF is further prevented. The present findings disclose a novel target for rapid actions of BDNF that might play important roles on synaptic transmission and plasticity in the brain.

  11. MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression.

    Science.gov (United States)

    Maheu, M; Lopez, J P; Crapper, L; Davoli, M A; Turecki, G; Mechawar, N

    2015-02-17

    Although multiple studies have reported that peripheral glial cell line-derived neurotrophic factor (GDNF) is reduced in depression, cerebral GDNF signalling has yet to be examined in this condition. Here, we report an isoform-specific decrease in GDNF family receptor alpha 1 (GFRA1) mRNA expression, resulting in lowered GFRα1a protein levels in basolateral amygdala (BLA) samples from depressed subjects. Downregulation of GFRα1a was associated with increased expression of microRNAs, including miR-511, predicted to bind to long 3' untranslated region (3'-UTR)-containing transcripts (GFRA1-L) coding for GFRα1a. Transfection of human neural progenitor cells (NPCs) with a miR-511 mimic was sufficient to repress GFRA1-L/GFRα1a without altering GFRα1b, and resulted in pathway-specific changes in immediate early gene activity. Unexpectedly, GFRα1a knockdown did not reduce NPC responses to GDNF. Rather, it greatly enhanced mitogen-activated protein kinase signalling. This effect appeared to be mediated by GDNF/soluble GFRα1/neural cell adhesion molecule binding, and substituting the soluble GFRα1a/GFRα1b content of miR-511-transfected NPCs with that of controls rescued signalling. In light of previous reports suggesting that GFRα1b can inhibit GFRα1a-induced neuroplasticity, we also assessed the association between GFRα1 and doublecortin (DCX; a hyperplastic marker) in human BLA. Although controls displayed coordinated expression of GFRα1a and b isoforms and these correlated positively with DCX, the only significant association observed among depressed subjects was a strongly negative correlation between GFRα1b and DCX. Taken together, these results suggest that microRNA-mediated reductions of GFRα1a in depression change the quality, rather than the quantity, of GDNF signalling. They also suggest that central GDNF signalling may represent a novel target for antidepressant treatment.

  12. Imipramine activates glial cell line-derived neurotrophic factor via early growth response gene 1 in astrocytes.

    Science.gov (United States)

    Kim, Yeni; Kim, Se Hyun; Kim, Yong Sik; Lee, Young Han; Ha, Kyooseob; Shin, Soon Young

    2011-06-01

    Recent evidence has suggested that deficits in glial plasticity contribute to the pathophysiology of depressive disorders. The present study explored early growth response 1 (EGR-1) transcriptional regulation of imipramine-induced glial cell line-derived neurotrophic factor (GDNF) expression in astrocytes. After we observed the induction of GDNF mRNA expression in rat astrocytes in response to imipramine, deletion mutant studies showed that the proximal region between -493 and -114 of the GDNF promoter, which contains three binding sites for EGR-1, was essential for maximal imipramine-induced activation of GDNF promoter. The dose-dependent upregulation of EGR-1 by imipramine, the activation of GDNF by the over-expression of EGR-1 without imipramine and the reduction in the imipramine-induced GDNF mRNA expression after silencing of endogenous EGR-1 demonstrated that EGR-1 is upregulated by imipramine to activate the GDNF promoter. Furthermore, imipramine-induced GDNF mRNA expression was strongly attenuated in primary astrocytes from Egr-1(-/-) mice, and the immunoreactivity to an anti-GDNF antibody in glial fibrillary acidic protein-positive cells was lower in imipramine-treated astrocytes from Egr-1(-/-) mice than in those from Egr-1(+/-) mice. To determine whether mitogen-activated protein kinases (MAPKs) were associated with imipramine-induced EGR-1 expression, we examined the induction of MAPK phosphorylation in response to imipramine. Pretreatment of rat primary astrocytes with the MAPK kinase inhibitor U0126 or the JNK inhibitor SP600125 strongly inhibited imipramine-stimulated EGR-1 expression. In conclusion, we found that imipramine induction of EGR-1 upregulated GDNF in astrocytes in a dose-dependent manner. This upregulation may occur through the MEK/ERK and JNK MAPK pathways, which suggests a new therapeutic mechanism of action for depressive disorders.

  13. Agmatine promotes expression of brain-derived neurotrophic factor in brainstem facial nucleus in the rat facial nerve injury model

    Institute of Scientific and Technical Information of China (English)

    Li Fang; Wenlong Luo

    2008-01-01

    BACKGROUND: Studies have shown that agmatine can reduce inhibition of neuronal regeneration by increasing cyclic adenosine monophosphate and brain-derived neurotrophic factor (BDNF) in the hippocampus of morphine-dependent rats. The hypothesis that agmatine exerts similar effects on facial nerve injury deserves further analysis.OBJECTIVE: To study the effects of peritoneal agmatine injection on BDNF levels in the rat brainstem after facial nerve injury.DESIGN, TIME AND SETTING: A controlled animal experiment was performed at the Department of Otolaryngology-Head and Neck Surgery at the Second Affiliated Hospital, Chongqing University of Medical Sciences (Chongqing, China), between October and December in 2007.MATERIALS: Twenty-four male Sprague-Dawley rats were randomly divided into a control, a lesion, and an agmatine treatment group, with eight rats in each group. Bilateral facial nerve anastomosis was induced in the lesion and agmatine treatment groups, while the control group remained untreated. A rat BDNF Enzyme-linked immunosorbent assay kit was used to measure BDNF levels in the brainstem facial nucleus.METHODS: Starting on the day of lesion, the agmatine group received a peritoneal injection of 100 mg/kg agmatine, once per day, for a week, whereas rats in the lesion group received saline injections.MAIN OUTCOME MEASURES: BDNF levels in the brainstem containing facial nucleus were measured by ELISA.RESULTS: Twenty-four rats were included in the final analysis without any loss. Two weeks after lesion, BDNF levels were significantly higher in the lesion group than in the control group (P<0.01). A significant increase was noted in the agmatine group compared to the lesion group (P<0.01).CONCLUSION: Agmatine can substantially increase BDNF levels in the rat brainstem after facial nerve injury.

  14. Long-term protective effects of AAV9-mesencephalic astrocyte-derived neurotrophic factor gene transfer in parkinsonian rats.

    Science.gov (United States)

    Hao, Fei; Yang, Chun; Chen, Sha-Sha; Wang, Yan-Yan; Zhou, Wei; Hao, Qiang; Lu, Tao; Hoffer, Barry; Zhao, Li-Ru; Duan, Wei-Ming; Xu, Qun-Yuan

    2017-05-01

    Intrastriatal injection of mesencephalic astrocyte-derived neurotrophic factor (MANF) protein has been shown to provide neuroprotective and neurorestorative effects in a 6-hydroxydopamine (6-OHDA) - lesioned rat model of Parkinson's disease. Here, we used an adeno-associated virus serotype 9 (AAV9) vector to deliver the human MANF (hMANF) gene into the rat striatum 10days after a 6-OHDA lesion to examine long-term effects of hMANF on nigral dopaminergic neurons and mechanisms underlying MANF neuroprotection. Intrastriatal injection of AAV9-hMANF vectors led to a robust and widespread expression of the hMANF gene in the injected striatum up to 24weeks. Increased levels of hMANF protein were also detected in the ipsilateral substantia nigra. The hMANF gene transfer promoted the survival of nigral dopaminergic neurons, regeneration of striatal dopaminergic fibers and an upregulation of striatal dopamine levels, resulting in a long-term improvement of rotational behavior up to 16weeks after viral injections. By using SH-SY5Y cells, we found that intra- and extracellular application of MANF protected cells against 6-OHDA-induced toxicity via inhibiting the endoplasmic reticulum stress and activating the PI3K/Akt/mTOR pathway. Our results suggest that AAV9-mediated hMANF gene delivery into the striatum exerts long-term neuroprotective and neuroregenerative effects on the nigrostriatal dopaminergic system in parkinsonian rats, and provide insights into mechanisms responsible for MANF neuroprotection. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. 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

    -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...... numbers of tyrosine hydroxylase-positive neurons in the cultured VM tissue. We conclude that lipid-mediated gene transfer employed on embryonic pig VM explant cultures is a safe and effective method to improve survival of dopaminergic neurons and may become a valuable tool to improve allo...

  16. The Effects of 12 Weeks Regular Aerobic Exercise on Brain-derived Neurotrophic Factor and Inflammatory Factors in Juvenile Obesity and Type 2 Diabetes Mellitus

    OpenAIRE

    Lee, Sung Soo; Yoo, Jae Ho; Kang, Sung; Woo, Jin Hee; Shin, Ki Ok; Kim, Kwi Beak; Cho, Su Youn; Roh, Hee Tae; Kim, Young Il

    2014-01-01

    [Purpose] The purpose of this study was to investigate the effects of 12 weeks regular aerobic exercise on brain-derived neurotrophic factor (BDNF) and inflammatory factors in juvenile obesity and type 2 diabetes mellitus (T2DM). Obesity and T2DM, typically common among adults, have recently become more prevalent in the Korean juvenile population, affecting not only their lipid profiles and oxidant stress levels, but also their BDNF and inflammatory factor levels. [Subjects] This study enroll...

  17. Study of brain-derived neurotrophic factor gene transgenic neural stem cells in the rat retina

    Institute of Scientific and Technical Information of China (English)

    ZHOU Xue-mei; YUAN Hui-ping; WU Dong-lai; ZHOU Xin-rong; SUN Da-wei; LI Hong-yi; SHAO Zheng-bo

    2009-01-01

    Background Neural stem cells (NSCs) transplantation and gene therapy have been widely investigated for treating the cerebullar and myelonic injuries, however, studies on the ophthalmology are rare. The aim of this study was to investigate the migration and differentiation of brain-derived neurotrophic factor (BDNF) gene transgenic NSCs transplanted into the normal rat retinas. Methods NSCs were cultured and purified in vitro and infected with recombinant retrovirus pLXSN-BDNF and pLXSN respectively, to obtain the BDNF overexpressed NSCs (BDNF-NSCs) and control cells (p-NSCs). The expression of BDNF genes in two transgenic NSCs and untreated NSCs were measured by fluorescent quantitative polymerase chain reaction (FQ-PCR) and enzyme-linked immunosorbent assay (ELISA). BDNF-NSCs and NSCs were infected with adeno-associated viruses-enhanced green fluorescent protein (AAV-EGFP) to track them in vivo and served as donor cells for transplantation into the subretinal space of normal rat retinas, phosphated buffer solution (PBS) served as pseudo transplantation for a negative control. Survival, migration, and differentiation of donor cells in host retinas were observed and analyzed with Heidelberg retina angiograph (HRA) and immunohistochemistry, respectively. Results NSCs were purified successfully by limiting dilution assay. The expression of BDNF gene in BDNF-NSCs was the highest among three groups both at mRNA level tested by FQ-PCR (P<0.05) and at protein level measured by ELISA (P<0.05), which showed that BDNF was overexpressed in BDNF-NSCs. The results of HRA demonstrated that graft cells could survive well and migrate into the host retinas, while the immunohistochemical analysis revealed that transplanted BDNF-NSCs differentiated into neuron more efficiently compared with the control NSCs 2 months after transplantation. Conclusions The seed cells of NSCs highly secreting BDNF were established. BDNF can promote NSCs to migrate and differentiate into neural cells in

  18. The relationship between serum brain-derived neurotrophic factor (BDNF) and cardiometabolic indices in schizophrenia.

    Science.gov (United States)

    Nurjono, Milawaty; Tay, Yi Hang; Lee, Jimmy

    2014-08-01

    Brain derived neurotrophic factor (BDNF), which has been implicated in the pathogenesis of schizophrenia, has been recently shown to be involved in the regulation of metabolism and energy homeostasis. This study seeks to examine the relationship between BDNF, metabolic indices and cardiovascular (CVD) risk in patients with schizophrenia. Medical histories, demographic information and anthropometric measurements were collected and analyzed from 61 participants with schizophrenia. Fasting glucose and lipids were measured in a central laboratory, and serum BDNF was analyzed using commercially available enzyme-linked immunosorbent assay (ELISA). The 10-year CVD risk for each participant was computed using the Framingham risk score (FRS). Linear regressions were performed to examine the relationships between serum BDNF with body mass index (BMI), blood pressure (BP), triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C) and glucose. To examine the relationship between serum BDNF and FRS, serum BDNF was categorized into quartiles, and a multiple regression was performed. After adjusting for age, gender and current smoking status, diastolic BP (dBP) (p=0.045) and TG (p=0.015) were found to be significantly associated with serum BDNF. Participants in the highest quartile of serum BDNF had a 3.3 times increase in FRS over those in the lowest quartile. Our findings support the possible regulatory role of BDNF in metabolism and cardiovascular homeostasis among patients with schizophrenia similar to that observed among the non-mentally ill. Serum BDNF not only present itself as a candidate biomarker of schizophrenia but also might be a viable marker of metabolic co-morbidities associated with schizophrenia.

  19. Inflammation and activity augment brain-derived neurotrophic factor peripheral release.

    Science.gov (United States)

    Qiao, L Y; Shen, S; Liu, M; Xia, C; Kay, J C; Zhang, Q L

    2016-03-24

    Brain-derived neurotrophic factor (BDNF) release to nerve terminals in the central nervous system is crucial in synaptic transmission and neuronal plasticity. However, BDNF release peripherally from primary afferent neurons has not been investigated. In the present study, we show that BDNF is synthesized by primary afferent neurons located in the dorsal root ganglia (DRG) in rat, and releases to spinal nerve terminals in response to depolarization or visceral inflammation. In two-compartmented culture that separates DRG neuronal cell bodies and spinal nerve terminals, application of 50mM K(+) to either the nerve terminal or the cell body evokes BDNF release to the terminal compartment. Inflammatory stimulation of the visceral organ (e.g. the urinary bladder) also facilitates an increase in spontaneous BDNF release from the primary afferent neurons to the axonal terminals. In the inflamed viscera, we show that BDNF immunoreactivity is increased in nerve fibers that are immuno-positive to the neuronal marker PGP9.5. Both BDNF and pro-BDNF levels are increased, however, pro-BDNF immunoreactivity is not expressed in PGP9.5-positive nerve-fiber-like structures. Determination of receptor profiles in the inflamed bladder demonstrates that BDNF high affinity receptor TrkB and general receptor p75 expression levels are elevated, with an increased level of TrkB tyrosine phosphorylation/activity. These results suggest a possibility of pro-proliferative effect in the inflamed bladder. Consistently we show that the proliferation marker Ki67 expression levels are enhanced in the inflamed organ. Our results imply that in vivo BDNF release to the peripheral organ is an important event in neurogenic inflammatory state.

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

    Directory of Open Access Journals (Sweden)

    Yunita Fediani

    2014-11-01

    Full Text Available 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 regular aerobic exercise on urinary BDNF levels in children. Methods This clinical study was performed in 67 children aged 6-8 years in Palembang. The intervention group (n=34 engaged in aerobic gymnastics three times per week for 8 weeks, while the control group (n=33 engaged in gymnastic only once per week. Measurements of urinary BDNF were performed on both groups before and after intervention. Mann-Whitney and Wilcoxon rank tests were used to analyze the differences between groups. Results There was no difference in urinary BDNF levels between the two groups prior to the intervention. After intervention, the mean urinary BDNF levels were significantly higher in the intervention group than in the control group, 230.2 (SD 264.4 pg/mL vs. 88.0 (SD 35.4 pg/mL, respectively (P=0.027. We also found that engaging in aerobic gymnastics significantly increased urinary BDNF levels from baseline in both groups (P=0.001. Conclusion Regular aerobic exercise can increase urinary BDNF levels and potentially improve cognitive function. Aerobic exercise should be a routine activity in school curriculums in combination with the learning process to improve children’s cognitive ability.[Paediatr Indones. 2014;54:351-7.].

  1. 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.

  2. Association between smoking behaviour and genetic variants of glial cell line-derived neurotrophic factor

    Indian Academy of Sciences (India)

    ESZTER KOTYUK; NORA NEMETH; ZSOLT RONAI; ZSOLT DEMETROVICS; MARIA SASVARI-SZEKELY; ANNA SZEKELY

    2016-12-01

    Glial cell line-derived neurotrophic factor (GDNF) promotes development and differentiation of dopaminergic neurons, thus it has an important role in dopamine-related neuropsychiatric disorders. Since the role of dopamine system in smoking iswell established, we hypothesized that GDNF gene variants may affect smoking behaviour. Self-reported data on smoking behaviour (never smoked, quit, occasional, or regular smokers) and level of nicotine addiction (Hooked on Nicotine Checklist and Fagerstrom Nicotine Addiction Scale), anxiety, as well as buccal samples were obtained from 930 Hungarian young adults (18–35 years). Genetic analysis involved eight GDNF single-nucleotide polymorphisms (SNP) (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111). Allele-wise association analyses of the eight GDNF SNPs provided a significant association between smoking behaviour and rs3096140 (P = 0.0039). The minor allele (C) was more frequent in those groups who smoked in some form (quit, occasional or regular smokers) as compared to those who neversmoked (P = 0.0046). This result remained significant after Bonferroni correction for multiple testing. In the ever smoking group, no significant differences were found in the level of nicotine addiction by the alleles of these polymorphisms. Also, nosignificant interaction of rs3096140 and smoking categories were observed on anxiety mean scores. Although previous data demonstrated an association between GDNF rs2910704 and severity of methamphetamine use to the best of our knowledge, this is the first study on the role of GDNF genetic variations in smoking behaviour. Our results suggest that GDNF rs3096140 might be involved in the genetic background of smoking, independent of anxiety characteristics.

  3. Short term memory, physical fitness, and serum brain-derived neurotrophic factor in obese adolescents

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    Rini Rossanti

    2015-09-01

    Full Text Available Background Obesity in adolescents is a major health problem and has been associated with low academic achievement. Brain-derived neurotrophic factor (BDNF, a neurotrophin, plays a role in appetite suppression and memory, and its secretion is enhanced by physical activity. This neurotrophin may be associated with academic achievement in obese. Objective To compare physical fitness and serum BDNF levels to short term memory levels in obese adolescents aged 10–14 years. Methods This comparative, cross-sectional, analytic study was carried out on 40 elementary and high school students in Bandung, West Java, who were recruited by stratified random sampling. Short term memory was assessed by a psychologist using the Wechsler Intelligence Scale for Children-III Digit Span test (WISC-III Digit Span. Physical fitness was assessed by a clinical exercise physiologist using the Asian Committee on the Standardization of Physical Fitness Test (ACSPFT. Serum BDNF levels were measured by ELISA test in a certified laboratory. ANOVA test was used to assess for a correlation between serum BDNF concentration and short term memory, as well as between physical fitness level and short term memory. Pearson’s correlation test was used to analyze for a correlation between serum BDNF and physical fitness levels. Results The majority of subjects were in the physical fitness categories of moderate or poor. Subjects had a mean BDNF level of 44,227.8 (SD 10,359 pg/mL. There was no statistically significant difference in physical fitness with either serum BDNF or with short term memory levels (P=0.139 and P=0.383, respectively. Also, no correlation was determined between serum BDNF and physical fitness levels (r=0.222; P=0.169. Conclusion In obese adolescents, short term memory levels are not significantly different between physical fitness levels nor between serum BDNF levels.

  4. Short term memory, physical fitness, and serum brain-derived neurotrophic factor in obese adolescents

    Directory of Open Access Journals (Sweden)

    Rini Rossanti

    2015-10-01

    Full Text Available Background Obesity in adolescents is a major health problem and has been associated with low academic achievement. Brainderived neurotrophic factor (BDNF, a neurotrophin, plays a role in appetite suppression and memory, and its secretion is enhanced by physical activity. This neurotrophin may be associated with academic achievement in obese. Objective To compare physical fitness and serum BDNF levels to short term memory levels in obese adolescents aged 10–14 years. Methods This comparative, cross-sectional, analytic study was carried out on 40 elementary and high school students in Bandung, West Java, who were recruited by stratified random sampling. Short term memory was assessed by a psychologist using the Wechsler Intelligence Scale for Children-III Digit Span test (WISC-III Digit Span. Physical fitness was assessed by a clinical exercise physiologist using the Asian Committee on the Standardization of Physical Fitness Test (ACSPFT. Serum BDNF levels were measured by ELISA test in a certified laboratory. ANOVA test was used to assess for a correlation between serum BDNF concentration and short term memory, as well as between physical fitness level and short term memory. Pearson’s correlation test was used to analyze for a correlation between serum BDNF and physical fitness levels. Results The majority of subjects were in the physical fitness categories of moderate or poor. Subjects had a mean BDNF level of 44,227.8 (SD 10,359 pg/mL. There was no statistically significant difference in physical fitness with either serum BDNF or with short term memory levels (P=0.139 and P=0.383, respectively. Also, no correlation was determined between serum BDNF and physical fitness levels (r=0.222; P=0.169. Conclusion In obese adolescents, short term memory levels are not significantly different between physical fitness levels nor between serum BDNF levels.

  5. Human Immunodeficiency Virus-1 Alters Brain-derived Neurotrophic Factor Processing in neurons

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    Bachis, Alessia; Avdoshina, Valeriya; Zecca, Luigi; Parsadanian, Maia; Mocchetti, Italo

    2012-01-01

    The molecular mechanisms leading to synaptic simplification and neuronal apoptosis in human immunodeficiency virus type 1 (HIV) positive subjects are unknown. The HIV protein gp120 reduced the length of neuronal processes similarly to the proneurotrophin pro brain-derived neurotrophic factor (proBDNF). Intriguingly, the effects of both proBDNF and gp120 were blocked by inhibitors of the p75 neurotrophin receptor, suggesting that proBDNF and gp120 share a similar mechanism of neurotoxicity. Therefore, we tested the hypothesis that gp120 affects the release of proBDNF. Using rat primary neurons we observed that gp120 promotes a time-dependent intracellular and extracellular accumulation of proBDNF concomitantly with a decrease in mature BDNF. A similar imbalance in the ratio proBDNF/mature BDNF was confirmed in postmortem brains of HIV positive subjects cognitive and motor impaired. Therefore, it is conceivable to formulate the hypothesis that HIV neurotoxicity includes a gp120-mediated alteration of BDNF processing. To determine the cellular mechanism whereby gp120 produces an accumulation of proBDNF, we examined the levels of intracellular and extracellular enzymes that proteolytically cleave proBDNF, furin and tissue plasminogen, respectively. In rat neurons exposed to gp120, intracellular furin levels decreased prior to cell death whereas tissue plasminogen changed only during apoptosis. Our data suggest that HIV, through gp120, reduces proBDNF processing by affecting furin levels and therefore causes an altered balance between anti-apoptotic and pro-apoptotic neurotrophins. Our studies identify a new mechanism that may explain how HIV promotes neuronal injury. PMID:22787033

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

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    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.

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

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    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.

  8. Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier.

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    Peng, Yu-Shiang; Lai, Po-Liang; Peng, Sydney; Wu, His-Chin; Yu, Siang; Tseng, Tsan-Yun; Wang, Li-Fang; Chu, I-Ming

    2014-01-01

    Parkinson's disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF) have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood-brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI) is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI) and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol) of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively) by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810). This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA) polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson's disease.

  9. Dopamine receptor activation increases glial cell line-derived neurotrophic factor in experimental stroke.

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    Kuric, Enida; Wieloch, Tadeusz; Ruscher, Karsten

    2013-09-01

    Treatment with levodopa enhances functional recovery after experimental stroke but its mechanisms of action are elusive. Reactive astrocytes in the ischemic hemisphere are involved in mechanisms promoting recovery and also express dopamine 1 (D1) and dopamine 2 (D2) receptors. Here we investigated if the activation of astrocytic dopamine receptors (D1 and D2) regulates the expression of glial cell line-derived neurotrophic factor (GDNF) after combined in vitro hypoxia/aglycemia (H/A) and studied the expression of GDNF in the ischemic brain after treatment with levodopa/benserazide following transient occlusion of the middle cerebral artery (tMCAO) in the rat. Twenty-four hours after H/A, GDNF levels were upregulated in exposed astrocytes compared to normoxic control cultures and further elevated by the addition of the selective D1 receptor agonist (R)-(+)-SKF-38393 hydrochloride while D1 receptor antagonism by R(+)-SCH-23390 hydrochloride significantly reduced GDNF. No effect on GDNF levels was observed by the application of the D2 receptor agonist R(-)-2,10,11-trihydroxy-N-propyl-noraporphine hydrobromide hydrate or S-(-)-eticlopride hydrochloride (D2 receptor antagonist). After tMCAO, GDNF was upregulated in D1 expressing reactive astrocytes in the peri-infarct area. In addition, treatment with levodopa/benserazide significantly increased GDNF levels in the infarct core and peri-infarct area after tMCAO without affecting the expression of glial fibrillar acidic protein (GFAP), an intermediate filament and marker of reactive gliosis. After stroke, GDNF levels increase in the ischemic hemisphere in rats treated with levodopa, implicating GDNF in the mechanisms of tissue reorganization and plasticity and in l-DOPA enhanced recovery of lost brain function. Our results support levodopa treatment as a potential recovery enhancing therapy in stroke patients.

  10. Association between smoking behaviour and genetic variants of glial cell line-derived neurotrophic factor.

    Science.gov (United States)

    Kotyuk, Eszter; Nemeth, Nora; Ronai, Zsolt; Demetrovics, Zsolt; Sasvari-Szekely, Maria; Szekely, Anna

    2016-12-01

    Glial cell line-derived neurotrophic factor (GDNF) promotes development and differentiation of dopaminergic neurons, thus it has an important role in dopamine-related neuropsychiatric disorders. Since the role of dopamine system in smoking is well established, we hypothesized that GDNF gene variants may affect smoking behaviour. Self-reported data on smoking behaviour (never smoked, quit, occasional, or regular smokers) and level of nicotine addiction (Hooked on Nicotine Checklist and Fagerstrom Nicotine Addiction Scale), anxiety, as well as buccal samples were obtained from 930 Hungarian young adults (18-35 years). Genetic analysis involved eight GDNF single-nucleotide polymorphisms (SNP) (rs1981844, rs3812047, rs3096140, rs2973041, rs2910702, rs1549250, rs2973050 and rs11111). Allele-wise association analyses of the eight GDNF SNPs provided a significant association between smoking behaviour and rs3096140 (P=0.0039). The minor allele (C) was more frequent in those groups who smoked in some form (quit, occasional or regular smokers) as compared to those who never smoked (P = 0.0046). This result remained significant after Bonferroni correction for multiple testing. In the ever smoking group, no significant differences were found in the level of nicotine addiction by the alleles of these polymorphisms. Also, no significant interaction of rs3096140 and smoking categories were observed on anxiety mean scores. Although previous data demonstrated an association between GDNF rs2910704 and severity of methamphetamine use to the best of our knowledge, this is the first study on the role of GDNF genetic variations in smoking behaviour. Our results suggest that GDNF rs3096140 might be involved in the genetic background of smoking, independent of anxiety characteristics.

  11. The role of brain-derived neurotrophic factor and its single nucleotide polymorphisms in stroke patients.

    Science.gov (United States)

    Kotlęga, Dariusz; Peda, Barbara; Zembroń-Łacny, Agnieszka; Gołąb-Janowska, Monika; Nowacki, Przemysław

    2017-03-06

    Stroke is the main cause of motoric and neuropsychological disability in adults. Recent advances in research into the role of the brain-derived neurotrophic factor in neuroplasticity, neuroprotection and neurogenesis might provide important information for the development of new poststroke-rehabilitation strategies. It plays a role as a mediator in motor learning and rehabilitation after stroke. Concentrations of BDNF are lower in acute ischemic-stroke patients compared to controls. Lower levels of BDNF are correlated with an increased risk of stroke, worse functional outcomes and higher mortality. BDNF signalling is dependent on the genetic variation which could affect an individual's response to recovery after stroke. Several single nucleotide polymorphisms of the BDNF gene have been studied with regard to stroke patients, but most papers analyse the rs6265 which results in a change from valine to methionine in the precursor protein. Subsequently a reduction in BDNF activity is observed. There are studies indicating the role of this polymorphism in brain plasticity, functional and morphological changes in the brain. It may affect the risk of ischemic stroke, post-stroke outcomes and the efficacy of the rehabilitation process within physical exercise and transcranial magnetic stimulation. There is a consistent trend of Met alleles' being connected with worse outcomes and prognoses after stroke. However, there is no satisfactory data confirming the importance of Met allele in stroke epidemiology and the post-stroke rehabilitation process. We present the current data on the role of BDNF and polymorphisms of the BDNF gene in stroke patients, concentrating on human studies.

  12. High voltage electric potentials to enhance brain-derived neurotrophic factor levels in the brain.

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    Yanamoto, Hiroji; Nakajo, Yukako; Kataoka, Hiroharu; Iihara, Koji

    2013-01-01

    Development of a safe method to increase brain-derived neurotrophic factor (BDNF) levels in the brain is expected to enhance learning and memory, induce tolerance to cerebral infarction or tolerance to depressive state, improve glucose metabolism, and suppress appetite and body weight. We have shown that repetitive applications of high-voltage electric potential (HELP) to the body increase BDNF levels in the brain, improving learning and memory in mice. Here, we investigated the effects of HELP treatment for a chronic period on the BDNF levels in the mouse brain, and on body weight in mice and humans. Adult mice were exposed to 3.1 or 5.4 kV HELP (on the body), 5 h a day for 24 weeks, and BDNF levels in the brain and alterations in body weight were analyzed. Humans [age, 53.2 ± 15.5 years old; BMI, 27.8 ± 5.6 (mean ± SD, n = 6)] were exposed to 3.9 kV HELP (on the body) for 1 h a day, continuing for 33 months (2.8 years) under the monitor of body weight. In mice, the HELP application elevated BDNF levels in the brain at least temporarily, affecting body weight in a voltage- and time-dependent manner. In humans, the HELP treatment reduced body weight compared to the pretreated initial values without any aversive effects (p BDNF, and 5.4 kV HELP was considered as excessive. HELP with an appropriate voltage can be utilized to increase BDNF levels in the brain for a prolonged period. We anticipate further investigations to clarify the effect of the optimal-leveled HELP therapy on memory disturbances, neurological deficits after stroke, depression, diabetes, obesity and metabolic syndrome.

  13. Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Robyn A Honea

    Full Text Available There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF, may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs impact Alzheimer's Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer's Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154 who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met, rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459. We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108. No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850. We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD

  14. Imipramine ameliorates pain-related negative emotion via induction of brain-derived neurotrophic factor.

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    Yasuda, Seiko; Yoshida, Mitsuhiro; Yamagata, Hirotaka; Iwanaga, Yasutake; Suenaga, Hiromi; Ishikawa, Kozo; Nakano, Masako; Okuyama, Satoshi; Furukawa, Yoshiko; Furukawa, Shoei; Ishikawa, Toshizo

    2014-11-01

    Depression-like behavior is often complicated by chronic pain. Antidepressants including imipramine (IMI) are widely used to treat chronic pain, but the mechanisms are not fully understood. Brain-derived neurotrophic factor (BDNF) is a neuromodulator that reduces depression by regulating synaptic transmission. We aimed to characterize the antidepressant effects of IMI without analgesia based on BDNF (trkB)-mediated signaling and gene expression in chronic pain. A chronic constriction injury (CCI) model was constructed in Sprague-Dawley (SD) rats. IMI (5 mg/kg, i.p.) was administered from day 10 after CCI. The pain response was assessed using the paw withdrawal latency (PWL) and depression was judged from the immobility time in a forced swim test. Anti-BDNF antibody, K252a, or 5,7-dihydroxytryptamine (5,7-DHT) were used to examine the antidepressant effects of imipramine. Changes in pERK1/2 (immunohistochemistry), 5-HT and BDNF (ELISA), and BDNF mRNA (RT-PCR) were measured in the anterior cingulate cortex (ACC), rostral ventromedial medulla (RVM), and spinal cord. After CCI, rats showed decreased PWL and increased immobility time. A low dose of IMI reduced the immobility time without having analgesic effects. This antidepressant effect was reversed by anti-BDNF antibody, K252a, and 5,7-DHT. IMI reduced excessive activation of pERK1/2 associated with decreased pCREB and BDNF mRNA, and these changes were reversed by 5,7-DHT. These results show that IMI reduces pain-related negative emotion without influencing pain and that this effect is diminished by denervation of 5-HT neurons and by anti-BDNF treatment. IMI also normalizes derangement of ERK/CREB coupling, which leads to induction of BDNF. This suggests a possible interaction between 5-HT and BDNF.

  15. Brain-derived neurotrophic factor and substrate utilization following acute aerobic exercise in obese individuals.

    Science.gov (United States)

    Slusher, A L; Whitehurst, M; Zoeller, R F; Mock, J T; Maharaj, A; Huang, C-J

    2015-05-01

    Brain-derived neurotrophic factor (BDNF) serves as a vital regulator of neuronal proliferation and survival, and has been shown to regulate energy homeostasis, glucose metabolism and body weight maintenance. Elevated concentrations of plasma BDNF have been associated with obesity and type 2 diabetes mellitus. Acute aerobic exercise transiently increases circulating BDNF, potentially correcting obesity-related metabolic impairment. The present study aimed to compare acute aerobic exercise elicited BDNF responses in obese and normal-weight subjects. Furthermore, we aimed to investigate whether acute exercise-induced plasma BDNF elevations would be associated with improved indices of insulin resistance, as well as substrate utilization [carbohydrate oxidation (CHOoxi) and fat oxidation (FAToxi)]. Twenty-two healthy, untrained subjects [11 obese (four men and seven women; age = 22.91 ± 4.44 years; body mass index = 35.72 ± 4.17 kg/m(2)) and 11 normal-weight (five men and six women; age = 23.27 ± 2.24 years; body mass index = 21.89 ± 1.63 kg/m(2))] performed 30 min of continuous submaximal aerobic exercise at 75% maximal oxygen consumption. Our analyses showed that the BDNF response to acute aerobic exercise was similar in obese and normal-weight subjects across time (time: P = 0.015; group: P = not significant) and was not associated with indices of IR. Although no differences in the rates of CHOoxi and FAToxi were found between both groups, total relative energy expenditure was significantly lower in obese subjects compared to normal-weight subjects (3.53 ± 0.25 versus 5.59 ± 0.85; P exercise-elicited BDNF elevation may not be sufficient to modulate indices of IR or the utilization of either carbohydrates or fats in obese individuals.

  16. Expression of brain-derived neurotrophic factor in rat hippocampus following focal cerebral ischemic injury

    Institute of Scientific and Technical Information of China (English)

    Yingping Li; Ruifang Guo; Kaifeng Lu

    2008-01-01

    BACKGROUND: The functional role of brain-derived neurotrophic factor (BDNF) is enhanced following cerebral ischemic injury providing neurons with an important self-protection mechanism in early stage ischemia/hypoxia.OBJECTIVE: To investigate the expression pattern of BDNF in different rat hippocampal regions following focal cerebral ischemic injury.DESIGN, TIME AND SETTING: We performed a comparative and neurobiological study of animals in the Department of Histology and Embryology and the Central Laboratory, Hebei Medical University from March to December 2003.MATERIALS: Forty healthy Sprague Dawley rats were randomly divided into a cerebral ischemla group and a sham operation group, with 20 rats per group.METHODS: In the cerebral ischemia group, we occluded the right middle cerebral artery with a suture,threading it to a depth of 17-19 mm. In the sham operation group, the threading depth was approximately 10 mm.MAIN OUTCOME MEASURES: We analyzed the expression of BDNF in different hippocampal regions by immunohistochemical staining of brain sections taken on post-operative days 7, 14, 21 and 30.RESULTS: Sham operation group: We observed a number of a few BDNF-positive cells with light staining in the hippocampal CAI CA4 regions and dentate gyrus. Cerebral ischemia group: compared with the sham operation group, BDNF increased on day 7, significantly increased on day 14, and reached a peak on day 21 (P < 0.05). Furthermore, immunologically reactive products were darkly stained, and neurons had long axons.BDNF was particularly highly expressed in the hippocampal CA3 and CA4 regions and dentate gyrus.CONCLUSION: Cerebral ischemic injury can damage hippocampal neurons. Neurons can increase their anti-ischemic capacity by increasing BDNF expression in the hippocampal CA3 and CA4 regions and dentate gyrus.

  17. Effects of multiparity on recognition memory, monoaminergic neurotransmitters, and brain-derived neurotrophic factor (BDNF).

    Science.gov (United States)

    Macbeth, Abbe H; Scharfman, Helen E; Maclusky, Neil J; Gautreaux, Claris; Luine, Victoria N

    2008-06-01

    Recognition memory and anxiety were examined in nulliparous (NP: 0 litters) and multiparous (MP: 5-6 litters) middle-aged female rats (12 months old) to assess possible enduring effects of multiparity at least 3 months after the last litter was weaned. MP females performed significantly better than NP females on the non-spatial memory task, object recognition, and the spatial memory task, object placement. Anxiety as measured on the elevated plus maze did not differ between groups. Monoaminergic activity and levels were measured in prefrontal cortex, CA1 hippocampus, CA3 hippocampus, and olfactory bulb (OB). NP and MP females differed in monoamine concentrations in the OB only, with MP females having significantly greater concentrations of dopamine and metabolite DOPAC, norepinephrine and metabolite MHPG, and the serotonin metabolite 5-HIAA, as compared to NP females. These results indicate a long-term change in OB neurochemistry as a result of multiparity. Brain-derived neurotrophic factor (BDNF) was also measured in hippocampus (CA1, CA3, dentate gyrus) and septum. MP females had higher BDNF levels in both CA1 and septum; as these regions are implicated in memory performance, elevated BDNF may underlie the observed memory task differences. Thus, MP females (experiencing multiple bouts of pregnancy, birth, and pup rearing during the first year of life) displayed enhanced memory task performance but equal anxiety responses, as compared to NP females. These results are consistent with previous studies showing long-term changes in behavioral function in MP, as compared to NP, rats and suggest that alterations in monoamines and a neurotrophin, BDNF, may contribute to the observed behavioral changes.

  18. Altered regulation of brain-derived neurotrophic factor protein in hippocampus following slice preparation.

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    Danzer, S C; Pan, E; Nef, S; Parada, L F; McNamara, J O

    2004-01-01

    Brain-derived neurotrophic factor (BDNF) and its cognate receptor tyrosine kinase B (TrkB) play important roles in regulating survival, structure, and function of CNS neurons. One method of studying the functions of these molecules has utilized in vitro hippocampal slice preparations. An important caveat to using slices, however, is that slice preparation itself might alter the expression of BDNF, thereby confounding experimental results. To address this concern, BDNF immunoreactivity was examined in rodent slices using two different methods of slice preparation. Rapid and anatomically selective regulation of BDNF content followed slice preparation using both methodologies; however, different patterns of altered BDNF immunoreactivity were observed. First, in cultured slices, BDNF content decreased in the dentate molecular layer and increased in the CA3 pyramidal cell layer and the mossy fiber pathway of the hippocampus after 30 min. Furthermore, an initially "punctate" pattern of BDNF labeling observed in the mossy fiber pathway of control sections changed to homogenous labeling of the pathway in vitro. In contrast to these findings, slices prepared as for acute slice physiology exhibited no change in BDNF content in the molecular layer and mossy fiber pathway 30 min after slicing, but exhibited significant increases in the dentate granule and CA3 pyramidal cell layers. These findings demonstrate that BDNF protein content is altered following slice preparation, that different methods of slice preparation produce different patterns of BDNF regulation, and raise the possibility that BDNF release and TrkB activation may also be regulated. These consequences of hippocampal slice preparation may confound analyses of exogenous or endogenous BDNF on hippocampal neuronal structure or function.

  19. Decreased plasma brain-derived neurotrophic factor levels in institutionalized elderly with depressive disorder.

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    Chu, Chin-Liang; Liang, Chih-Kuang; Chou, Ming-Yueh; Lin, Yu-Te; Pan, Chih-Chuan; Lu, Ti; Chen, Liang-Kung; Chow, Philip C

    2012-06-01

    To compare the differences in plasma brain-derived neurotrophic factor (BDNF) levels among institutionalized ethnic Chinese elderly participants with major depression, those with subclinical depression, and a nondepressed control group. A cross-sectional study. The veterans' home in southern Taiwan. One hundred sixty-seven residents. Questionnaires including the Minimum Data Set Nursing Home 2.1, Chinese-language version, and the short-form Geriatric Depression Scale, Chinese-language version. Depressive disorder was diagnosed by a well-trained psychiatrist using DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) criteria. We measured plasma BDNF levels in the following 3 groups: nondepressive subjects (n = 122), subclinically depressive subjects (n = 33), and subjects with major depression (n = 12). Plasma BDNF was assayed using the sandwich ELISA method. We noted a significantly negative association between age and plasma BDNF in the regression model. There was no significant correlation between BDNF plasma levels and body weight or platelet counts. We found that plasma BDNF was significantly lower in the major depressive group (mean, 115.1 pg/mL; SD, 57.2) than in the nondepressive group (mean, 548.8 pg/mL; SD, 370.6; P depressive group (mean, 231.8 pg/mL; SD, 92.4; P depressive disorder but also in those with subclinical depression. This makes the plasma BDNF level a potential biological marker for clinical or subclinical depression. Copyright © 2012 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.

  20. Genetic increase in brain-derived neurotrophic factor levels enhances learning and memory.

    Science.gov (United States)

    Nakajo, Yukako; Miyamoto, Susumu; Nakano, Yoshikazu; Xue, Jing-Hui; Hori, Takuya; Yanamoto, Hiroji

    2008-11-19

    Brain-derived neurotrophic factor (BDNF), a neurotrophin, is known to promote neuronal differentiation stimulating neurite outgrowth in the developing CNS, and is also known to modulate synaptic plasticity, thereby contributing to learning and memory in the mature brain. Here, we investigated the role of increased levels of intracerebral BDNF in learning and memory function. Using genetically engineered transgenic BDNF overexpressing mice (RTG-BDNF), young adult, homozygous (+/+), heterozygous (+/-), or wild-type (-/-) littermates, we analyzed escape latency to a hidden-platform and swimming velocity in the Morris Water Maze test (MWM) with modifications for the mice. The MWM comprised 4 trials per day over 5 consecutive days (sessions) without prior or subsequent training. In a separate set of animals, BDNF protein levels in the cortex, thalamostriatum and the hippocampus were measured quantitatively using ELISA. In the BDNF (+/-) mice, the BDNF levels in the cortex, the thalamostriatum and the hippocampus were significantly high, compared to the wild-type littermates; 238%, 158%, and 171%, respectively (PBDNF levels in the BDNF (+/+) mice were not elevated. The BDNF (+/-), but not the (+/+) mice, demonstrated significantly shorter escape latency, shorter total path length in the MWM, and more frequent arrivals at the location where the platform had been placed previously in the probe trial, compared with the wild-type littermates (PBDNF-transgenic mice, increased BDNF levels in the brain were found to enhance spatial learning and memory function. Although it has been postulated that excessive BDNF is deteriorating for neuronal survival or neurite outgrowth, further investigations are needed to clarify the mechanism of paradoxical lack of increase in BDNF levels in the (+/+) mouse brain.

  1. Correlation of brain-derived neurotrophic factor to cognitive impairment following traumatic brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    Dezhi Kang; Zhang Guo

    2008-01-01

    BACKGROUND: In vitro and in vivo studies have confirmed that brain-derived neurotrophic factor (BDNF) can promote survival and differentiation of cholinergic, dopaminergic and motor neurons, and axonal regeneration. BDNF has neuroprotective effects on the nervous system. OBJECTIVE: To explore changes in BDNF expression and cognitive function in rats after brain injury DESIGN, TIME AND SETTING: The neuropathology experiment was performed at the Second Research Room, Department of Neurosurgery, Fujian Medical University (China) from July 2007 to July 2008. MATERIALS: A total of 72 healthy, male, Sprague Dawley, rats were selected for this study. METHODS: Rat models of mild and moderate traumatic brain injury were created by percussion, according to Feeney's method (n = 24, each group). A bone window was made in rats from the sham operation group (n = 24), but no attack was conducted. MAIN OUTCOME MEASURES: At days 1,2, 4 and 7 following injury, BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was examined by immunohistochemistry (streptavidin-biotin-peroxidase complex method). Changes in rat cognitive function were assessed by the walking test, balance-beam test and memory function detection. RESULTS: Cognitive impairment was aggravated at day 2, and recovered to normal at days 3 and 7 in rats from the mild and moderate traumatic brain injury groups. BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain was increased at 1 day, decreased at day 2, and then gradually increased in the mild and moderate traumatic brain injury groups. BDNF expression was greater in rats from the moderate traumatic brain injury group than in the sham operation and mild traumatic brain injury groups (P < 0.05). CONCLUSION: BDNF expression in the rat frontal lobe cortex, hippocampus and basal forebrain is correlated to cognitive impairment after traumatic brain injury. BDNF has a protective effect on cognitive function in rats

  2. Both 5' and 3' flanks regulate Zebrafish brain-derived neurotrophic factor gene expression

    Directory of Open Access Journals (Sweden)

    Heinrich Gerhard

    2004-05-01

    Full Text Available Abstract Background Precise control of developmental and cell-specific expression of the brain-derived neurotrophic factor (BDNF gene is essential for normal neuronal development and the diverse functions of BDNF in the adult organism. We previously showed that the zebrafish BDNF gene has multiple promoters. The complexity of the promoter structure and the mechanisms that mediate developmental and cell-specific expression are still incompletely understood. Results Comparison of pufferfish and zebrafish BDNF gene sequences as well as 5' RACE revealed three additional 5' exons and associated promoters. RT-PCR with exon-specific primers showed differential developmental and organ-specific expression. Two exons were detected in the embryo before transcription starts. Of the adult organs examined, the heart expressed a single 5' exon whereas the brain, liver and eyes expressed four of the seven 5' exons. Three of the seven 5' exons were not detectable by RT-PCR. Injection of promoter/GFP constructs into embryos revealed distinct expression patterns. The 3' flank profoundly affected expression in a position-dependent manner and a highly conserved sequence (HCS1 present in 5' exon 1c in a dehancer-like manner. Conclusions The zebrafish BDNF gene is as complex in its promoter structure and patterns of differential promoter expression as is its murine counterpart. The expression of two of the promoters appears to be regulated in a temporally and/or spatially highly circumscribed fashion. The 3' flank has a position-dependent effect on expression, either by affecting transcription termination or post-transcriptional steps. HCS1, a highly conserved sequence in 5' exon 1c, restricts expression to primary sensory neurons. The tools are now available for detailed genetic and molecular analyses of zebrafish BDNF gene expression.

  3. Neuroprotection elicited by nerve growth factor and brain-derived neurotrophic factor released from astrocytes in response to methylmercury.

    Science.gov (United States)

    Takemoto, Takuya; Ishihara, Yasuhiro; Ishida, Atsuhiko; Yamazaki, Takeshi

    2015-07-01

    The protective roles of astrocytes in neurotoxicity induced by environmental chemicals, such as methylmercury (MeHg), are largely unknown. We found that conditioned medium of MeHg-treated astrocytes (MCM) attenuated neuronal cell death induced by MeHg, suggesting that astrocytes-released factors can protect neuronal cells. The increased expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) was observed in MeHg-treated astrocytes. NGF and BDNF were detected in culture media as homodimers, which are able to bind specific tyrosine kinase receptors, tropomyosin related kinase (Trk) A and TrkB, respectively. The TrkA antagonist and TrkB antagonist abolished the protective effects of MCM in neuronal cell death induced by MeHg. Taken together, astrocytes synthesize and release NGF and BDNF in response to MeHg to protect neurons from MeHg toxicity. This study is considered to show a novel defense mechanism against MeHg-induced neurotoxicity.

  4. Expression of neurotrophic factors in injured spinal cord after transplantation of human-umbilical cord blood stem cells in rats.

    Science.gov (United States)

    Chung, Hyo-jin; Chung, Wook-hun; Lee, Jae-Hoon; Chung, Dai-Jung; Yang, Wo-Jong; Lee, A-Jin; Choi, Chi-Bong; Chang, Hwa-Seok; Kim, Dae-Hyun; Suh, Hyun Jung; Lee, Dong-Hun; Hwang, Soo-Han; Do, Sun Hee; Kim, Hwi-Yool

    2016-03-01

    We induced percutaneous spinal cord injuries (SCI) using a balloon catheter in 45 rats and transplanted human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) at the injury site. Locomotor function was significantly improved in hUCB-MSCs transplanted groups. Quantitative ELISA of extract from entire injured spinal cord showed increased expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and neurotrophin-3 (NT-3). Our results show that treatment of SCI with hUCB-MSCs can improve locomotor functions, and suggest that increased levels of BDNF, NGF and NT-3 in the injured spinal cord were the main therapeutic effect.

  5. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.

    Science.gov (United States)

    Lin, Chih-Yang; Hung, Shih-Ya; Chen, Hsien-Te; Tsou, Hsi-Kai; Fong, Yi-Chin; Wang, Shih-Wei; Tang, Chih-Hsin

    2014-10-15

    Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

  6. Music exposure differentially alters the levels of brain-derived neurotrophic factor and nerve growth factor in the mouse hypothalamus.

    Science.gov (United States)

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

    2007-12-18

    It has been reported that music may have physiological effects on blood pressure, cardiac heartbeat, respiration, and improve mood state in people affected by anxiety, depression and other psychiatric disorders. However, the physiological bases of these phenomena are not clear. Hypothalamus is a brain region involved in the regulation of body homeostasis and in the pathophysiology of anxiety and depression through the modulation of hypothalamic-pituitary-adrenal (HPA) axis. Hypothalamic functions are also influenced by the presence of the neurotrophins brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), which are proteins involved in the growth, survival and function of neurons in the central nervous system. The aim of this study was to investigate the effect of music exposure in mice on hypothalamic levels of BDNF and NGF. We exposed young adult mice to slow rhythm music (6h per day; mild sound pressure levels, between 50 and 60 dB) for 21 consecutive days. At the end of the treatment mice were sacrificed and BDNF and NGF levels in the hypothalamus were measured by enzyme-linked immunosorbent assay (ELISA). We found that music exposure significantly enhanced BDNF levels in the hypothalamus. Furthermore, we observed that music-exposed mice had decreased NGF hypothalamic levels. Our results demonstrate that exposure to music in mice can influence neurotrophin production in the hypothalamus. Our findings also suggest that physiological effects of music might be in part mediated by modulation of neurotrophins.

  7. Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: complexity of steroid hormone-growth factor interactions in the adult CNS.

    OpenAIRE

    SCHARFMAN, HELEN E.; MacLusky, Neil J.

    2006-01-01

    In the CNS, there are widespread and diverse interactions between growth factors and estrogen. Here we examine the interactions of estrogen and brain-derived neurotrophic factor (BDNF), two molecules that have historically been studied separately, despite the fact that they seem to share common targets, effects, and mechanisms of action. The demonstration of an estrogen-sensitive response element on the BDNF gene provided an impetus to explore a direct relationship between estrogen and BDNF, ...

  8. Brain-derived Neurotrophic Factor Signaling Pathway: Modulation by Acupuncture in Telomerase Knockout Mice.

    Science.gov (United States)

    Lin, Dong; Wu, Qiang; Lin, Xiaoyang; Borlongan, Cesar V; He, Zhi-Xu; Tan, Jun; Cao, Chuanhai; Zhou, Shu-Feng

    2015-01-01

    Telomerase is a critical enzyme that is involved in aging and cancer and that is thought to be a part of multiple neurological diseases. To investigate the telomerase response in the brain to acupuncture, the study examined the levels of expression of brain-derived neurotrophic factor (BDNF) and its downstream signaling molecules, including tyrosine kinase receptor Β (TrkB), p75 neurotrophin receptor (p75NTR), protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK1/2), and nuclear factor κΒ (NF-κΒ). Both telomerase-deficient (Terc⁻/⁻) mice (Terc⁻/⁻ group) and normal, wild-type (WT) mice (WT group) were randomly assigned to 1 of 3 subgroups, 1 receiving acupuncture (acupuncture subgroup), 1 receiving sham acupuncture therapy (sham subgroup), and 1 receiving no treatment (control subgroup). The study occurred at the University of South Florida Health Byrd Alzheimer's Institute (Tampa, FL, USA). The 2 acupuncture subgroups received acupuncture at the stomach 36 (ST-36) position for 30 min/d for 4 d. For the 2 sham groups, the sham point was set at a location approximately 3 mm to the lateral side of the tail on the gluteus muscle following the same schedule. After 4 d, the mice were sacrificed, and the brain tissues were collected. The protein levels in the hippocampus and dentate gyrus (DG) of each mouse were determined by western blotting and immunostaining assays. The Terc⁻/⁻ group showed downregulated hippocampal BDNF expression compared with the WT mice. Acupuncture at ST-36 for 4 d upregulated BDNF, TrkB, p75NTR, Akt, and ERK1/2 in the DG and hippocampus of the telomerase-deficient mice, but that result was not seen in the WT mice with normally functioning telomerase. The use of acupuncture in pathologies associated with telomerase deficiencies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), may provide some benefit in terms of eliciting better clinical responses. The research team believes that result occurs

  9. 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

  10. 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.

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

    Science.gov (United States)

    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.

  12. Effects of aerobic exercise training on peripheral brain-derived neurotrophic factor and eotaxin-1 levels in obese young men

    OpenAIRE

    Cho, Su Youn; Roh, Hee Tae

    2016-01-01

    [Purpose] The aim of the present study was to investigate the effects of aerobic exercise training on the levels of peripheral brain-derived neurotrophic factor and eotaxin-1 in obese young men. [Subjects and Methods] The subjects included sixteen obese young men with a body mass index greater than 25 kg/m2. They were randomly divided between control and exercise groups (n = 8 in each group). The exercise group performed treadmill exercise for 40 min, 3 times a week for 8 weeks at the intensi...

  13. Roles of brain-derived neurotrophic factor/tropomyosin-related kinase B (BDNF/TrkB) signalling in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Fang; Kang, Zhilong; Li, Wen; Xiao, Zhicheng; Zhou, Xinfu

    2012-07-01

    Alzheimer's disease (AD) is one of the most common causes of dementia in the elderly. It is characterized by extracellular deposition of the neurotoxic peptide, amyloid-beta (Aβ) peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. However, the pathogenesis of AD is not fully understood. The aim of this review is to discuss the possible role of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signalling in the development of AD, focusing on BDNF/TrkB signalling in the production of Aβ, tau hyperphosphorylation and cognition decline, and exploring new possibilities for AD intervention.

  14. Brain-derived Neurotrophic Factor Promotes Differentiation and Maturation of Adult-born Neurons Through GABAergic Transmission

    OpenAIRE

    Waterhouse, Emily G; An, Juan Ji; Orefice, Lauren L.; Baydyuk, Maryna; Liao, Guey-Ying; Zheng, Kang; Lu, Bai; Xu, Baoji

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) has been implicated in regulating adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus; however, the mechanism underlying this regulation remains unclear. In this study, we found that Bdnf mRNA localized to distal dendrites of dentate gyrus granule cells isolated from wild-type mice, but not from Bdnfklox/klox mice where the long 3′ untranslated region (UTR) of Bdnf mRNA is truncated. KCl-induced membrane depolarization stimulated rele...

  15. New insight in expression, transport, and secretion of brain-derived neurotrophic factor: Implications in brainrelated diseases

    Institute of Scientific and Technical Information of China (English)

    Naoki; Adachi; Tadahiro; Numakawa; Misty; Richards; Shingo; Nakajima; Hiroshi; Kunugi

    2014-01-01

    Brain-derived neurotrophic factor(BDNF) attracts increasing attention from both research and clinical fields because of its important functions in the central nervous system. An adequate amount of BDNF is critical to develop and maintain normal neuronal circuits in the brain. Given that loss of BDNF function has beenreported in the brains of patients with neurodegenerative or psychiatric diseases, understanding basic properties of BDNF and associated intracellular processes is imperative. In this review, we revisit the gene structure, transcription, translation, transport and secretion mechanisms of BDNF. We also introduce implications of BDNF in several brain-related diseases including Alzheimer’s disease, Huntington’s disease, depression and schizophrenia.

  16. 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...

  17. Brain-derived neurotrophic factor and epidermal growth factor activate neuronal m-calpain via mitogen-activated protein kinase-dependent phosphorylation.

    Science.gov (United States)

    Zadran, Sohila; Jourdi, Hussam; Rostamiani, Karoline; Qin, Qingyu; Bi, Xiaoning; Baudry, Michel

    2010-01-20

    Calpain is a calcium-dependent protease that plays a significant role in synaptic plasticity, cell motility, and neurodegeneration. Two major calpain isoforms are present in brain, with mu-calpain (calpain1) requiring micromolar calcium concentrations for activation and m-calpain (calpain2) needing millimolar concentrations. Recent studies in fibroblasts indicate that epidermal growth factor (EGF) can activate m-calpain independently of calcium via mitogen-activated protein kinase (MAPK)-mediated phosphorylation. In neurons, MAPK is activated by both brain-derived neurotrophic factor (BDNF) and EGF. We therefore examined whether these growth factors could activate m-calpain by MAPK-dependent phosphorylation using cultured primary neurons and HEK-TrkB cells, both of which express BDNF and EGF receptors. Calpain activation was monitored by quantitative analysis of spectrin degradation and by a fluorescence resonance energy transfer (FRET)-based assay, which assessed the truncation of a calpain-specific peptide flanked by the FRET fluorophore pair DABCYL and EDANS. In both cell types, BDNF and EGF rapidly elicited calpain activation, which was completely blocked by MAPK and calpain inhibitors. BDNF stimulated m-calpain but not mu-calpain serine phosphorylation, an effect also blocked by MAPK inhibitors. Remarkably, BDNF- and EGF-induced calpain activation was preferentially localized in dendrites and dendritic spines of hippocampal neurons and was associated with actin polymerization, which was prevented by calpain inhibition. Our results indicate that, in cultured neurons, both BDNF and EGF activate m-calpain by MAPK-mediated phosphorylation. These results strongly support a role for calpain in synaptic plasticity and may explain why m-calpain, although widely expressed in CNS, requires nonphysiological calcium levels for activation.

  18. 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.

  19. Chronic ethanol ingestion, type 2 diabetes mellitus, and brain-derived neurotrophic factor (BDNF) in rats.

    Science.gov (United States)

    Jung, Kyu-In; Ju, Anes; Lee, Hee-Mi; Lee, Seong-Su; Song, Chan-Hee; Won, Wang-Youn; Jeong, Jae-Seung; Hong, Oak-Kee; Kim, Jae-Hwa; Kim, Dai-Jin

    2011-01-07

    Chronic alcohol consumption contributes to the development of type 2 diabetes mellitus (T2DM) while decreasing the level of brain-derived neurotrophic factor (BDNF). BDNF may be an important regulator of glucose metabolism, so it may be associated with an increased risk for T2DM in alcoholism. We evaluated the association of chronic heavy alcohol exposure, T2DM and BDNF level. Ten week-old type 2 diabetic OLETF rats and non-diabetic LETO rats of similar weight were used. The rats were randomized by weight into four treatment groups: (1) OLETF-Ethanol (O-E, n=13), (2) OLETF-Control (O-C, n=15), (3) LETO-Ethanol (L-E, n=11), and (4) LETO-Control (L-C, n=14). The ethanol groups were fed an isocaloric liquid diet containing ethanol while the control groups were fed with the same diet containing maltose-dextran over a 6-week period using a pair-feeding control model in order to regulate different caloric ingestion. After 6 weeks of feeding, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and BDNF levels were analyzed. Prior to IP-GTT, the mean glucose levels in the O-E, O-C, L-E, and L-C groups were 90.38±12.84, 102.13±5.04, 95.18±6.43, and 102.36±4.43mg/dL, respectively. Thirty minutes after intraperitoneal injection, the mean glucose levels were 262.62±63.77, 229.07±51.30, 163.45±26.63, and 156.64±34.42mg/dL, respectively; the increased amount of the mean glucose level in the O-E group was significantly higher than that in the O-C group (palcohol ingestion may aggravate T2DM and may possibly lower BDNF level.

  20. Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier

    Directory of Open Access Journals (Sweden)

    Peng YS

    2014-06-01

    Full Text Available Yu-Shiang Peng,1,* Po-Liang Lai,2,* Sydney Peng,1 His-Chin Wu,3 Siang Yu,1 Tsan-Yun Tseng,4 Li-Fang Wang,5 I-Ming Chu1 1Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 2Department of Orthopedic Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, 3Department of Materials Engineering, Tatung University, Taipei, 4Graduate School of Biotechnology and Bioengineering, College of Engineering, Yuan Ze University, Chung-Li, 5Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan *Yu-Shiang Peng and Po-Liang Lai contributed equally to this work Abstract: Parkinson’s disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood–brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810. This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the

  1. Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression.

    Science.gov (United States)

    Adlard, P A; Cotman, C W

    2004-01-01

    Exercise is increasingly recognized as an intervention that can reduce CNS dysfunctions such as cognitive decline, depression and stress. Previously we have demonstrated that brain-derived neurotrophic factor (BDNF) is increased in the hippocampus following exercise. In this study we tested the hypothesis that exercise can counteract a reduction in hippocampal BDNF protein caused by acute immobilization stress. Since BDNF expression is suppressed by corticosterone (CORT), circulating CORT levels were also monitored. In animals subjected to 2 h immobilization stress, CORT was elevated immediately following, and at 1 h after the cessation of stress, but remained unchanged from baseline up to 24 h post-stress. The stress protocol resulted in a reduction in BDNF protein at 5 and 10 h post-stress that returned to baseline at 24 h. To determine if exercise could prevent this stress-induced reduction in BDNF protein, animals were given voluntary access to running wheels for 3 weeks prior to the stress. Stressed animals, in the absence of exercise, again demonstrated an initial elevation in CORT (at 0 h) and a subsequent decrease in hippocampal BDNF at the 10 h time point. Exercising animals, both non-stressed and stressed, demonstrated circulating CORT and hippocampal BDNF protein levels that were significantly elevated above control values at both time points examined (0 and 10 h post-stress). Thus, the persistently high CORT levels in exercised animals did not affect the induction of BDNF with exercise, and the effect of immobilization stress on BDNF protein was overcome. To examine the role of CORT in the stress-related regulation of BDNF protein, experiments were carried out in adrenalectomized (ADX) animals. BDNF protein was not downregulated as a result of immobilization stress in ADX animals, while there continued to be an exercise-induced upregulation of BDNF. This study demonstrates that CORT modulates stress-related alterations in BDNF protein. Further, exercise

  2. Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia: A systematic review

    Science.gov (United States)

    Cui, Huiru; Jin, Yi; Wang, Jijun; Weng, Xuchu; Li, Chunbo

    2012-01-01

    Background There is increasing interest in the role of brain-derived neurotrophic factor (BDNF) in the onset and course of schizophrenia, but there are conflicting reports about serum levels of BDNF in patients with schizophrenia. Aim Conduct a meta-analysis combining studies from China and other countries that have evaluated the relationship of serum BDNF levels to schizophrenia. Method We used Cochrane methodology and RevMan 5.1 software to identify and pool the results of studies. Electronic searches of western and Chinese registries and follow-up assessment of references located 268 potential articles. Twenty-five articles (20 in English and 5 in Chinese) published before December 2011 that used case-control methods, included patients with schizophrenia who had no concurrent disorders, and used ELISA technology to assess serum BDNF were included in the analysis. The main outcome was the pooled standardized mean difference (SMD) between cases and controls. The quality of the studies was independently assessed by two raters using the GRADE system. The heterogeneity, sensitivity and potential publication bias of the studies was evaluated using RevMan. Results The pooled sample included 1663 patients with schizophrenia and 1355 controls. Fifteen of the included studies were rated as ‘poor quality’ and 10 were rated as ‘very poor quality’. The results of the studies were quite heterogenous (I2=95%) but subgroup analyses found that the heterogeneity was not related to country of origin, sample size, age, gender, prior use of antipsychotic medication, or study quality. The pooled SMD (computed using a random-effect model because of study heterogeneity) was -0.74 (95% CI, -0.99∼-0.50; Z=5.99, pbias. Conclusion Despite the robust statistical findings of lower serum BDNF in patients with schizophrenia than in controls, given the low quality of the available studies and the substantial heterogeneity between studies, the evidence of lower serum BDNF in patients

  3. Brain-derived neurotrophic factor expression predicts adverse pathological & clinical outcomes in human breast cancer

    Directory of Open Access Journals (Sweden)

    Mokbel Kefah

    2011-07-01

    Full Text Available Abstract Introduction Brain-derived neurotrophic factor (BDNF has established physiological roles in the development and function of the vertebrate nervous system. BDNF has also been implicated in several human malignancies, including breast cancer (BC. However, the precise biological role of BDNF and its utility as a novel biomarker have yet to be determined. The objective of this study was to determine the mRNA and protein expression of BDNF in a cohort of women with BC. Expression levels were compared with normal background tissues and evaluated against established pathological parameters and clinical outcome over a 10 year follow-up period. Methods BC tissues (n = 127 and normal tissues (n = 33 underwent RNA extraction and reverse transcription, BDNF transcript levels were determined using real-time quantitative PCR. BDNF protein expression in mammary tissues was assessed with standard immuno-histochemical methodology. Expression levels were analyzed against tumour size, grade, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI and clinical outcome over a 10 year follow-up period. Results Immuno-histochemical staining revealed substantially greater BDNF expression within neoplastic cells, compared to normal mammary epithelial cells. Significantly higher mRNA transcript levels were found in the BC specimens compared to background tissues (p = 0.007. The expression of BDNF mRNA was demonstrated to increase with increasing NPI; NPI-1 vs. NPI-2 (p = 0.009. Increased BDNF transcript levels were found to be significantly associated with nodal positivity (p = 0.047. Compared to patients who remained disease free, higher BDNF expression was significantly associated with local recurrence (LR (p = 0.0014, death from BC (p = 0.018 and poor prognosis overall (p = 0.013. After a median follow up of 10 years, higher BDNF expression levels were significantly associated with reduced overall survival (OS (106 vs. 136 months, p = 0.006. BDNF

  4. Brain-derived neurotrophic factor inducing angiogenesis through modulation of matrix-degrading proteases

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Background Recent studies have proved that brain-derived neurotrophic factor (BDNF) possesses angiogenic activity in vitro and in vivo. However, the proangiogenic mechanism of BDNF has not yet been provided with enough information. To explore the proangiogenic mechanism of BDNF, we investigated the effects of BDNF on extracellular proteolytic enzymes, including matrix metalloproteinases (MMPs) and serine proteases, particularly the urokinase-type plasminogen activator (uPA)-plasmin system in human umbilical vein endothelial cells (HUVECs) model. Methods Tube formation assay was performed in vitro to evaluate the effects of BDNF on angiogenesis. The HUVECs were treated with various concentrations of BDNF (25-400 ng/ml) for different (6-48 hours), reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assay MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA in HUVECs, and the conditioned medium was analyzed for MMP and uPA activity by gelatin zymography and fibrin zymography, respectively. uPA, plasminogen activator inhibitor (PAI)-1, tissue inhibitors of metalloproteinase (TIMP)-1, and TIMP-2 were quantified by western blotting analysis. Results BDNF elicited robust and elongated angiogeneis in two-dimensional cultures of HUVECs in comparison with control. The stimulation of serum-starved HUVECs with BDNF caused obvious increase in MMP-2 and MMP-9 mRNA expression and induced the pro-MMP-2 and pro-MMP-9 activation without significant differences in proliferation. However, BDNF had no effect on TIMP-1 and TIMP-2 production. BDNF increased uPA and PAI-1 production in a dose-dependent manner. Maximal activation of uPA and PAI-1 expression in HUVECs was induced by 100 ng/ml BDNF, while effects of 200 ng/ml and 400 ng/ml BDNF were slightly reduced in comparison with with those of 100 ng/ml. Protease activity for uPA was also increased by BDNF in a dose-dependent manner. BDNF also stimulated uPA and PAI-1 production beyond that in control cultures in a time

  5. Decreased serum levels of brain-derived neurotrophic factor in schizophrenic patients with deficit syndrome

    Directory of Open Access Journals (Sweden)

    Akyol ES

    2015-03-01

    Full Text Available Esra Soydas Akyol,1 Yakup Albayrak,2 Murat Beyazyüz,3 Nurkan Aksoy,4 Murat Kuloglu,5 Kenji Hashimoto6 1Deparment of Psychiatry, Yenimahalle Education and Research Hospital, Ankara, Turkey; 2Department of Psychiatry, Faculty of Medicine, Namik Kemal University, Tekirdag, Turkey; 3Department of Psychiatry, Biga State Hospital, Çanakkale, Turkey; 4Department of Biochemistry, Yenimahalle Education and Research Hospital, Ankara, Turkey; 5Department of Psychiatry, Faculty of Medicine, Akdeniz University, Antalya, Turkey; 6Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan Background: Brain-derived neurotrophic factor (BDNF is a well-established neurotrophin that plays a role in the pathophysiology of numerous psychiatric disorders. Many studies have investigated the serum BDNF levels in patients with schizophrenia. However, there are restricted data in the literature that compare the serum BDNF levels in patients with deficit and nondeficit syndromes. In this study, we aimed to compare the serum BDNF levels between schizophrenic patients with deficit or nondeficit syndrome and healthy controls.Methods: After fulfilling the inclusion and exclusion criteria, 58 patients with schizophrenia and 36 healthy controls were included in the study. The patients were grouped as deficit syndrome (N=23 and nondeficit syndrome (N=35 according to the Schedule for the Deficit Syndrome. Three groups were compared in terms of the sociodemographic and clinical variants and serum BDNF levels.Results: The groups were similar in terms of age, sex, body mass index, and smoking status. The serum BDNF levels in patients with deficit syndrome were significantly lower than those in healthy controls. In contrast, the serum BDNF levels in patients with nondeficit syndrome were similar to those in healthy controls.Conclusion: This study suggests that decreased BDNF levels may play a role in the pathophysio­logy of schizophrenic

  6. Intraspinal transplantation of motoneuron-like cell combined with delivery of polymer-based glial cell line-derived neurotrophic factor for repair of spinal cord contusion injury

    Institute of Scientific and Technical Information of China (English)

    Alireza Abdanipour; Taki Tiraihi; Taher Taheri

    2014-01-01

    To evaluate the effects of glial cell line-derived neurotrophic factor transplantation combined with adipose-derived stem cells-transdifferentiated motoneuron delivery on spinal cord con-tusion injury, we developed rat models of spinal cord contusion injury, 7 days later, injected adipose-derived stem cells-transdifferentiated motoneurons into the epicenter, rostral and caudal regions of the impact site and simultaneously transplanted glial cell line-derived neuro-trophic factor-gelfoam complex into the myelin sheath. Motoneuron-like cell transplantation combined with glial cell line-derived neurotrophic factor delivery reduced cavity formations and increased cell density in the transplantation site. The combined therapy exhibited superior promoting effects on recovery of motor function to transplantation of glial cell line-derived neurotrophic factor, adipose-derived stem cells or motoneurons alone. These ifndings suggest that motoneuron-like cell transplantation combined with glial cell line-derived neurotrophic factor delivery holds a great promise for repair of spinal cord injury.

  7. Brain-derived neurotrophic factor (BDNF) serum basal levels is not affected by power training in mobility-limited older adults - A randomized controlled trial

    DEFF Research Database (Denmark)

    Hvid, Lars G; Nielsen, Martin KF; Simonsen, Casper

    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....

  8. Intracerebroventricular administration of α-ketoisocaproic acid decreases brain-derived neurotrophic factor and nerve growth factor levels in brain of young rats.

    Science.gov (United States)

    Wisniewski, Miriam S W; Carvalho-Silva, Milena; Gomes, Lara M; Zapelini, Hugo G; Schuck, Patrícia F; Ferreira, Gustavo C; Scaini, Giselli; Streck, Emilio L

    2016-04-01

    Maple syrup urine disease (MSUD) is an inherited aminoacidopathy resulting from dysfunction of the branched-chain keto acid dehydrogenase complex, leading to accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine and valine as well as their corresponding transaminated branched-chain α-ketoacids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. However, the effect of accumulating α-ketoacids in MSUD on neurotrophic factors has not been investigated. Thus, the objective of the present study was to evaluate the effects of acute intracerebroventricular administration of α-ketoisocaproic acid (KIC) on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the brains of young male rats. Ours results showed that intracerebroventricular administration of KIC decreased BDNF levels in hippocampus, striatum and cerebral cortex, without induce a detectable change in pro-BDNF levels. Moreover, NGF levels in the hippocampus were reduced after intracerebroventricular administration of KIC. In conclusion, these data suggest that the effects of KIC on demyelination and memory processes may be mediated by reduced trophic support of BDNF and NGF. Moreover, lower levels of BDNF and NGF are consistent with the hypothesis that a deficit in this neurotrophic factor may contribute to the structural and functional alterations of brain underlying the psychopathology of MSUD, supporting the hypothesis of a neurodegenerative process in MSUD.

  9. 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

    2014-11-01

    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.

  10. Calcitonin gene-related peptide regulation of glial cell-line derived neurotrophic factor in differentiated rat myotubes.

    Science.gov (United States)

    Rosa, Elyse; Cha, Jieun; Bain, James R; Fahnestock, Margaret

    2015-03-01

    Glial cell-line derived neurotrophic factor (GDNF) is the most potent trophic factor for motoneuron survival and neuromuscular junction formation. GDNF is upregulated in injured or denervated skeletal muscle and returns to normal levels following reinnervation. However, the mechanism by which GDNF is regulated in denervated muscle is not well understood. The nerve-derived neurotransmitter calcitonin gene-related peptide (CGRP) is upregulated following neuromuscular injury and is subsequently released from motoneurons at the neuromuscular junction. CGRP also promotes nerve regeneration, but the mechanism is not well understood. The current study investigates whether this increase in CGRP regulates GDNF, thus playing a key role in promoting regeneration of injured nerves. This study demonstrates that CGRP increases GDNF secretion without affecting its transcription or translation. Rat L6 myoblasts were differentiated into myotubes and subsequently treated with CGRP. GDNF mRNA expression levels were quantified by quantitative real-time reverse transcription-polymerase chain reaction, and secreted GDNF was quantified in the conditioned medium by ELISA. CGRP treatment increased secreted GDNF protein without altering GDNF mRNA levels. The translational inhibitor cycloheximide did not affect CGRP-induced GDNF secreted protein levels, whereas the secretional inhibitor brefeldin A blocked the CGRP-induced increase in GDNF. This study highlights the importance of injury-induced upregulation of CGRP by exposing its ability to increase GDNF levels and demonstrates a secretional mechanism for regulation of this key regeneration-promoting neurotrophic factor.

  11. Brain-Derived neurotrophic factor and suicide in schizophrenia: Critical role of neuroprotective mechanisms as an emerging hypothesis

    Directory of Open Access Journals (Sweden)

    Amresh Shrivastava

    2016-01-01

    Full Text Available 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.

  12. Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder.

    Science.gov (United States)

    Wang, Hongyan; Zhang, Yingquan; Qiao, Mingqi

    2013-03-25

    The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.

  13. Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signaltransduction pathway in depressive disorder

    Institute of Scientific and Technical Information of China (English)

    Hongyan Wang; Yingquan Zhang; Mingqi Qiao

    2013-01-01

    The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.

  14. Effect of glatiramer acetate on peripheral blood brain-derived neurotrophic factor and phosphorylated TrkB levels in relapsing-remitting multiple sclerosis.

    Science.gov (United States)

    Vacaras, Vitalie; Major, Zsigmond Z; Muresanu, Dafin F; Krausz, Tibor L; Marginean, Ioan; Buzoianu, Dana A

    2014-01-01

    Glatiramer acetate (GA) is one of the most widely used disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis; is assumed to have inductor effects on neurotrophic factor expression. One of these neurotrophic factor systems is the brain-derived neurotrophic factor (BDNF)/receptor tyrosine kinase B (TrkB) pathway. Peripheral blood is thought to contain soluble BDNF, and some blood cells express TrkB. We attempted to determine whether GA treatment leads to changes in plasma BDNF levels and TrkB activation. Such a phenomenon are relapsing-remitting multiple sclerosis patients is significantly reduced; GA treatment is not influencing peripheral BDNF levels, after one year of sustained therapy, not from the point of view of total free BDNF nor the phosphorylated TrkB.

  15. Brain-derived neurotrophic factor superinduction parallels anti-epileptic--neuroprotective treatment in the pilocarpine epilepsy model.

    Science.gov (United States)

    Biagini, G; Avoli, M; Marcinkiewicz, J; Marcinkiewicz, M

    2001-03-01

    Antiepileptic drugs provide neuroprotection in several animal models of brain damage, including those induced by status epilepticus (SE). The mechanisms involved in this action are unknown, but neurotrophic factors such as brain-derived neurotrophic factor (BDNF) may play a role. In this study we investigated the changes in BDNF levels in rats in which SE had been induced by pilocarpine injection (400 mg/kg i.p.) and continued for several hours (unprotected group). In other animals (protected groups), SE was suppressed after 30 min by intraperitoneal injection of either diazepam (10 mg/kg) + pentobarbital (30 mg/kg) or paraldehyde (0.3 mg/kg). In diazepam + pentobarbital-treated rats the hippocampal damage caused by SE was significantly lower (p rats treated with diazepam + pentobarbital. In contrast, a decrease of BDNF immunoreactivity occurred in the unprotected group. In conclusion, these results show that neuroprotection induced by anti-epileptic drugs in pilocarpine-treated rats is accompanied by strong potentiation of BDNF synthesis in brain regions involved in SE.

  16. 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.

  17. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

    Science.gov (United States)

    Larsson, E; Nanobashvili, A; Kokaia, Z; Lindvall, O

    1999-11-01

    The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.

  18. Brain-derived neurotrophic factor in neuroimmunology: lessons learned from multiple sclerosis patients and experimental autoimmune encephalomyelitis models.

    Science.gov (United States)

    Lühder, Fred; Gold, Ralf; Flügel, Alexander; Linker, Ralf A

    2013-04-01

    The concept of neuroprotective autoimmunity implies that immune cells, especially autoantigen-specific T cells, infiltrate the central nervous system (CNS) after injury and contribute to neuroregeneration and repair by secreting soluble factors. Amongst others, neurotrophic factors and neurotrophins such as brain-derived neurotropic factor (BDNF) are considered to play an important role in this process. New data raise the possibility that this concept could also be extended to neuroinflammatory diseases such as multiple sclerosis (MS) where autoantigen-specific T cells infiltrate the CNS, causing axonal/neuronal damage on the one hand, but also providing neuroprotective support on the other hand. In this review, we summarize the current knowledge on BDNF levels analyzed in MS patients in different compartments and its correlation with clinical parameters. Furthermore, new approaches in experimental animal models are discussed that attempt to decipher the functional relevance of BDNF in autoimmune demyelination.

  19. Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects.

    Science.gov (United States)

    Quiroz, Jorge A; Machado-Vieira, Rodrigo; Zarate, Carlos A; Manji, Husseini K

    2010-01-01

    The monovalent cation lithium partially exerts its effects by activating neurotrophic and neuroprotective cellular cascades. Here, we discuss the effects of lithium on oxidative stress, programmed cell death (apoptosis), inflammation, glial dysfunction, neurotrophic factor functioning, excitotoxicity, and mitochondrial stability. In particular, we review evidence demonstrating the action of lithium on cyclic adenosine monophosphate (cAMP)-mediated signal transduction, cAMP response element binding activation, increased expression of brain-derived neurotrophic factor, the phosphatidylinositide cascade, protein kinase C inhibition, glycogen synthase kinase 3 inhibition, and B-cell lymphoma 2 expression. Notably, we also review data from clinical studies demonstrating neurotrophic effects of lithium. We expect that a better understanding of the clinically relevant pathophysiological targets of lithium will lead to improved treatments for those who suffer from mood as well as neurodegenerative disorders. Copyright 2010 S. Karger AG, Basel.

  20. Treatment of rat spinal cord injury with the neurotrophic factor albumin-oleic acid: translational application for paralysis, spasticity and pain.

    Directory of Open Access Journals (Sweden)

    Gerardo Avila-Martin

    Full Text Available Sensorimotor dysfunction following incomplete spinal cord injury (iSCI is often characterized by the debilitating symptoms of paralysis, spasticity and pain, which require treatment with novel pleiotropic pharmacological agents. Previous in vitro studies suggest that Albumin (Alb and Oleic Acid (OA may play a role together as an endogenous neurotrophic factor. Although Alb can promote basic recovery of motor function after iSCI, the therapeutic effect of OA or Alb-OA on a known translational measure of SCI associated with symptoms of spasticity and change in nociception has not been studied. Following T9 spinal contusion injury in Wistar rats, intrathecal treatment with: i Saline, ii Alb (0.4 nanomoles, iii OA (80 nanomoles, iv Alb-Elaidic acid (0.4/80 nanomoles, or v Alb-OA (0.4/80 nanomoles were evaluated on basic motor function, temporal summation of noxious reflex activity, and with a new test of descending modulation of spinal activity below the SCI up to one month after injury. Albumin, OA and Alb-OA treatment inhibited nociceptive Tibialis Anterior (TA reflex activity. Moreover Alb-OA synergistically promoted early recovery of locomotor activity to 50 ± 10% of control and promoted de novo phasic descending inhibition of TA noxious reflex activity to 47 ± 5% following non-invasive electrical conditioning stimulation applied above the iSCI. Spinal L4-L5 immunohistochemistry demonstrated a unique increase in serotonin fibre innervation up to 4.2 ± 1.1 and 2.3 ± 0.3 fold within the dorsal and ventral horn respectively with Alb-OA treatment when compared to uninjured tissue, in addition to a reduction in NR1 NMDA receptor phosphorylation and microglia reactivity. Early recovery of voluntary motor function accompanied with tonic and de novo phasic descending inhibition of nociceptive TA flexor reflex activity following Alb-OA treatment, mediated via known endogenous spinal mechanisms of action, suggests a clinical application of this novel

  1. Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo.

    Science.gov (United States)

    Nakajima, Hidemitsu; Itakura, Masanori; Sato, Keishi; Nakamura, Sunao; Azuma, Yasu-Taka; Takeuchi, Tadayoshi

    2017-03-04

    Synthesis of poly(ADP-ribose) (PAR) is catalyzed by PAR polymerase-1 (PARP-1) in neurons. PARP1 plays a role in various types of brain damage in neurodegenerative disorders. In neurons, overactivation of PARP-1 during oxidative stress induces robust PAR formation, which depletes nicotinamide adenine dinucleotide levels and leads to cell death. However, the role of the newly-formed PAR in neurodegenerative disorders remains elusive. We hypothesized that the effects of PAR could occur in the extracellular space after it is leaked from damaged neurons. Here we report that extracellular PAR (EC-PAR) functions as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor (GDNF) in astrocytes during neuronal cell death, both in vitro and in vivo. In primary rat astrocytes, exogenous treatment with EC-PAR produced GDNF but not other neurotrophic factors. The effect was concentration-dependent and did not affect cell viability in rat C6 astrocytoma cells. Topical injection of EC-PAR into rat striatum upregulated GDNF levels in activated astrocytes and improved pathogenic rotation behavior in a unilateral 6-hydroxydopamine model of Parkinson disease in rats. These findings indicate that EC-PAR acts as a neurotrophic enhancer by upregulating GDNF levels. This effect protects the remaining neurons following oxidative stress-induced brain damage, such as that seen with Parkinson disease.

  2. 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…

  3. 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…

  4. 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

  5. Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates Neuropathology in a Mouse Model of Alzheimer’s Disease

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    David J. Braun

    2017-03-01

    Full Text Available Damage occurring to noradrenergic neurons in the locus coeruleus (LC contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC. BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value to reduce neurodegenerative processes normally limited by LC noradrenergic activities.

  6. Knockdown of brain-derived neurotrophic factor in specific brain sites precipitates behaviors associated with depression and reduces neurogenesis.

    Science.gov (United States)

    Taliaz, D; Stall, N; Dar, D E; Zangen, A

    2010-01-01

    Depression has been associated with reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. In addition, animal studies suggest an association between reduced hippocampal neurogenesis and depressive-like behavior. These associations were predominantly established based on responses to antidepressant drugs and alterations in BDNF levels and neurogenesis in depressive patients or animal models for depressive behavior. Nevertheless, there is no direct evidence that the actual reduction of the BDNF protein in specific brain sites can induce depressive-like behaviors or affect neurogenesis in vivo. Using BDNF knockdown by RNA interference and lentiviral vectors injected into specific subregions of the hippocampus we show that a reduction in BDNF expression in the dentate gyrus, but not the CA3, reduces neurogenesis and affects behaviors associated with depression. Moreover, we show that BDNF has a critical function in neuronal differentiation, but not proliferation in vivo. Finally, we found that a specific BDNF knockdown in the ventral subiculum induces anhedonic-like behavior. These findings provide substantial support for the neurotrophic hypothesis of depression and specify anatomical and neurochemical targets for potential antidepressant interventions. Moreover, the specific effect of BDNF reduction on neuronal differentiation has broader implications for the study of neurodevelopment and neurodegenerative diseases.

  7. Assessment of oxidative stress parameters of brain-derived neurotrophic factor heterozygous mice in acute stress model

    Directory of Open Access Journals (Sweden)

    Gulay Hacioglu

    2016-04-01

    Full Text Available Objective(s: Exposing to stress may be associated with increased production of reactive oxygen species (ROS. Therefore, high level of oxidative stress may eventually give rise to accumulation of oxidative damage and development of numerous neurodegenerative diseases. It has been presented that brain-derived neurotrophic factor (BDNF supports neurons against various neurodegenerative conditions. Lately, there has been growing evidence that changes in the cerebral neurotrophic support and especially in the BDNF expression and its engagement with ROS might be important in various disorders and neurodegenerative diseases. Hence, we aimed to investigate protective effects of BDNF against stress-induced oxidative damage. Materials and Methods: Five- to six-month-old male wild-type and BDNF knock-down mice were used in this study. Activities of catalase (CAT and superoxide dismutase (SOD enzymes, and the amount of malondialdehyde (MDA were assessed in the cerebral homogenates of studied groups in response to acute restraint stress. Results: Exposing to acute physiological stress led to significant elevation in the markers of oxidative stress in the cerebral cortexes of experimental groups. Conclusion: As BDNF-deficient mice were observed to be more susceptible to stress-induced oxidative damage, it can be suggested that there is a direct interplay between oxidative stress indicators and BDNF levels in the brain.

  8. RNA interference-mediated knockdown of brain-derived neurotrophic factor (BDNF) promotes cell cycle arrest and apoptosis in B-cell lymphoma cells.

    Science.gov (United States)

    Xia, D; Li, W; Zhang, L; Qian, H; Yao, S; Qi, X

    2014-01-01

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin superfamily that has been reported to be involved in a number of neurological and psychological situations. Recently, high expression level of BDNF is observed in diverse human malignancies, delineating a role of BDNF in tumorigenesis. Nevertheless, its effect on B-cell lymphoma remains unclear. In this study, RNA interference technology mediated by short hairpin RNA (shRNA) was performed to inhibit endogenous BDNF expression in B-cell lymphoma cells. Results showed that knockdown of BDNF reduced cell growth and proliferation of Raji and Ramos cells. Furthermore, down-regulation of BDNF induced a cell cycle arrest at G0/G1 phase in Raji cells, and consequently led to cell apoptosis in vitro. Meanwhile, down-regulation of Bcl-2 and up-regulation of Bax, activated caspase-3 and caspase-9 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in Raji cells when endogenous BDNF was inhibited. Besides, we also found that suppression of BDNF in Raji cells increased their sensitivity to chemotherapeutic drug, 5-Fluorouracil (5-FU). Our research provides a promising therapeutic strategy for human B-cell lymphoma by targeting BDNF.

  9. Brain-derived neurotrophic factor mediates neuroprotection against Aβ-induced toxicity through a mechanism independent on adenosine 2A receptor activation.

    Science.gov (United States)

    Jerónimo-Santos, André; Fonseca-Gomes, João; Guimarães, Diogo Andrade; Tanqueiro, Sara Ramalho; Ramalho, Rita Mira; Ribeiro, Joaquim Alexandre; Sebastião, Ana Maria; Diógenes, Maria José

    2015-01-01

    Brain-derived neurotrophic factor (BDNF) promotes neuronal survival through TrkB-FL activation. The activation of adenosine A2A receptors (A2AR) is essential for most of BDNF-mediated synaptic actions, such as synaptic plasticity, transmission and neurotransmitter release. We now aimed at evaluating the A2AR influence upon BDNF-mediated neuroprotection against Aβ25-35 toxicity in cultured neurons. Results showed that BDNF increases cell survival and reduces the caspase-3 and calpain activation induced by amyloid-β (Aβ) peptide, in a mechanism probably dependent on PLCγ pathway. This BDNF-mediated neuroprotection is not affected by A2AR activation or inhibition. Moreover neither activation nor inhibition of A2AR, per se, significantly influenced Aβ-induced neuronal death on calpain-mediated cleavage of TrkB induced by Aβ. In conclusion, these results suggest that, in opposition to the fast synaptic actions of BDNF, the neuroprotective actions of this neurotrophin against a strong Aβ insult do not require the activation of A2AR.

  10. Brain-derived neurotrophic factor activation of extracellular signal-regulated kinase is autonomous from the dominant extrasynaptic NMDA receptor extracellular signal-regulated kinase shutoff pathway.

    Science.gov (United States)

    Mulholland, P J; Luong, N T; Woodward, J J; Chandler, L J

    2008-01-24

    NMDA receptors bidirectionally modulate extracellular signal-regulated kinase (ERK) through the coupling of synaptic NMDA receptors to an ERK activation pathway that is opposed by a dominant ERK shutoff pathway thought to be coupled to extrasynaptic NMDA receptors. In the present study, synaptic NMDA receptor activation of ERK in rat cortical cultures was partially inhibited by the highly selective NR2B antagonist Ro25-6981 (Ro) and the less selective NR2A antagonist NVP-AAM077 (NVP). When Ro and NVP were added together, inhibition appeared additive and equal to that observed with the NMDA open-channel blocker MK-801. Consistent with a selective coupling of extrasynaptic NMDA receptors to the dominant ERK shutoff pathway, pre-block of synaptic NMDA receptors with MK-801 did not alter the inhibitory effect of bath-applied NMDA on ERK activity. Lastly, in contrast to a complete block of synaptic NMDA receptor activation of ERK by extrasynaptic NMDA receptors, activation of extrasynaptic NMDA receptors had no effect upon ERK activation by brain-derived neurotrophic factor. These results suggest that the synaptic NMDA receptor ERK activation pathway is coupled to both NR2A and NR2B containing receptors, and that the extrasynaptic NMDA receptor ERK inhibitory pathway is not a non-selective global ERK shutoff.

  11. Brain-derived neurotrophic factor controls activity-dependent maturation of CA1 synapses by downregulating tonic activation of presynaptic kainate receptors.

    Science.gov (United States)

    Sallert, Marko; Rantamäki, Tomi; Vesikansa, Aino; Anthoni, Heidi; Harju, Kirsi; Yli-Kauhaluoma, Jari; Taira, Tomi; Castren, Eero; Lauri, Sari E

    2009-09-09

    Immature hippocampal synapses express presynaptic kainate receptors (KARs), which tonically inhibit glutamate release. Presynaptic maturation involves activity-dependent downregulation of the tonic KAR activity and consequent increase in release probability; however, the molecular mechanisms underlying this developmental process are unknown. Here, we have investigated whether brain derived neurotrophic factor (BDNF), a secreted protein implicated in developmental plasticity in several areas of the brain, controls presynaptic maturation by regulating KARs. Application of BDNF in neonate hippocampal slices resulted in increase in synaptic transmission that fully occluded the immature-type KAR activity in area CA1. Conversely, genetic ablation of BDNF was associated with delayed synaptic maturation and persistent presynaptic KAR activity, suggesting a role for endogenous BDNF in the developmental regulation of KAR function. In addition, our data suggests a critical role for BDNF TrkB signaling in fast activity-dependent regulation of KARs. Selective acute inhibition of TrkB receptors using a chemical-genetic approach prevented rapid change in synapse dynamics and loss of tonic KAR activity that is typically seen in response to induction of LTP at immature synapses. Together, these data show that BDNF-TrkB-dependent maturation of glutamatergic synapses is tightly associated with a loss of endogenous KAR activity. The coordinated action of these two receptor mechanisms has immediate physiological relevance in controlling presynaptic efficacy and transmission dynamics at CA3-CA1 synapses at a stage of development when functional contact already exists but transmission is weak.

  12. LncRNA analysis of mouse spermatogonial stem cells following glial cell-derived neurotrophic factor treatment

    Directory of Open Access Journals (Sweden)

    Lufan Li

    2015-09-01

    Full Text Available Spermatonial stem cells (SSCs are the foundation of spermatogenesis. Long non-coding RNAs (lncRNAs are a class of non-coding RNAs with at least 200 bp in length, which play important roles in various biological processes. Growth factor glial cell line-derived neurotrophic factor (GDNF, secreted from testis niches, is critical for self-renewal of SSCs in vitro and in vivo. Using Illumina HiSeq™ 2000 high throughput sequencing, we found 55924 lncRNAs which were regulated by GDNF in SSCs in vitro; these included 21,929 known lncRNAs from NONCODE library (version 3.0 and 33,975 predicted lncRNAs which were identified using Coding Potential Calculator. Analyses of these data should provide new insights into regulated mechanism in SSC self-renewal and proliferation. The data have been deposited in the Gene Expression Omnibus (series GSE66998.

  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.

  14. 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 cohort consisted of 395 singleton births (206 boys and 189 girls), gestational age ranging from 38 to 42 weeks. Serum BDNF was measured by sandwich ELISA. Maternal smoking habits and other relevant factors were obtained by interviewing the mothers. The exposure to MeHg was estimated from Hg...... concentrations in cord blood, whereas exposure to PCB was estimated based on maternal serum concentrations. Only MeHg exposure affected the serum BDNF, which decreased in a concentration-dependent manner in girls born to nonsmoking mothers. Maternal smoking significantly increased BNDF in girls but not in boys...

  15. Effect of yoga on pain, brain-derived neurotrophic factor, and serotonin in premenopausal women with chronic low back pain.

    Science.gov (United States)

    Lee, Moseon; Moon, Woongjoon; Kim, Jaehee

    2014-01-01

    Background. Serotonin and brain-derived neurotrophic factor (BDNF) are known to be modulators of nociception. However, pain-related connection between yoga and those neuromodulators has not been investigated. Therefore, we aimed to evaluate the effect of yoga on pain, BDNF, and serotonin. Methods. Premenopausal women with chronic low back pain practiced yoga three times a week for 12 weeks. At baseline and after 12 weeks, back pain intensity was measured using visual analogue scale (VAS), and serum BDNF and serotonin levels were evaluated. Additionally, back flexibility and level of depression were assessed. Results. After 12-week yoga, VAS decreased in the yoga group (P yoga group (P yoga group (P yoga group, while it reduced (P yoga group, whereas it tended to increase in the control group (P = 0.07). Conclusions. We propose that BDNF may be one of the key factors mediating beneficial effects of yoga on chronic low back pain.

  16. Brain-derived neurotrophic factor and neurotrophin-3 activate striatal dopamine and serotonin metabolism and related behaviors: interactions with amphetamine.

    Science.gov (United States)

    Martin-Iverson, M T; Todd, K G; Altar, C A

    1994-03-01

    To investigate behavioral and neurochemical effects of neurotrophic factors in vivo, rats received continuous 14 d infusions of either brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or vehicle unilaterally into the substantia nigra. BDNF and NT-3 decreased body weights, an effect that was sustained over the infusion period. BDNF elevated daytime and nocturnal locomotion compared with infusions of vehicle or NT-3. At 2 weeks, a systemic injection of amphetamine (1.5 mg/kg, s.c.) increased the frequencies and durations of rotations contraversive to the side of BDNF and NT-3 infusions. Both factors attenuated amphetamine-induced locomotion without affecting amphetamine-induced stereotyped behaviors such as sniffing, head movements, and snout contact with cage surfaces. Only BDNF induced backward walking, and this response was augmented by amphetamine. BDNF, but not NT-3, increased dopamine turnover in the striatum ipsilateral to the infusion relative to the contralateral striatum. Both trophic factors decreased dopamine turnover in the infused substantia nigra relative to the contralateral hemisphere and increased 5-HT turnover in the striatum of both sides. Contraversive rotations were positively correlated with dopamine content decreases and 5-HT turnover increases in the striatum ipsilateral to the infused substantia nigra. Backward walking was positively correlated with increased dopamine and 5-HT turnover in the striatum of the infused hemisphere. Supranigral infusions of BDNF and NT-3 alter circadian rhythms, spontaneous motor activity, body weights, and amphetamine-induced behaviors including locomotion and contraversive rotations. These behavioral effects of the neurotrophins are consistent with a concomitant activation of dopamine and 5-HT systems in vivo.

  17. Pharmacological Activation Gi/o Protein Increases Glial Cell Line-Derived Neurotrophic Factor Production through Fibroblast Growth Factor Receptor and Extracellular Signal-Regulated Kinase Pathway in Primary Cultured Rat Cortical Astrocytes.

    Science.gov (United States)

    Hisaoka-Nakashima, Kazue; Matsumoto, Chie; Azuma, Honami; Taki, Sayaka; Takebayashi, Minoru; Nakata, Yoshihiro; Morioka, Norimitsu

    2017-01-01

    A significant reduction of glial cell line-derived neurotrophic factor (GDNF) has been identified in the pathophysiology of neurodegenerative and neuropsychiatric disorders. Thus, clarification of the mechanism of GDNF production, and modulating brain GDNF levels could be a novel therapeutic approach. A previous study demonstrated that antidepressant amitriptyline-induced GDNF production was significantly inhibited by pertussis toxin (PTX), a Gi/o protein inhibitor in astrocytes, the main source of GDNF in the brain. However, it is not known whether direct activation of Gi/o protein might induce GDNF expression, and what mechanisms might be involved after Gi/o protein activation. The current study investigated Gi/o protein-initiated GDNF production in rat cortical astrocytes using activators that directly activate Gi/o protein, mastoparan and compound48/80. Treatment of astrocytes with either mastoparan or compound48/80 increased GDNF mRNA expression at 3 and 6 h, and GDNF protein release at 24 h. Treatment of astrocyte with either mastoparan or compound48/80 increased brain-derived neurotrophic factor (BDNF) mRNA expression as well as GDNF. Mastoparan and compound48/80-induced GDNF mRNA expression were significantly inhibited by not only PTX, but also fibroblast growth factor receptor (FGFR) inhibitors, and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. In fact, both FGFR substrate2α (FRS2α) and ERK phosphorylation were increased by treatment with either mastoparan or compound48/80, and these were significantly blocked by PTX. Thus, direct, receptor-independent Gi/o protein activation increases GDNF production through FGFR/ERK signaling pathway. The current results indicate a critical role of Gi/o signaling in the regulation of GDNF expression in astrocytes.

  18. 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

    2016-12-20

    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 minutes 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 to 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.

  19. Carbon nanotube-collagen three-dimensional culture of mesenchymal stem cells promotes expression of neural phenotypes and secretion of neurotrophic factors.

    Science.gov (United States)

    Lee, Jae Ho; Lee, Ja-Yeon; Yang, Sung Hee; Lee, Eun-Jung; Kim, Hae-Won

    2014-10-01

    Microenvironments provided by three-dimensional (3-D) hydrogels mimic native tissue conditions, supplying appropriate physical cues for regulating stem cell behaviors. Here, we focused on carbon nanotubes (CNTs) dispersed within collagen hydrogels to provide 3-D microenvironmental conditions for mesenchymal stem cells (MSCs) in stimulating biological functions for neural regeneration. Small concentrations of CNTs (0.1-1wt.%) did not induce toxicity to MSCs, and even improved the proliferative potential of the cells. MSCs cultured within the CNT-collagen hydrogel expressed considerable levels of neural markers, including GAP43 and βIII tubulin proteins by immunostaining as well as GAP43 and synapse I genes by reverse transcriptase polymerase chain reaction (RT-PCR). Of note was that neurotrophic factors, particularly nerve growth factor and brain derived neurotrophic factor, were significantly promoted by the incorporation of CNTs as confirmed by RT-PCR and Western blot analysis. A model experiment involving neuritogenesis of PC12 cells influenced by those releasing neurotrophic factors from MSCs cultured within the CNT-collagen hydrogel demonstrated the significant enhancement in neurite outgrowth behaviors. Taken together, collagen hydrogel provides excellent 3-D conditions for MSC growth, and a small incorporation of CNTs within the hydrogel significantly stimulates MSC expression of neural markers and secretion of neurotrophic factors.

  20. Upregulated gene expression of local brain-derived neurotrophic factor and nerve growth factor after intracisternal administration of marrow stromal cells in rats with traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    胡德志; 周良辅; 朱剑虹; 毛颖; 吴雪海

    2005-01-01

    Objective: To examine the effects of rat marrow stromal cells (rMSCs) on gene expression of local brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) after injection of rMSCs into Cistern Magnum of adult rats subjected to traumatic brain injury(TBI).Results: Group cell transplantation had higher BDNF and NGF gene expressions than Group saline control during a period of less than 3 weeks (P<0.05).Conclusions: rMSCs transplantation via Cistern Magnum in rats subjected to traumatic brain injury can enhance expressions of local brain NGF and BDNF to a certain extent.

  1. Effect of glial cell line-derived neurotrophic factor on peripheral nerve regeneration in adult rat

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhe-yu; LI Jian-hong; ZHENG Xing-dong; LU Chang-lin; HE Cheng

    2001-01-01

    Objective: To study the effect of glial cell line-derived neurotrophic (GDNF) on adult peripheral nerve regeneration. Methods: Transectioned sciatic nerve in adult rats was sutured into silicone channel. GDNF or SAL solution was injected into the silicone channels during operation. Four weeks later, the effect of GDNF on axonal regeneration was evaluated by degenerative neurofiber staining and HRP retrograde tracing. Results: Compared with SAL group, the percentage of degenerative neurofiber areas decreased from 17.3% to 1.9% ( P<0.01 ) and the ratio of labeled spinal somas number was significantly increased from 43.5% to 68.3% ( P<0.01 ) in GDNF group. Conclusion: The results suggest that exogenous GDNF can obviously enhance adult peripheral nerve regeneration.

  2. Additive clinical value of serum brain-derived neurotrophic factor for prediction of chronic heart failure outcome.

    Science.gov (United States)

    Kadowaki, Shinpei; Shishido, Tetsuro; Honda, Yuki; Narumi, Taro; Otaki, Yoichiro; Kinoshita, Daisuke; Nishiyama, Satoshi; Takahashi, Hiroki; Arimoto, Takanori; Miyamoto, Takuya; Watanabe, Tetsu; Kubota, Isao

    2016-04-01

    The importance of the central nervous system in cardiovascular events has been recognized. Recently, brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is involved in depression mechanisms and also in stress and anxiety. Because BDNF is reported about cardioprotective role, we elucidated whether BDNF is associated with cardiovascular events in patients with chronic heart failure (CHF). We examined serum BDNF levels in 134 patients with CHF and 23 control subjects. The patients were followed to register cardiac events for a median of 426 days. BDNF was significantly lower in CHF patients than in control subjects (25.8 ± 8.4 vs 14.7 ± 8.4, P BDNF was also lower in patients with cardiac events than in event-free patients (16.1 ± 8.0 vs 12.5 ± 8.5, P BDNF was determined by performing receiver operating characteristic curve analysis. Kaplan-Meier analysis demonstrated that patients with low levels of BDNF experienced higher rates of cardiac events than those with high levels of BDNF. Multivariate Cox hazard analysis demonstrated that low BDNF levels (≤12.4 ng/mL) were an independent prognostic factor for cardiac events (hazard ratio 2.932, 95 % confidence interval 1.622-5.301; P = 0.0004). Adding levels of BDNF to the model with BNP levels, age, and eGFR for the prediction of cardiac events yielded significant net reclassification improvement of 0.429 (P BDNF levels were found in patients with CHF, and these levels were found to be independently associated with an increased risk of cardiac events.

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

    Institute of Scientific and Technical Information of China (English)

    Joon Ha Park; Ok kyu Park; Yan Bingchun; Ji Hyeon Ahn; In Hye Kim; Jae-Chul Lee; Seung-Hae Kwon

    2014-01-01

    Background 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 (Tsl) against ischemic damage in the gerbil hippocampal CA1 region (CA1) after transient cerebral ischemia and examined its neuroprotective mechanism.Methods The gerbils were divided into vehicle-treated-sham-group,vehicle-treated-ischemia-group,Tsl-treated-shamgroup,and Tsl-treated-ischemia-group.Tsl was administrated intraperitoneally three times (once a day for three days) before ischemia-reperfusion.The neuroprotective effect of Tsl was examined using H&E staining,neuronal nuclei (NeuN) immunohistochemistry and Fluoro-Jade B staining.To investigate the neuroprotective mechanism of Tsl after ischemiareperfusion,immunohistochemical (IHC) and Western blotting analyses for Cu,Zn-superoxide dismutase (SOD1),Mnsuperoxide dismutase (SOD2),brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-I (IGF-I) were performed.Results Treatment with Tsl protected pyramidal neurons from ischemia-induced neuronal death in the CA1 after ischemia-reperfusion.In addition,treatment with Tsl maintained the levels of SOD1 and SOD2 as determined by IHC and Western blotting in the CA1 after ischemiareperfusion compared with the vehicle-ischemia-group.In addition,treatment with Tsl increased the levels of BDNF and IGF-I determined by IHC and Western blotting in the Tsl-treated-sham-group compared with the vehicle-treatedsham-group,and their levels were maintained in thestratum pyramidale of the ischemic CA1 in the Tsl-treatedischemia-group.Conclusion Treatment with Tsl protects pyramidal neurons of the CA1 from ischemic damage induced by transient cerebral ischemia via the maintenance of antioxidants and the

  4. Immunomodulator CD200 promotes neurotrophic activity by interacting with and activating the fibroblast growth factor receptor

    DEFF Research Database (Denmark)

    Pankratova, Stanislava; Bjornsdottir, 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...... phosphorylation was abrogated by CD200R, whereas FGF2-induced FGFR activation was inhibited by CD200. We also identified a sequence motif located in the first Ig-like module of CD200, likely representing the minimal CD200 binding site for FGFR. The FGFR binding motif overlaps with the CD200R binding site......, suggesting that they can compete for CD200 binding in cells that express both receptors. We propose that CD200 in neurons functions as a ligand of FGFR....

  5. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val(66)Met

    NARCIS (Netherlands)

    Elzinga, Bernet M.; Molendijk, Marc L.; Voshaar, Richard C. Oude; Bus, Boudewijn A. A.; Prickaerts, Jos; Spinhoven, Philip; Penninx, Brenda J. W. H.

    2011-01-01

    Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, the effects o

  6. The impact of childhood abuse and recent stress on serum brain-derived neurotrophic factor and the moderating role of BDNF Val66Met

    NARCIS (Netherlands)

    Elzinga, B.M.; Molendijk, M.L.; Oude Voshaar, R.C.; Bus, B.A.A.; Prickaerts, J.; Spinhoven, P.; Penninx, B.J.

    2011-01-01

    RATIONALE: Recent findings show lowered brain-derived neurotrophic factor (BDNF) levels in major depressive disorder (MDD). Exposure to stressful life events may (partly) underlie these BDNF reductions, but little is known about the effects of early or recent life stress on BDNF levels. Moreover, th

  7. Increase in serum brain-derived neurotrophic factor in met allele carriers of the BDNF Val66Met polymorphism is specific to males.

    NARCIS (Netherlands)

    Bus, B.A.A.; Arias Vasquez, A.; Franke, B.; Prickaerts, J.; Graaf, J. de; Oude Voshaar, R.C.

    2012-01-01

    BACKGROUND: Association studies of the Val66Met polymorphism and serum brain-derived neurotrophic factor (BDNF) levels have yielded conflicting results. Recently, sex-specific differences in BDNF levels were demonstrated. As these might explain the reported inconsistencies, we tested sex interaction

  8. Brain-derived neurotrophic factor expression in dorsal root ganglion neurons in response to reanastomosis of the distal stoma after nerve grafting

    Institute of Scientific and Technical Information of China (English)

    Wei Yu; Jian Wang; Mingzhu Xu; Hanjiao Qin; Shusen Cui

    2012-01-01

    Studies have shown that retreatment of the distal stoma after nerve grafting can stimulate nerve regeneration. The present study attempted to verify the effects of reanastomosis of the distal stoma, after nerve grafting, on nerve regeneration by assessing brain-derived neurotrophic factor expression in 2-month-old rats. Results showed that brain-derived neurotrophic factor expression in L2-4 dorsal root ganglia began to increase 3 days after autologous nerve grafting post sciatic nerve injury, peaked at 14 days, decreased at 28 days, and reached similar levels to the sham-surgery group at 56 days. Brain-derived neurotrophic factor expression in L2-4 dorsal root ganglia began to increase 3 days after reanastomosis of the distal stoma, 59 days after autologous nerve grafting post sciatic nerve injury, significantly increased at 63 days, peaked at 70 days, and gradually decreased thereafter, but remained higher compared with the sham-surgery group up to 112 days. The results of this study indicate that reanastomosis of the distal stoma after orthotopic nerve grafting stimulated brain-derived neurotrophic factor expression in L2-4 dorsal root ganglia.

  9. The role of brain-derived neurotrophic factor in the regulation of cell growth and gene expression in melanotrope cells of Xenopus laevis.

    NARCIS (Netherlands)

    Jenks, B.G.; Kuribara, M.; Kidane, A.H.; Kramer, B.M.; Roubos, E.W.; Scheenen, W.J.

    2012-01-01

    Brain-derived neurotrophic factor (BDNF) is, despite its name, also found outside the central nervous system (CNS), but the functional significance of this observation is largely unknown. This review concerns the expression of BDNF in the pituitary gland. While the presence of the neurotrophin in th

  10. Local delivery of brain-derived neurotrophic factor on the perforated round window membrane in Guinea pigs : A possible clinical application

    NARCIS (Netherlands)

    Havenith, Sarah; Versnel, Huib; Klis, Sjaak F L; Grolman, Wilko

    2015-01-01

    Hypothesis/Background: Local delivery of neurotrophic factors on the intact round window membrane (RWM) of hair cell-deprived cochleas reduces degeneration of the cochlear nerve. In an animal model of profound hearing loss, we investigated whether this otoprotective effect could be enhanced by perfo

  11. Promoting Neuroplasticity for Motor Rehabilitation After Stroke: Considering the Effects of Aerobic Exercise and Genetic Variation on Brain-Derived Neurotrophic Factor

    OpenAIRE

    Mang, Cameron S.; Campbell, Kristin L.; Ross, Colin J.D.; Boyd, Lara A.

    2013-01-01

    Recovery of motor function after stroke involves relearning motor skills and is mediated by neuroplasticity. Recent research has focused on developing rehabilitation strategies that facilitate such neuroplasticity to maximize functional outcome poststroke. Although many molecular signaling pathways are involved, brain-derived neurotrophic factor (BDNF) has emerged as a key facilitator of neuroplasticity involved in motor learning and rehabilitation after stroke. Thus, rehabilitation strategie...

  12. Activation of signaling pathways following localized delivery of systemically administered neurotrophic factors across the blood-brain barrier using focused ultrasound and microbubbles

    Science.gov (United States)

    Baseri, Babak; Choi, James J.; Deffieux, Thomas; Samiotaki, Gesthimani; Tung, Yao-Sheng; Olumolade, Oluyemi; Small, Scott A.; Morrison, Barclay, III; Konofagou, Elisa E.

    2012-04-01

    The brain-derived neurotrophic factor (BDNF) has been shown to have broad neuroprotective effects in addition to its therapeutic role in neurodegenerative disease. In this study, the efficacy of delivering exogenous BDNF to the left hippocampus is demonstrated in wild-type mice (n = 7) through the noninvasively disrupted blood-brain barrier (BBB) using focused ultrasound (FUS). The BDNF bioactivity was found to be preserved following delivery as assessed quantitatively by immunohistochemical detection of the pTrkB receptor and activated pAkt, pMAPK, and pCREB in the hippocampal neurons. It was therefore shown for the first time that systemically administered neurotrophic factors can cross the noninvasively disrupted BBB and trigger neuronal downstream signaling effects in a highly localized region in the brain. This is the first time that the administered molecule is tracked through the BBB and localized in the neuron triggering molecular effects. Additional preliminary findings are shown in wild-type mice with two additional neurotrophic factors such as the glia-derived neurotrophic factor (n = 12) and neurturin (n = 2). This further demonstrates the impact of FUS for the early treatment of CNS diseases at the cellular and molecular level and strengthens its premise for FUS-assisted drug delivery and efficacy.

  13. 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, whet

  14. 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 wit

  15. 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.

  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. 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

    .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.......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...

  18. Cytokines, brain-derived neurotrophic factor and C-reactive protein in bipolar I disorder - Results from a prospective study

    DEFF Research Database (Denmark)

    Jacoby, Anne Sophie; Munkholm, Klaus; Vinberg, Maj;

    2016-01-01

    BACKGROUND: Peripheral blood brain-derived neurotrophic factor (BDNF) and inflammatory markers may reflect key pathophysiological mechanisms in bipolar disorder in relation to disease activity and neuroprogression. AIMS: To investigate whether neutrophins and inflammatory marker vary with mood...... states and are increased in patients with bipolar disorder type I during euthymia as well as in all affective states as a group, compared to levels in healthy control subjects. METHODS: In a prospective 6-12 months follow-up study, we investigated state specific, intra-individual alterations in levels...... of BDNF, hsCRP, IL-1β, IL-6, IL-8, IL-18 and TNF-α in 60 patients with bipolar I disorder with an acute severe manic index episode and in subsequent euthymic and depressive and manic states and compared with repeated measurements in healthy control subjects. Data were analysed with linear mixed effects...

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

    Directory of Open Access Journals (Sweden)

    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.

  20. GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor.

    Science.gov (United States)

    Marty, S; Berninger, B; Carroll, P; Thoenen, H

    1996-03-01

    Gamma-Aminobutyric acid (GABA) switches from enhancing to repressing brain-derived neurotrophic factor (BDNF) mRNA synthesis during the maturation of hippocampal neurons in vitro. Interneurons do not produce BDNF themselves, but BDNF enhances their differentiation. Therefore, the question arose whether hippocampal interneurons regulate their phenotype by regulating BDNF expression and release from adjacent cells. The GABA(A) receptor agonist muscimol and BDNF increased the size and neuropeptide Y (NPY) immunoreactivity of hippocampal interneurons. However, GABAergic stimulation failed to increase NPY immunoreactivity in cultures from BDNF knockout embryos. At later developmental stages, when GABA represses BDNF synthesis, treatment with muscimol induced a decrease in cell size and NPY immunoreactivity of interneurons. Interneurons might thus control their phenotype through the regulation of BDNF synthesis in, and release from, their target neurons.

  1. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: A review.

    Science.gov (United States)

    Huang, T; Larsen, K T; Ried-Larsen, M; Møller, N C; Andersen, L B

    2014-02-01

    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.

  2. 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

    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. PMID:28101102

  3. Sequence analysis and functional study of the Han Nationality glial cell line-derived neurotrophic factor transcript

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhe-yu; HUANG Ai-jun; LU Chang-lin; WU Xiang-fu; HE Cheng

    2001-01-01

    To study the sequence and function of the glial cell line-derived neurotrophic factor (GDNF) transcript in subjects of Han nationality. Methods: The Han nationality GDNF transcript was amplified by RT-PCR and expressed by baculovirus expression system. Biological activity of the expressed product was measured by the primary culture of midbrain dopaminergic neurons. Results: There only existed the shorter GDNF transcript of 555 bp in the Han nationality. The secretory expression product of the shorter transcript in insect cells promoted the survival and differentiation of dopaminergic neurons. Conclusion: It is found that there is a 78 bp deletion in the Han nationality GDNF transcript compared with the reported 633 bp GDNF transcript. The 78 bp deletion does not affect the secretory expression and biological activity of GDNF mature protein.

  4. Glial cell line-derived neurotrophic factor (GDNF) expression and NMJ plasticity in skeletal muscle following endurance exercise.

    Science.gov (United States)

    Gyorkos, A M; McCullough, M J; Spitsbergen, J M

    2014-01-17

    Glial cell line-derived neurotrophic factor (GDNF) supports and maintains the neuromuscular system during development and through adulthood by promoting neuroplasticity. The aim of this study was to determine if different modes of exercise can promote changes in GDNF expression and neuromuscular junction (NMJ) morphology in slow- and fast-twitch muscles. Rats were randomly assigned to a run training (run group), swim training (swim group), or sedentary control group. GDNF protein content was determined by enzyme-linked immunosorbant assay. GDNF protein content increased significantly in soleus (SOL) following both training protocols (PGDNF content and total end plate area were positively correlated. End plate area decreased in EDL of the run group and increased in SOL of the swim group. The results indicate that GDNF expression and NMJ morphological changes are activity dependent and that different changes may be observed by varying the exercise intensity in slow- and fast-twitch fibers.

  5. Enhanced brain-derived neurotrophic factor delivery by ultrasound and microbubbles promotes white matter repair after stroke.

    Science.gov (United States)

    Rodríguez-Frutos, Berta; Otero-Ortega, Laura; Ramos-Cejudo, Jaime; Martínez-Sánchez, Patricia; Barahona-Sanz, Inés; Navarro-Hernanz, Teresa; Gómez-de Frutos, María Del Carmen; Díez-Tejedor, Exuperio; Gutiérrez-Fernández, María

    2016-09-01

    Ultrasound-targeted microbubble destruction (UTMD) has been shown to be a promising tool to deliver proteins to select body areas. This study aimed to analyze whether UTMD was able to deliver brain-derived neurotrophic factor (BDNF) to the brain, enhancing functional recovery and white matter repair, in an animal model of subcortical stroke induced by endothelin (ET)-1. UTMD was used to deliver BDNF to the brain 24 h after stroke. This technique was shown to be safe, given there were no cases of hemorrhagic transformation or blood brain barrier (BBB) leakage. UTMD treatment was associated with increased brain BDNF levels at 4 h after administration. Targeted ultrasound delivery of BDNF improved functional recovery associated with fiber tract connectivity restoration, increasing oligodendrocyte markers and remyelination compared to BDNF alone administration in an experimental animal model of white matter injury.

  6. Brain-derived neurotrophic factor and Bcl-2 expression in rat brain areas following chronic morphine treatment

    Institute of Scientific and Technical Information of China (English)

    Huiping Yu; Hua Hu; Huaqing Meng; Wei Deng; Yixiao Fu; Qinghua Luo

    2011-01-01

    The ventral tegmental area and the locus coeruleus are associated with psychological and physical dependence of opioid addiction. To date, very little is known about brain-derived neurotrophic factor (BDNF) and Bcl-2 gene and protein changes following morphine addiction. The present study utilized immunohistochemistry and in situ hybridization techniques, which revealed that there were increased BDNF levels, but decreased Bcl-2 levels in the prefrontal cortex, locus coeruleus, hippocampus, and the ventral tegmental area during morphine-dependence formation and abstinence. However, the levels of BDNF remained unchanged, and Bcl-2 expression was increased in the nucleus accumbens. These results showed that BDNF and Bcl-2 are involved in the development of morphine dependence, and precipitation of abstinence syndrome.

  7. Expression of brain-derived neurotrophic factor mRNA in rat hippocampus after treatment with antipsychotic drugs.

    Science.gov (United States)

    Bai, Ou; Chlan-Fourney, Jennifer; Bowen, Rudy; Keegan, David; Li, Xin-Min

    2003-01-01

    Typical and atypical antipsychotic drugs, though both effective, act on different neurotransmitter receptors and are dissimilar in some clinical effects and side effects. The typical antipsychotic drug haloperidol has been shown to cause a decrease in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in neuronal cell survival, differentiation, and neuronal connectivity. However, it is still unknown whether atypical antipsychotic drugs similarly regulate BDNF expression. We examined the effects of chronic (28 days) administration of typical and atypical antipsychotic drugs on BDNF mRNA expression in the rat hippocampus using in situ hybridization. Quantitative analysis revealed that the typical antipsychotic drug haloperidol (1 mg/kg) down-regulated BDNF mRNA expression in both CA1 (P BDNF mRNA expression in CA1, CA3, and dentate gyrus regions of the rat hippocampus compared with their respective controls (P BDNF mRNA expression in rat hippocampus.

  8. Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese population.

    Science.gov (United States)

    Xu, Jie; Liu, Yun; Wang, Peng; Li, Sheng; Wang, Yabing; Li, Jun; Zhou, Daizhan; Chen, Zhuo; Zhao, Teng; Wang, Ting; Xu, He; Yang, Yifeng; Feng, Guoyin; He, Lin; Yu, Lan

    2010-01-05

    Brain-derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and services many biological functions such as neural survival, differentiation, and plasticity. Previous studies have suggested that the Val66Met (also known as rs6265 or G196A) variant of BDNF is associated with bipolar disorder (BPD), but the results have been inconclusive. We therefore genotyped the Val66Met polymorphism in a Han Chinese population sample (498 cases and 501 control subjects). We found that the BDNF genotype is associated with BPD in this population (chi(2) = 9.4666, df = 2, P = 0.00884). Furthermore, our data suggested that the Met allele rather than the Val allele increased the risk for BPD in our Han population (OR = 1.44; 95% CI = 1.070-1.950; P = 0.016). Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

  9. No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis.

    Science.gov (United States)

    Blanco, Y; Gómez-Choco, M; Arostegui, J L; Casanova, B; Martínez-Rodríguez, J E; Boscá, I; Munteis, E; Yagüe, J; Graus, F; Saiz, A

    2006-04-03

    Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).

  10. Chronic intermittent hypoxia-induced deficits in synaptic plasticity and neurocognitive functions: a role for brain-derived neurotrophic factor

    Institute of Scientific and Technical Information of China (English)

    Hui XIE; Wing-ho YUNG

    2012-01-01

    Obstructive sleep apnea (OSA) is well known for its metabolic as well as neurobehavioral consequences.Chronic intermittent hypoxia (IH) is a major component of OSA.In recent years,substantial advances have been made in elucidating the cellular and molecular mechanisms underlying the effect of chronic IH on neurocognitive functions,many of which are based on studies in animal models.A number of hypotheses have been put forward to explain chronic IH-induced neurological dysfunctions.Among these,the roles of oxidative stress and apoptosis-related neural injury are widely accepted.Here,focusing on results derived from animal studies,we highlight a possible role of reduced expression of brain-derived neurotrophic factor (BDNF) in causing impairment in long-term synaptic plasticity and neurocognitive functions during chronic IH.The possible relationship between BDNF and previous findings on this subject will be elucidated.

  11. 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.

  12. Agavins Increase Neurotrophic Factors and Decrease Oxidative Stress in the Brains of High-Fat Diet-Induced Obese Mice

    Directory of Open Access Journals (Sweden)

    Elena Franco-Robles

    2016-08-01

    Full Text Available Background: Fructans obtained from agave, called agavins, have recently shown significant benefits for human health including obesity. Therefore, we evaluated the potential of agavins as neuroprotectors and antioxidants by determining their effect on brain-derived neurotrophic factor (BDNF and glial-derived neurotrophic factor (GDNF as well as oxidative brain damage in of obese mice. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD and treated daily with 5% (HFD/A5 or 10% (HFD/A10 of agavins or a standard diet (SD for 10 weeks. The levels of BDNF and GDNF were evaluated by ELISA. The oxidative stress was evaluated by lipid peroxidation (TBARS and carbonyls. SCFAs were also measured with GC-FID. Differences between groups were assessed using ANOVA and by Tukey’s test considering p < 0.05. Results: The body weight gain and food intake of mice HFD/A10 group were significantly lower than those in the HFD group. Agavins restored BDNF levels in HFD/A5 group and GDNF levels of HFD/A5 and HFD/A10 groups in cerebellum. Interestingly, agavins decreased TBARS levels in HFD/A5 and HFD/A10 groups in the hippocampus, frontal cortex and cerebellum. Carbonyl levels were also lower in HFD/A5 and HFD/A10 for only the hippocampus and cerebellum. It was also found that agavins enhanced SCFAs production in feces. Conclusion: Agavins may act as bioactive ingredients with antioxidant and protective roles in the brain.

  13. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

    Science.gov (United States)

    Qian, Qi; Liu, Qiuji; Zhou, Dongming; Pan, Hongyu; Liu, Zhiwei; He, Fangping; Ji, Suying; Wang, Dongpi; Bao, Wangxiao; Liu, Xinyi; Liu, Zhaoling; Zhang, Heng; Zhang, Xiaoqin; Zhang, Ling; Wang, Mingkai; Xu, Ying; Huang, Fude; Luo, Benyan; Sun, Binggui

    2017-02-13

    Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a(f/f) mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL(+) cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

  14. Glial cell line-derived neurotrophic factor promotes barrier maturation and wound healing in intestinal epithelial cells in vitro.

    Science.gov (United States)

    Meir, Michael; Flemming, Sven; Burkard, Natalie; Bergauer, Lisa; Metzger, Marco; Germer, Christoph-Thomas; Schlegel, Nicolas

    2015-10-15

    Recent data suggest that neurotrophic factors from the enteric nervous system are involved in intestinal epithelial barrier regulation. In this context the glial cell line-derived neurotrophic factor (GDNF) was shown to affect gut barrier properties in vivo directly or indirectly by largely undefined processes in a model of inflammatory bowel disease (IBD). We further investigated the potential role and mechanisms of GDNF in the regulation of intestinal barrier functions. Immunostaining of human gut specimen showed positive GDNF staining in enteric neuronal plexus and in enterocytes. In Western blots of the intestinal epithelial cell lines Caco2 and HT29B6, significant amounts of GDNF were detected, suggesting that enterocytes represent an additional source of GDNF. Application of recombinant GDNF on Caco2 and HT29B6 cells for 24 h resulted in significant epithelial barrier stabilization in monolayers with immature barrier functions. Wound-healing assays showed a significantly faster closure of the wounded areas after GDNF application. GDNF augmented cAMP levels and led to significant inactivation of p38 MAPK in immature cells. Activation of p38 MAPK signaling by SB-202190 mimicked GDNF-induced barrier maturation, whereas the p38 MAPK activator anisomycin blocked GDNF-induced effects. Increasing cAMP levels had adverse effects on barrier maturation, as revealed by permeability measurements. However, increased cAMP augmented the proliferation rate in Caco2 cells, and GDNF-induced proliferation of epithelial cells was abrogated by the PKA inhibitor H89. Our data show that enterocytes represent an additional source of GDNF synthesis. GDNF contributes to wound healing in a cAMP/PKA-dependent manner and promotes barrier maturation in immature enterocytes cells by inactivation of p38 MAPK signaling.

  15. 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

  16. Effects of fluoxetine on brain-derived neurotrophic factor serum concentration and cognition in patients with vascular dementia

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    Liu X

    2014-03-01

    Full Text Available Xuan Liu,1,2 Junjian Zhang,1 Dong Sun,1 Yuanteng Fan,1 Hongbin Zhou,2 Binfang Fu21Department of Neurology, Zhongnan Hospital, Wuhan University, Wuhan, 2Department of Neurology, Xiangyang Central Hospital, Medical College, Hubei University of Arts and Science, Xiangyang, Hubei, People’s Republic of ChinaBackground: Selective serotonin reuptake inhibitors improve cognition in patients with stroke and increase the expression of brain-derived neurotrophic factor (BDNF in the rat hippocampus. However, the effects of selective serotonin reuptake inhibitors on cognition and serum BDNF levels in patients with vascular dementia are largely unknown. We performed an open-label study to investigate the effects of fluoxetine, a selective serotonin reuptake inhibitor, on cognition and serum BDNF levels in patients with vascular dementia.Methods: Fifty patients with vascular dementia were randomly allocated to receive fluoxetine (20 mg/day; n=25 or no fluoxetine (control group; n=25 for 12 weeks. Both groups received secondary prevention of stroke. Serum BDNF level, Mini-Mental State Examination (MMSE score, Ten-Point Clock Drawing score, and Digit Span Test and Verbal Fluency Test scores were measured at baseline and at week 12 in the both groups.Results: The baseline serum BDNF level correlated significantly with the MMSE score. MMSE score, Ten-Point Clock Drawing score, and serum BDNF level increased significantly in the fluoxetine group but not in the control group. The increase in serum BDNF level correlated with the increase in MMSE score in the fluoxetine group.Conclusion: Fluoxetine may potentially improve cognition in patients with vascular dementia and requires further investigation. BDNF may play an important role in cognitive recovery.Keywords: brain-derived neurotrophic factor, cognition, fluoxetine, improvement, neuroplasticity, vascular dementia

  17. Brain-derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast-spiking GABAergic interneurons.

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    Berghuis, Paul; Dobszay, Marton B; Sousa, Kyle M; Schulte, Gunnar; Mager, Peter P; Härtig, Wolfgang; Görcs, Tamás J; Zilberter, Yuri; Ernfors, Patrik; Harkany, Tibor

    2004-09-01

    GABAergic interneurons with high-frequency firing, fast-spiking (FS) cells, form synapses on perisomatic regions of principal cells in the neocortex and hippocampus to control the excitability of cortical networks. Brain-derived neurotrophic factor (BDNF) is essential for the differentiation of multiple interneuron subtypes and the formation of their synaptic contacts. Here, we examined whether BDNF, alone or in conjunction with sustained KCl-induced depolarization, drives functional FS cell differentiation and the formation of inhibitory microcircuits. Homogeneous FS cell cultures were established by target-specific isolation using the voltage-gated potassium channel 3.1b subunit as the selection marker. Isolated FS cells expressed parvalbumin, were surrounded by perineuronal nets, formed immature inhibitory connections and generated slow action potentials at 12 days in vitro. Brain-derived neurotrophic factor (BDNF) promoted FS cell differentiation by increasing the somatic diameter, dendritic branching and the frequency of action potential firing. In addition, BDNF treatment led to a significant up-regulation of synaptophysin and vesicular GABA transporter expression, components of the synaptic machinery critical for GABA release, which was paralleled by an increase in synaptic strength. Long-term membrane depolarization alone was detrimental to dendritic branching. However, we observed that BDNF and KCl exerted additive effects, as reflected by the significantly accelerated maturation of synaptic contacts and high discharge frequencies, and was required for the formation of reciprocal connections between FS cells. Our results show that BDNF, along with membrane depolarization, is critical for FS cells to establish inhibitory circuitries during corticogenesis.

  18. 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.

  19. The exposure to nicotine affects expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in neonate rats.

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    Xiaoyu, Wang

    2015-02-01

    In the current study effect of nicotine on expression of neurotrophins, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) has been studied in hippocampus and frontal cortex during development of brain in rats. Neurotrophins are factors that help in development of brain among which BDNF and NGF are very important, expressed at different stages during the developmental process. Different sedatives are reported to alter the expression of these factors. In this study, three groups of neonate rats (1-5, 5-10 and 10-15 days age) were used each having 20 rats. Ten were subjected to a dose of 66 μg of nicotine while other ten received the same amount of saline at the same time interval. Then expression of the BDNF and NGF was observed in hippocampus and frontal cortex tissue using immunoassay. Western blotting was used to observe the presence of BDNF in hippocampus as well as frontal cortex. In all groups there was a significant decrease in concentration of neurotrophic factors where nicotine was applied as compared to control. The highest expression of BDNF and NGF in hippocampus and frontal cortex was observed in 10-15 days group (G3) and in 5-10 group (G2) as compared to the control, P BDNF and it effects the development of brain in neonates that can further impair brain functions.

  20. Signaling of glial cell line-derived neurotrophic factor and its receptor GFRα1 induce Nurr1 and Pitx3 to promote survival of grafted midbrain-derived neural stem cells in a rat model of Parkinson disease.

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    Lei, Zhinian; Jiang, Yu; Li, Tao; Zhu, Jianbao; Zeng, Shuilin

    2011-09-01

    Glial cell line-derived neurotrophic factor (GDNF) and its receptor GFRα1 have been implicated in the survival of ventral midbrain dopaminergic (DA) neurons, but the molecular mechanisms bywhich GDNF generates DA neurons in grafted midbrain-derived neural stem cells (mNSCs) are not understood. Midbrain-derived neural stem cells isolated from rat embryonic mesencephalon (embryonic day 12) were treated with GDNF or in combination with GFRα1 small interfering RNA. Reverse transcription-polymerase chain reaction, Western blot, and immunocytochemistry were used totest the expression of the orphan nuclear receptor Nurr1 and thetranscription factor Pitx3 and newborn tyrosine hydroxylase (TH)-positive cells. Treatment of mNSCs with GDNF increased mNSCs' sphere diameter, reduced expression of caspase 3, and increased expression of Bcl-2. Glial cell line-derived neurotrophic factor-treated mNSCs enhanced Nurr1 and Pitx3 expression and the fraction of TH-, TH/Pitx3-, and TH/Nurr1-positive cells in culture. Grafted GDNF-treated mNSCs significantly decreased apomorphine-induced rotation behavior in 6-hydroxydopamine-lesioned rats. Glialcell line-derived neurotrophic factor-treated mNSCs showed increased numbers of TH/Pitx3- and TH/Nurr1-postivie cells. The effect elicited by GDNF was inhibited by small interfering RNA-mediated knockdown of GFRα1. Our data demonstrate the contribution of GDNF to DA neuron development and may also elucidate pathogenetic mechanisms in Parkinson disease and contribute to the development of novel therapies for the disorder.

  1. Brain-derived neurotrophic factor enhances the basal rate of protein synthesis by increasing active eukaryotic elongation factor 2 levels and promoting translation elongation in cortical neurons.

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    Takei, Nobuyuki; Kawamura, Mihoko; Ishizuka, Yuta; Kakiya, Naomasa; Inamura, Naoko; Namba, Hisaaki; Nawa, Hiroyuki

    2009-09-25

    The constitutive and activity-dependent components of protein synthesis are both critical for neural function. Although the mechanisms controlling extracellularly induced protein synthesis are becoming clear, less is understood about the molecular networks that regulate the basal translation rate. Here we describe the effects of chronic treatment with various neurotrophic factors and cytokines on the basal rate of protein synthesis in primary cortical neurons. Among the examined factors, brain-derived neurotrophic factor (BDNF) showed the strongest effect. The rate of protein synthesis increased in the cortical tissues of BDNF transgenic mice, whereas it decreased in BDNF knock-out mice. BDNF specifically increased the level of the active, unphosphorylated form of eukaryotic elongation factor 2 (eEF2). The levels of active eEF2 increased and decreased in BDNF transgenic and BDNF knock-out mice, respectively. BDNF decreased kinase activity and increased phosphatase activity against eEF2 in vitro. Additionally, BDNF shortened the ribosomal transit time, an index of translation elongation. In agreement with these results, overexpression of eEF2 enhanced protein synthesis. Taken together, our results demonstrate that the increased level of active eEF2 induced by chronic BDNF stimulation enhances translational elongation processes and increases the total rate of protein synthesis in neurons.

  2. Role of PI3-K/Akt pathway and its effect on glial cell line-derived neurotrophic factor in midbrain dopamine cells

    Institute of Scientific and Technical Information of China (English)

    Hong-jun WANG; Jun-ping CAO; Jing-kao YU; Dian-shuai GAO

    2007-01-01

    Aim: To explore the intracellular mechanisms underlying the survival/differentia-don effect of the glial cell line-derived neurotrophic factor (GDNF) on dopamine(DA) cells. Methods: Midbrain slice culture and primary cell culture were established, and the cultures were divided into 3 groups: control group, GDNF group, and the phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) pathway-inhibited group. Then the expression of tyrosine hydroxylase (TH) was detected by immunostaining as well as Western blotting. Results: GDNF treatment induced an increase in the number of TH-immunoreactive (ir) cells and the neurite number of TH-ir cells, as well as in the level of TH expression in cultures (Number of TH-ir cells in the slice culture: control group, 8.76±0.75; GDNF group, 18.63±0.95.Number of TH-ir cells and neurite number of TH-ir cells in cell culture: controlgroup, 3.65±0.88 and 2.49±0.42; GDNF group, 6.01±0.43 and 4.89±0.46). Meanwhile, the stimulation of cultured cells with GDNF increased the phosphorylation of Akt, which is a downstream effector of PI3-K/Akt. The effects of GDNF were specifically blocked by the inhibitor of the PI3-K/Akt pathway, wortmannin (Number of TH-ir cells in slice culture: PI3-K/Akt pathway-inhibited group, 6.98±0.58. Num-ber of TH-ir cells and neurite number of TH-ir cells in cell culture: PI3-K/Aktpathway-inhibited group, 3.79±0.62 and 2.50±0.25, respectively). Conclusion: The PI3-K/Akt pathway mediates the survival/differentiation effect of GDNF on DA cells.8±0.58.

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

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    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.

  4. INCREASED EXPRESSION OF GLIAL CELL LINE-DERIVED NEUROTROPHIC FACTOR IN RAT BRAIN AFTER TRAUMATIC BRAIN INJURY

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    V. Rahimi-Movaghar

    2005-04-01

    Full Text Available Glial cell line-derived neurotrophic factor (GDNF plays important roles not only for the differentiation of neurons during normal development but also for the survival and recovery of many populations of mature neurons. The effect of traumatic brain injury (TBI on the expression of GDNF is currently unknown. To determine if there is alteration in GDNF after TBI we examined the effect of controlled cortical impact (CCI injury on GDNF protein levels at 6 hours, 1 day, 1 week, and 4 weeks following injury by utilizing a commercially available antibody specific to GDNF. Rats were anesthetized and surgically prepared for CCI injury (4 m/sec, 2.7 mm and sham surgery. Injured and sham animals (n=6 per group were sacrificed at 6 hours, 1 day, 1 week, and 4 weeks and perfused with 4% paraformaldehyde. Coronal sections (35 mm thick were cut through the hippocampus. An increased expression of GDNF protein was observed by immunohistochemistry in the dentate gyrus of hippocampus and the cortex in injured rats compared to sham controls. The increased expression of GDNF was more evidently observed in the ipsilateral dentate gyrus and the area around the contusion in the cortex. In the cortex, GDNF immunoreactivity appeared greatest in cells with glial morphology but in the hippocampus, GDNF immunoreactivity was greatest in neuronal-like cells. These changes were observed at 1 day, 1 and 4 weeks postinjury. We speculate that the up-regulation of the GDNF protein may reflect its neurotrophic and neuroprotective effect on dopaminergic system responding to the TBI insult.

  5. "Regulation of the intracerebroventricular administration of brain-derived neurotrophic factor on baroreflex function and insulin sensitivity in rats".

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    Wang, Ming-Fu; Chan, Yin-Ching; Lee, Hsu-Tung; Hong, Ling-Zong

    2012-06-30

    "In addition to its well-established neurotrophic effects, brain-derived neurotrophic factor (BDNF) has also been shown to regulate glucose metabolism. The present study was conducted to determine whether BDNF has effects on baroreflex sensitivity (BRS) and whole-body insulin sensitivity through modulation of autonomic nervous function in normal rats. Male Sprague-Dawley rats were treated with intracerebroventricular BDNF (20 μg per rat, 10μl; BDNF) or artificial cerebrospinal fluid (10 μl; control) at an infusion rate of 1 μl/min in conscious state. The whole-body insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp technique. BRS in response to phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS) was assessed using linear regression analysis. The sympathetic and parasympathetic influences on BRS were investigated by pharmacological autonomic blockade. When compared to the control rats, blood glucose levels were slightly but significantly decreased in BDNF-treated rats. However, plasma insulin levels were reduced by about 30%. The whole-body insulin sensitivity was increased in BDNF-treated rats. In addition, blood pressure was increased but heart rate remained unchanged after BDNF treatment. Enhanced PE-BRS was also observed in the BDNF-treated rats, which was attributed to the abnormal parasympathetic activation as revealed by the results of the pharmacological blockade study with methylatropine. Results of the present demonstrate that central BDNF plays an important role in the regulation of whole-body insulin sensitivity and baroreflex function. The data indicate that the alteration of autonomic nervous function may play a role in the effects of BDNF."

  6. Coordinate action of pre- and postsynaptic brain-derived neurotrophic factor is required for AMPAR trafficking and acquisition of in vitro classical conditioning.

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    Li, W; Keifer, J

    2008-08-26

    Brain-derived neurotrophic factor (BDNF) has been implicated in mechanisms of synaptic plasticity such as long-term potentiation (LTP), but its role in associative learning remains largely unknown. In the present study, we investigated the function of BDNF and its receptor tropomyosin-related kinase B (TrkB) in an in vitro model of classical conditioning using pond turtles, Pseudemys scripta elegans. Conditioning resulted in a significant increase in BDNF and phospho (p)-Trk expression. Bath application of antibodies directed against TrkB, but not TrkA or TrkC, abolished acquisition of conditioning, as did a receptor tyrosine kinase inhibitor K252a and an inhibitor of nitric oxide synthase 7-nitroindazole. Significantly, injections of BDNF Ab into the nerve roots of presynaptic axonal projections or postsynaptic motor neurons prevented acquisition of conditioning, suggesting that BDNF is required on both sides of the synapse for modification to occur. The presynaptic proteins synaptophysin and synapsin I were increased upon conditioning or BDNF application. Furthermore, BDNF application alone mimicked conditioning-induced synaptic insertion of GluR1 and GluR4 AMPAR subunits into synapses, which was inhibited by co-application of BDNF and K252a. Data also show that extracellular signal-regulated kinase (ERK) was activated in BDNF-treated preparations. We conclude that coordinate pre- and postsynaptic actions of BDNF are required for acquisition of in vitro classical conditioning.

  7. Brain-derived neurotrophic factor facilitates TrkB down-regulation and neuronal injury after status epilepticus in the rat hippocampus.

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    Unsain, Nicolás; Montroull, Laura Ester; Mascó, Daniel Hugo

    2009-10-01

    Brain-derived neurotrophic factor (BDNF) is involved in many aspects of neuronal biology and hippocampal physiology. Status epilepticus (SE) is a condition in which prolonged seizures lead to neuronal degeneration. SE-induced in rodents serves as a model of Temporal Lobe Epilepsy with hippocampal sclerosis, the most frequent epilepsy in humans. We have recently described a strong correlation between TrkB decrease and p75ntr increase with neuronal degeneration (Neuroscience 154:978, 2008). In this report, we report that local, acute intra-hippocampal infusion of function-blocking antibodies against BDNF prevented both early TrkB down-regulation and neuronal degeneration after SE. Conversely, the infusion of recombinant human BDNF protein after SE greatly increased neuronal degeneration. The inhibition of BDNF mRNA translation by the infusion of antisense oligonucleotides induced a rapid decrease of BDNF protein levels, and a delayed increase. If seizures were induced at the time endogenous BDNF was decreased, SE-induced neuronal damage was prevented. On the other hand, if seizures were induced at the time endogenous BDNF was increased, SE-induced neuronal damage was exacerbated. These results indicate that under a pathological condition BDNF exacerbates neuronal injury.

  8. Brain-derived neurotrophic factor levels influence the balance of migration and differentiation of subventricular zone cells, but not guidance to the olfactory bulb.

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    Petridis, Athanasios K; El Maarouf, Abderrahman

    2011-02-01

    New progenitor cells in the subventricular zone (SVZ) migrate rostrally and differentiate into interneurons in the olfactory bulb (OB) throughout life. Brain-derived neurotrophic factor (BDNF) may influence the normal progression of this migration. In the present study, mouse SVZ explant cultures were used to investigate how BDNF modulates the behavior of these migrating progenitors. Concentrations of BDNF in the physiological range (e.g. 1ng/mL) stimulated migration, whereas doses of 10 ng/mL or higher induced SVZ cell differentiation and reduced migration. Pharmacological inhibition of the mitogen-activated protein kinase (MAPK) pathway blocked the BDNF-induced differentiation of SVZ progenitors, indicating that differentiation of SVZ progenitors in response to high-dose BDNF is initiated through MAPK. Physiological concentrations of BDNF, like the presence of polysialic acid in the tissue, stimulated migration of cells from the explant without affecting the speed at which this occurs. Interestingly, in vivo immunohistochemical and molecular analysis showed similar levels of BDNF in both the SVZ and OB; that is, there was no positive gradient attracting SVZ cells towards the OB. Our data show that SVZ cells respond differently to different concentrations of BDNF.

  9. Brain-derived neurotrophic factor-mediated retrograde signaling required for the induction of long-term potentiation at inhibitory synapses of visual cortical pyramidal neurons.

    Science.gov (United States)

    Inagaki, Tsuyoshi; Begum, Tahamina; Reza, Faruque; Horibe, Shoko; Inaba, Mie; Yoshimura, Yumiko; Komatsu, Yukio

    2008-06-01

    High-frequency stimulation (HFS) induces long-term potentiation (LTP) at inhibitory synapses of layer 5 pyramidal neurons in developing rat visual cortex. This LTP requires postsynaptic Ca2+ rise for induction, while the maintenance mechanism is present at the presynaptic site, suggesting presynaptic LTP expression and the necessity of retrograde signaling. We investigated whether the supposed signal is mediated by brain-derived neurotrophic factor (BDNF), which is expressed in pyramidal neurons but not inhibitory interneurons. LTP did not occur when HFS was applied in the presence of the Trk receptor tyrosine kinase inhibitor K252a in the perfusion medium. HFS produced LTP when bath application of K252a was started after HFS or when K252a was loaded into postsynaptic cells. LTP did not occur in the presence of TrkB-IgG scavenging BDNF or function-blocking anti-BDNF antibody in the medium. In cells loaded with the Ca2+ chelator BAPTA, the addition of BDNF to the medium enabled HFS to induce LTP without affecting baseline synaptic transmission. These results suggest that BDNF released from postsynaptic cells activates presynaptic TrkB, leading to LTP. Because BDNF, expressed activity dependently, regulates the maturation of cortical inhibition, inhibitory LTP may contribute to this developmental process, and hence experience-dependent functional maturation of visual cortex.

  10. 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

  11. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

    Science.gov (United States)

    Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

    2016-01-15

    Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

  12. Activated microglia induce bone marrow mesenchymal stem cells to produce glial cell-derived neurotrophic factor and protect neurons against oxygen-glucose deprivation injury

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    Bingke Lv

    2016-12-01

    Full Text Available In this study, we investigated interactions among microglia (MG, bone marrow mesenchymal stem cells (BMSCs and neurons in cerebral ischemia and the potential mechanisms using an in vitro oxygen-glucose deprivation (OGD model. Rat BMSCs were incubated with conditioned medium (CM from in vitro cultures of OGD-activated rat MG and murine BV2 MG cells. Effects of glial cell-derived neurotrophic factor (GDNF on rat neuron viability, apoptosis, lactate dehydrogenase (LDH leakage and mitochondrial membrane potential (MMP were analyzed in this model. OGD-activated MG promoted GDNF production by BMSCs (P < 0.01. TNFα, but not IL6 or IL1β, promoted GDNF production by BMSCs (P < 0.001. GDNF or CM pre-treated BMSCs elevated neuronal viability and suppressed apoptosis (P < 0.05 or P < 0.01; these effects were inhibited by the RET antibody. GDNF activated MEK/ERK and PI3K/AKT signaling but not JNK/c-JUN. Furthermore, GDNF upregulated B cell lymphoma 2 (BCL2 and heat shock 60 kDa protein 1 (HSP60 levels, suppressed LDH leakage, and promoted MMP. Thus, activated MG produce TNFα to stimulate GDNF production by BMSCs, which prevents and repairs OGD-induced neuronal injury, possibly via regulating MEK/ERK and PI3K/AKT signaling. These findings will facilitate the prevention and treatment of neuronal injury by cerebral ischemia.

  13. Effects of simvastatin on the expression of inducible nitric oxide synthase and brain-derived neurotrophic factor in a lipopolysaccharide-induced rat model of Parkinson disease.

    Science.gov (United States)

    Tan, Wang; Xue-bin, Cao; Tian, Zhang; Xiao-wu, Chen; Pei-pei, Huang; Zhi-bin, Chen; Bei-sha, Tang

    2016-01-01

    To investigate the effects of simvastatin on the expression of inducible nitric oxide synthase (iNOS) and brain-derived neurotrophic factor (BDNF) in the substantia nigra in a lipopolysaccharide (LPS)-induced rat model of Parkinson disease (PD), and to study the mechanisms underlying the neuroprotective effects of simvastatin in PD. The LPS-PD model was established by injection of LPS (5 mg/mL, 2.0 μL) into the right substantia nigra compacta (SNC). Rats in the sham-operated group received saline. The simvastatin treatment group was intraperitoneally administered simvastatin (5 mg/kg, 2.0 μL) at 1 h before, and daily for 14 days after surgery, while the sham-operated and LPS-model groups received saline. Iba-1-positive cells and tyrosine hydroxylase (TH), as well as iNOS and BDNF in the SNC were detected by immunohistochemistry and Western blotting, respectively. The effect of simvastatin in the PD model was also examined in behavioral tests. The LPS-model group exhibited typical animal PD behaviors. Compared with the control group, the LPS-model group exhibited a decreased number of DA neurons (p model, possibly by promoting neuronal repair and regeneration, and by inhibiting oxidative stress, thus improving substantia nigra function.

  14. Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3β/Mitochondrial Fission Pathway.

    Science.gov (United States)

    Liu, Yanan; Yan, Yasheng; Inagaki, Yasuyoshi; Logan, Sarah; Bosnjak, Zeljko J; Bai, Xiaowen

    2017-07-01

    Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotrophic growth factors such as brain-derived neurotrophic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 μM or dimethyl sulfoxide as control for 6 hours. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or cocultures containing either low or high density of astrocytes (1:9 or 1:1 ratio of astrocytes to neurons ratio [ANR], respectively). The astrocyte-conditioned medium was collected 12 hours after propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using enzyme-linked immunosorbent assay. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B inhibitor cyclotraxin-B, glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 before propofol exposure. Western blot was performed for quantification of the level of protein kinase B and GSK3β. Mitochondrial shape was visualized through translocase of the outer membrane 20 staining. Propofol increased cell death in neurons by 1.8-fold (% of PI-positive cells [PI%] = 18.6; 95% confidence interval [CI], 15.2-21.9, P .05]). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in

  15. A role for histone acetylation mechanisms in adolescent alcohol exposure-induced deficits in hippocampal brain-derived neurotrophic factor expression and neurogenesis markers in adulthood.

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    Sakharkar, Amul J; Vetreno, Ryan P; Zhang, Huaibo; Kokare, Dadasaheb M; Crews, Fulton T; Pandey, Subhash C

    2016-12-01

    Binge drinking during adolescence is a risk factor for neuropsychiatric disorders that can develop later in life. Histone acetylation is an important epigenetic mechanism that contributes to neurodevelopment. We investigated the effects of adolescent intermittent ethanol (AIE) exposure, as opposed to normal saline (AIS) exposure, on histone acetylation-mediated regulation of brain-derived neurotrophic factor (BDNF) expression and developmental stages of neurogenesis (proliferating and immature neurons) in the hippocampus in adulthood. AIE exposure increased whole hippocampal histone deacetylase (HDAC) activity and decreased binding protein of cyclic adenosine monophosphate response element binding protein (CBP) and histone H3-K9 acetylation levels in the CA1, CA2, and CA3 regions of the hippocampus. BDNF protein and exon IV mRNA levels in the CA1 and CA3 regions of the hippocampus of AIE-exposed adult rats were decreased as compared to AIS-exposed adult rats. AIE-induced anxiety-like behaviors and deficits in histone H3 acetylation at BDNF exon IV promoter in the hippocampus during adulthood, which were reversed by treatment with the HDAC inhibitor, trichostatin A (TSA). Similarly, neurogenesis was inhibited by AIE in adulthood as demonstrated by the decrease in Ki-67 and doublecortin (DCX)-positive cells in the dentate gyrus, which was normalized by TSA treatment. These results indicate that AIE exposure increases HDACs and decreases CBP levels that may be associated with a decrease in histone H3 acetylation in the hippocampus. These epigenetic changes potentially decrease BDNF expression and inhibit neurogenesis in the hippocampus that may be involved in AIE-induced behavioral abnormalities, including anxiety, in adulthood.

  16. The brain-derived neurotrophic factor (BDNF gene Val66Met polymorphism affects memory performance in older adults

    Directory of Open Access Journals (Sweden)

    Lucas A. de Azeredo

    Full Text Available Objective: Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Methods: Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR, delayed verbal recall (DVR, and memory retention rate. Results: BDNF Met allele carriers had lower DVR scores (p = 0.004 and a decline in memory retention (p = 0.017 when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088. Conclusion: These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  17. The brain-derived neurotrophic factor (BDNF) gene Val66Met polymorphism affects memory performance in older adults.

    Science.gov (United States)

    Azeredo, Lucas A de; De Nardi, Tatiana; Levandowski, Mateus L; Tractenberg, Saulo G; Kommers-Molina, Julia; Wieck, Andrea; Irigaray, Tatiana Q; Silva, Irênio G da; Grassi-Oliveira, Rodrigo

    2017-01-01

    Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults. Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate. BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088). These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.

  18. Glial cell line-derived neurotrophic factor attenuates behavioural deficits and regulates nigrostriatal dopaminergic and peptidergic markers in 6-hydroxydopamine-lesioned adult rats: comparison of intraventricular and intranigral delivery.

    Science.gov (United States)

    Lapchak, P A; Miller, P J; Collins, F; Jiao, S

    1997-05-01

    The effects of intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor were tested on low dose (0.05 mg/kg) apomorphine-induced rotations and tyrosine hydroxylase activity in the substantia nigra and striatum of stable 6-hydroxydopamine-lesioned rats. In addition, we determined if 6-hydroxydopamine lesions in the absence or presence of treatment affected neuropeptide (substance P, met-enkephalin, dynorphin) content in the striatum. Glial cell line-derived neurotrophic factor, when administered intranigrally, prevented apomorphine-induced rotational behaviour for 11 weeks following a single injection. In comparison, intraventricularly-administered glial cell line-derived neurotrophic factor produced a transient reduction in rotational behaviour that lasted for two to three weeks following a single injection. We also show that rotational behaviour is reduced following each subsequent intraventricular injection of glial cell line-derived neurotrophic factor given every six weeks, a time-point when baseline rotation deficits were re-established. Intranigrally- or intraventricularly-administered glial cell line-derived neurotrophic factor significantly reduced weight gain in all 6-hydroxydopamine-lesioned rats in this study. Following behavioural analysis where a confirmed improvement of behaviour was established, tissues were dissected for neurochemical analysis. In lesioned rats with intranigral injections of administered glial cell line-derived neurotrophic factor, significant increases of nigral, but not striatal tyrosine hydroxylase activity were measured. Additionally, 6-hydroxydopamine lesions significantly increased striatal dynorphin (61-139%) and met-enkephalin (81-139%), but not substance P levels. In these rats, intranigrally-administered glial cell line-derived neurotrophic factor injections reversed lesion-induced increases in nigral dynorphin A levels and increased nigral dopamine levels, but did not alter nigral met

  19. 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.

  20. 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.

  1. Gray matter volume in adolescent anxiety: an impact of the brain-derived neurotrophic factor Val(66)Met polymorphism?

    Science.gov (United States)

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

    2013-02-01

    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(66)Met polymorphism may modulate such brain morphometry profiles. Using voxel-based morphometry and magnetic resonance imaging, associations of BDNF and clinical anxiety with regional GMVs of anterior cingulate cortex, insula, amygdala, and hippocampus were examined in 39 affected (17 Met allele carriers, 22 Val/Val homozygotes) and 63 nonaffected adolescents (27 [corrected] Met allele carriers, 36 [corrected] Val/Val homozygotes). Amygdala and anterior hippocampal GMVs were significantly smaller in patients than in healthy comparison adolescents, with a reverse pattern for the insula. Post-hoc regression analyses indicated a specific contribution of social phobia to the GMV reductions in the amygdala and hippocampus. In addition, insula and dorsal-anterior cingulate cortex (ACC) GMVs were modulated by BDNF genotype. In both regions, and GMVs were larger in the Val/Val homozygote patients than in individuals carrying the Met allele. These results implicate reduced GMV in the amygdala and hippocampus in pediatric anxiety, particularly social phobia. In addition, the data suggest that genetic factors may modulate differences in the insula and dorsal ACC. Published by Elsevier Inc.

  2. Expression of neurotrophic factors in the dorsal root ganglion in a rat model of lumbar disc herniation.

    Science.gov (United States)

    Obata, Koichi; Tsujino, Hiroaki; Yamanaka, Hiroki; Yi, Dai; Fukuoka, Tetsuo; Hashimoto, Norio; Yonenobu, Kazuo; Yoshikawa, Hideki; Noguchi, Koichi

    2002-09-01

    A variety of molecules released by inflammatory reactions in the dorsal root and dorsal root ganglion (DRG) may play important roles in the pathology of neuronal abnormalities in lumbar disc herniation. In order to elucidate the pathophysiological mechanisms of painful radiculopathy, secondary to lumbar disc herniation, we evaluated pain-related behavior and the change of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG and dorsal root using a rat model of lumbar disc herniation. In the nucleus pulposus (NP) group, the left L4/5 nerve roots were exposed after hemilaminectomies and autologous intervertebral discs, which were obtained from coccygeal intervertebral discs, were implanted on each of the exposed nerve roots without mechanical compression. Rats in the NP group, but not the sham-operated rats, developed mechanical allodynia on the ipsilateral hind paw for 1 day after surgery and showed a significant increase in the number of NGF-immunoreactive (IR) cells in the nerve root and DRG. NGF-IR cells in the nerve root and DRG included macrophages and Schwann cells, because these cells were labeled for NGF and ED-1 or glial fibrillary acid protein by dual immunostaining. A significant increase in the percentage of BDNF-IR neurons in the DRG was observed in the NP group at 3 days after surgery and the increase in BDNF mRNA expression was confirmed using in situ hybridization histochemistry and reverse transcription-polymerase chain reaction. We also injected NGF into the endoneurial space of the normal rat spinal nerve root and found that the NGF injection produced dose-dependent mechanical allodynia on the ipsilateral hind paw at 1 day after surgery and an increase in the percentage of BDNF-IR neurons in the DRG at 3 days after surgery compared to the group receiving saline injection. These findings suggest that in the lumbar disc herniation model, i.e. neuritis of the nerve root, increased NGF produced by the

  3. Adenoviral-mediated glial cell line-derived neurotrophic factor gene transfer has a protective effect on sciatic nerve following constriction-induced spinal cord injury.

    Science.gov (United States)

    Chou, An-Kuo; Yang, Ming-Chang; Tsai, Hung-Pei; Chai, Chee-Yin; Tai, Ming-Hong; Kwan, Aij-Li; Hong, Yi-Ren

    2014-01-01

    Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good

  4. Reduced levels of brain-derived neurotrophic factor contribute to synaptic imbalance during the critical period of respiratory development in rats.

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    Gao, Xiu-Ping; Liu, Qiuli; Nair, Bindu; Wong-Riley, Margaret T T

    2014-07-01

    Previously, our electrophysiological studies revealed a transient imbalance between suppressed excitation and enhanced inhibition in hypoglossal motoneurons of rats on postnatal days (P) 12-13, a critical period when abrupt neurochemical, metabolic, ventilatory and physiological changes occur in the respiratory system. The mechanism underlying the imbalance is poorly understood. We hypothesised that the imbalance was contributed by a reduced expression of brain-derived neurotrophic factor (BDNF), which normally enhances excitation and suppresses inhibition. We also hypothesised that exogenous BDNF would partially reverse this synaptic imbalance. Immunohistochemistry/single-neuron optical densitometry, real-time quantitative PCR (RT-qPCR) and whole-cell patch-clamp recordings were done on hypoglossal motoneurons in brainstem slices of rats during the first three postnatal weeks. Our results indicated that: (1) the levels of BDNF and its high-affinity tyrosine receptor kinase B (TrkB) receptor mRNAs and proteins were relatively high during the first 1-1.5 postnatal weeks, but dropped precipitously at P12-13 before rising again afterwards; (2) exogenous BDNF significantly increased the normally lowered frequency of spontaneous excitatory postsynaptic currents but decreased the normally heightened amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) during the critical period; (3) exogenous BDNF also decreased the normally heightened frequency of miniature IPSCs at P12-13; and (4) the effect of exogenous BDNF was partially blocked by K252a, a TrkB receptor antagonist. Thus, our results are consistent with our hypothesis that BDNF and TrkB play an important role in the synaptic imbalance during the critical period. This may have significant implications for the mechanism underlying sudden infant death syndrome.

  5. Tricyclic Antidepressant Amitriptyline-induced Glial Cell Line-derived Neurotrophic Factor Production Involves Pertussis Toxin-sensitive Gαi/o Activation in Astroglial Cells.

    Science.gov (United States)

    Hisaoka-Nakashima, Kazue; Miyano, Kanako; Matsumoto, Chie; Kajitani, Naoto; Abe, Hiromi; Okada-Tsuchioka, Mami; Yokoyama, Akinobu; Uezono, Yasuhito; Morioka, Norimitsu; Nakata, Yoshihiro; Takebayashi, Minoru

    2015-05-29

    Further elaborating the mechanism of antidepressants, beyond modulation of monoaminergic neurotransmission, this study sought to elucidate the mechanism of amitriptyline-induced production of glial cell line-derived neurotrophic factor (GDNF) in astroglial cells. Previous studies demonstrated that an amitriptyline-evoked matrix metalloproteinase (MMP)/FGF receptor (FGFR)/FGFR substrate 2α (FRS2α)/ERK cascade is crucial for GDNF production, but how amitriptyline triggers this cascade remains unknown. MMP is activated by intracellular mediators such as G proteins, and this study sought to clarify the involvement of G protein signaling in amitriptyline-evoked GDNF production in rat C6 astroglial cells (C6 cells), primary cultured rat astrocytes, and normal human astrocytes. Amitriptyline-evoked GDNF mRNA expression and release were inhibited by pertussis toxin (PTX), a Gα(i/o) inhibitor, but not by NF449, a Gα(s) inhibitor, or YM-254890, a Gαq inhibitor. The activation of the GDNF production cascade (FGFR/FRS2α/ERK) was also inhibited by PTX. Deletion of Gα(ο1) and Gα(i3) by RNAi demonstrated that these G proteins play important roles in amitriptyline signaling. G protein activation was directly analyzed by electrical impedance-based biosensors (CellKey(TM) assay), using a label-free (without use of fluorescent proteins/probes or radioisotopes) and real time approach. Amitriptyline increased impedance, indicating Gα(i/o) activation that was suppressed by PTX treatment. The impedance evoked by amitriptyline was not affected by inhibitors of the GDNF production cascade. Furthermore, FGF2 treatment did not elicit any effect on impedance, indicating that amitriptyline targets PTX-sensitive Gα(i/o) upstream of the MMP/FGFR/FRS2α/ERK cascade. These results suggest novel targeting for the development of antidepressants.

  6. Melanocortin 4 receptor activates ERK-cFos pathway to increase brain-derived neurotrophic factor expression in rat astrocytes and hypothalamus.

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    Ramírez, D; Saba, J; Carniglia, L; Durand, D; Lasaga, M; Caruso, C

    2015-08-15

    Melanocortins are neuropeptides with well recognized anti-inflammatory and anti-apoptotic effects in the brain. Of the five melanocortin receptors (MCR), MC4R is abundantly expressed in the brain and is the only MCR present in astrocytes. We have previously shown that MC4R activation by the α-melanocyte stimulating hormone (α-MSH) analog, NDP-MSH, increased brain-derived neurotrophic factor (BDNF) expression through the classic cAMP-Protein kinase A-cAMP responsive element binding protein pathway in rat astrocytes. Now, we examined the participation of the mitogen activated protein kinases pathway in MC4R signaling. Rat cultured astrocytes treated with NDP-MSH 1 µM for 1 h showed increased BDNF expression. Inhibition of extracellular signal-regulated kinase (ERK) and ribosomal p90 S6 kinase (RSK), an ERK substrate, but not of p38 or JNK, prevented the increase in BDNF expression induced by NDP-MSH. Activation of MC4R increased cFos expression, a target of both ERK and RSK. ERK activation by MC4R involves cAMP, phosphoinositide-3 kinase (PI3K) and the non receptor tyrosine kinase, Src. Both PI3K and Src inhibition abolished NDP-MSH-induced BDNF expression. Moreover, we found that intraperitoneal injection of α-MSH induces BDNF and MC4R expression and activates ERK and cFos in male rat hypothalamus. Our results show for the first time that MC4R-induced BDNF expression in astrocytes involves ERK-RSK-cFos pathway which is dependent on PI3K and Src, and that melanocortins induce BDNF expression and ERK-cFos activation in rat hypothalamus. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Brain-derived neurotrophic factor produced by human umbilical tissue-derived cells is required for its effect on hippocampal dendritic differentiation.

    Science.gov (United States)

    Alder, Janet; Kramer, Brian C; Hoskin, Casey; Thakker-Varia, Smita

    2012-06-01

    The potential for nonembryonic cells to promote differentiation of neuronal cells has therapeutic implications for regeneration of neurons damaged by stroke or injury and avoids many ethical and safety concerns. The authors have assessed the capacity of human umbilical tissue-derived cells (hUTC) and human mesenchymal stromal cells (hMSC) to enhance differentiation of rodent hippocampal neurons. Co-culture of hippocampal cells with hUTC or hMSC in transwell inserts for 3 days resulted in increase of several dendritic parameters including the number and length of primary dendrites. The effect of hUTC or hMSC on dendritic maturation was only apparent on neurons grown for 2 weeks in vitro prior to co-culture. Changes in dendritic morphology in the presence of hUTC were also accompanied by increased expression of the presynaptic marker synaptotagmin and the postsynaptic marker postsynaptic density protein 95 kDa (PSD95) suggesting that there may also be an increase in the number of synapses formed in the presence of hUTC. The effect of hUTC and hMSC on hippocampal cells in co-culture was comparable to those induced by treatment with recombinant human brain-derived neurotrophic factor (BDNF) implying that a similar factor may be released from hUTC or hMSC. Analysis of hUTC-conditioned medium by ELISA demonstrated that BDNF was indeed secreted. An antibody that blocks the actions of BDNF partially inhibited the actions of hUTC on dendritic morphology suggesting that BDNF is at least one of the factors secreted from the cells to promote dendritic maturation. These results indicate that hUTC secrete biologically active BDNF, which can affect dendritic morphology.

  8. 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

  9. Preservation of biological activity of glial cell line-derived neurotrophic factor (GDNF) after microencapsulation and sterilization by gamma irradiation.

    Science.gov (United States)

    Checa-Casalengua, P; Jiang, C; Bravo-Osuna, I; Tucker, B A; Molina-Martínez, I T; Young, M J; Herrero-Vanrell, R

    2012-10-15

    A main issue in controlled delivery of biotechnological products from injectable biodegradable microspheres is to preserve their integrity and functional activity after the microencapsulation process and final sterilization. The present experimental work tested different technological approaches to maintain the biological activity of an encapsulated biotechnological product within PLGA [poly (lactic-co-glycolic acid)] microspheres (MS) after their sterilization by gamma irradiation. GDNF (glial cell line-derived neurotrophic factor), useful in the treatment of several neurodegenerative diseases, was chosen as a labile model protein. In the particular case of optic nerve degeneration, GDNF has been demonstrated to improve the damaged retinal ganglion cells (RGC) survival. GDNF was encapsulated in its molecular state by the water-in-oil-in-water (W/O/W) technique or as solid according to the solid-in-oil-in-water (S/O/W) method. Based on the S/O/W technique, GDNF was included in the PLGA microspheres alone (S/O/W 1) or in combination with an antioxidant (vitamin E, Vit E) (S/O/W 2). Microspheres were sterilized by gamma-irradiation (dose of 25 kGy) at room and low (-78 °C) temperatures. Functional activity of GDNF released from the different microspheres was evaluated both before and after sterilization in their potential target cells (retinal cells). Although none of the systems proposed achieved with the goal of totally retain the structural stability of the GDNF-dimer, the protein released from the S/O/W 2 microspheres was clearly the most biologically active, showing significantly less retinal cell death than that released from either W/O/W or S/O/W 1 particles, even in low amounts of the neurotrophic factor. According to the results presented in this work, the biological activity of biotechnological products after microencapsulation and sterilization can be further preserved by the inclusion of the active molecule in its solid state in combination with

  10. Spatial memory training modifies the expression of brain-derived neurotrophic factor tyrosine kinase receptors in young and aged rats.

    Science.gov (United States)

    Silhol, M; Arancibia, S; Maurice, T; Tapia-Arancibia, L

    2007-05-25

    Aging leads to alterations in the function of the hippocampus, a brain structure largely involved in learning processes. This study aimed at examining the basal levels and the impact of a learning-associated task on brain-derived neurotrophic factor (BDNF), on BDNF full-length catalytic receptor (TrkB.FL) and on the truncated forms (TrkB.T1 and TrkB.T2) receptor expression (mRNA and protein) in the hippocampus of young (2-month-old) and aged (24-month-old) Wistar rats. Spatial memory was evaluated using a water-maze procedure involving visible and invisible platform location learning. Aged rats showed higher latencies during the first two training days but rapidly exhibited learning performances similar to patterns observed with young rats. Real-time PCR measurements showed that aged rats had significantly higher levels of trkB.FL mRNAs than young rats under basal conditions. In situ hybridization analysis indicated that the highest level of trkB.FL mRNA (mRNA encoding for TrkB.FL receptor) was noted in the dentate gyrus, and in the CA2 and CA3 hippocampal layers. In contrast, there was no marked difference in trkB.T1 signal in any hippocampal region. Training induced a significant reduction in trkB.FL mRNA levels solely in aged rats. In contrast, in young and aged rats, trkB.T2 mRNA levels were significantly increased after training. Measurements of proteins revealed that learning significantly increased TrkB.FL content in aged rats. Untrained aged rats presented higher levels of BDNF and brain-derived neurotrophic factor precursor (proBDNF) proteins than young rats. Training strongly increased precursor BDNF metabolism in young and aged rats, resulting in increased levels of proBDNF in the two groups but in old rats the mature BDNF level did not change. This study shows that Wistar rats present age-related differences in the levels of BDNF and TrkB isoforms and that spatial learning differentially modifies some of these parameters in the hippocampus.

  11. Cyclic AMP response element binding protein and brain-derived neurotrophic factor: Molecules that modulate our mood?

    Indian Academy of Sciences (India)

    A Nair; V A Vaidya

    2006-09-01

    Depression is the major psychiatric ailment of our times, afflicting ∼20% of the population. Despite its prevalence, the pathophysiology of this complex disorder is not well understood. In addition, although antidepressants have been in existence for the past several decades, the mechanisms that underlie their therapeutic effects remain elusive. Building evidence implicates a role for the plasticity of specific neuro-circuitry in both the pathophysiology and treatment of depression. Damage to limbic regions is thought to contribute to the etiology of depression and antidepressants have been reported to reverse such damage and promote adaptive plasticity. The molecular pathways that contribute to the damage associated with depression and antidepressant-mediated plasticity are a major focus of scientific enquiry. The transcription factor cyclic AMP response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) are targets of diverse classes of antidepressants and are known to be regulated in animal models and in patients suffering from depression. Given their role in neuronal plasticity, CREB and BDNF have emerged as molecules that may play an important role in modulating mood. The purpose of this review is to discuss the role of CREB and BDNF in depression and as targets/mediators of antidepressant action.

  12. Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome

    Science.gov (United States)

    Bueno, Marta; Esteba-Castillo, Susanna; Novell, Ramon; Giménez-Palop, Olga; Coronas, Ramon; Gabau, Elisabeth; Corripio, Raquel; Baena, Neus; Viñas-Jornet, Marina; Guitart, Míriam; Torrents-Rodas, David; De