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Sample records for brain blood muscle

  1. Magnesium enhances exercise performance via increasing glucose availability in the blood, muscle, and brain during exercise.

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    Hsuan-Ying Chen

    Full Text Available Glucose mobilization and utilization in the periphery and central nervous system are important during exercise and are responsible for exercise efficacy. Magnesium (Mg is involved in energy production and plays a role in exercise performance. This study aimed to explore the effects of Mg on the dynamic changes in glucose and lactate levels in the muscle, blood and brain of exercising rats using a combination of auto-blood sampling and microdialysis. Sprague-Dawley rats were pretreated with saline or magnesium sulfate (MgSO4, 90 mg/kg, i.p. 30 min before treadmill exercise (20 m/min for 60 min. Our results indicated that the muscle, blood, and brain glucose levels immediately increased during exercise, and then gradually decreased to near basal levels in the recovery periods of both groups. These glucose levels were significantly enhanced to approximately two-fold (P<0.05 in the Mg group. Lactate levels in the muscle, blood, and brain rapidly and significantly increased in both groups during exercise, and brain lactate levels in the Mg group further elevated (P<0.05 than those in the control group during exercise. Lactate levels significantly decreased after exercise in both groups. In conclusion, Mg enhanced glucose availability in the peripheral and central systems, and increased lactate clearance in the muscle during exercise.

  2. Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study

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    Morild Inge

    2007-10-01

    Full Text Available Abstract Background The main forms of mercury (Hg exposure in the general population are methylmercury (MeHg from seafood, inorganic mercury (I-Hg from food, and mercury vapor (Hg0 from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg in the tissues was evaluated. Methods Samples of blood, brain (occipital lobe cortex, pituitary, thyroid, abdominal muscle and toenails were collected at autopsy of 30 deceased individuals, age from 47 to 91 years of age. Concentrations of total-Hg and I-Hg in blood and brain cortex were determined by cold vapor atomic fluorescence spectrometry and total-Hg in other tissues by sector field inductively coupled plasma-mass spectrometry (ICP-SFMS. Results The median concentrations of MeHg (total-Hg minus I-Hg and I-Hg in blood were 2.2 and 1.0 μg/L, and in occipital lobe cortex 4 and 5 μg/kg, respectively. There was a significant correlation between MeHg in blood and occipital cortex. Also, total-Hg in toenails correlated with MeHg in both blood and occipital lobe. I-Hg in both blood and occipital cortex, as well as total-Hg in pituitary and thyroid were strongly associated with the number of dental amalgam surfaces at the time of death. Conclusion In a fish-eating population, intake of MeHg via the diet has a marked impact on the MeHg concentration in the brain, while exposure to dental amalgam restorations increases the I-Hg concentrations in the brain. Discrimination between mercury species is

  3. Effects of Changes in Colored Light on Brain and Calf Muscle Blood Concentration and Oxygenation

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    J. Weinzirl

    2011-01-01

    Full Text Available Color light therapy is a therapeutic method in complementary medicine. In color therapy, light of two contrasting colors is often applied in a sequential order. The aim of this study was to investigate possible physiological effects, i.e., changes in the blood volume and oxygenation in the brain and calf muscle of healthy subjects who were exposed to red and blue light in sequential order. The hypothesis was that if a subject is first exposed to blue and then red light, the effect of the red light will be enhanced due to the contrastingly different characteristics of the two colors. The same was expected for blue light, if first exposing a subject to red and then to blue light. Twelve healthy volunteers (six male, six female were measured twice on two different days by near-infrared spectroscopy during exposure to colored light. Two sequences of colored light were applied in a controlled, randomized, crossover design: first blue, then red, and vice versa. For the brain and muscle, the results showed no significant differences in blood volume and oxygenation between the two sequences, and a high interindividual physiological variability. Thus, the hypothesis had to be rejected. Comparing these data to results from a previous study, where subjects were exposed to blue and red light without sequential color changes, shows that the results of the current study appear to be similar to those of red light exposure. This may indicate that the exposure to red light was preponderant and thus effects of blue light were outweighed.

  4. Speech therapy changes blood circulation and oxygenation in the brain and muscle: a near-infrared spectrophotometry study.

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    Wolf, Martin; von Bonin, Dietrich; Wolf, Ursula

    2011-01-01

    Recently it has been shown that artistic speech therapy (AST) has effects on heart rate variability. The aim of this pilot study was to investigate whether AST also affects hemodynamics and tissue oxygenation in the brain and skeletal muscle measured by near infrared spectrophotometry(NIRS). The results show that ATS has effects on important physiological parameters, i.e., it leads to a decrease in cerebral blood flow during recitation and to brain activation thereafter.

  5. Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle

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    Vernetti, Lawrence; Gough, Albert; Baetz, Nicholas; Blutt, Sarah; Broughman, James R.; Brown, Jacquelyn A.; Foulke-Abel, Jennifer; Hasan, Nesrin; In, Julie; Kelly, Edward; Kovbasnjuk, Olga; Repper, Jonathan; Senutovitch, Nina; Stabb, Janet; Yeung, Catherine; Zachos, Nick C.; Donowitz, Mark; Estes, Mary; Himmelfarb, Jonathan; Truskey, George; Wikswo, John P.; Taylor, D. Lansing

    2017-01-01

    Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements. PMID:28176881

  6. A validated method for simultaneous determination of codeine, codeine-6-glucuronide, norcodeine, morphine, morphine-3-glucuronide and morphine-6-glucuronide in post-mortem blood, vitreous fluid, muscle, fat and brain tissue by LC-MS.

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    Frost, Joachim; Løkken, Trine N; Brede, Wenche R; Hegstad, Solfrid; Nordrum, Ivar S; Slørdal, Lars

    2015-04-01

    The toxicodynamics and, to a lesser degree, toxicokinetics of the widely used opiate codeine remain a matter of controversy. To address this issue, analytical methods capable of providing reliable quantification of codeine metabolites alongside codeine concentrations are required. This article presents a validated method for simultaneous determination of codeine, codeine metabolites codeine-6-glucuronide (C6G), norcodeine and morphine, and morphine metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in post-mortem whole blood, vitreous fluid, muscle, fat and brain tissue by high-performance liquid chromatography mass spectrometry. Samples were prepared by solid-phase extraction. The validated ranges were 1.5-300 ng/mL for codeine, norcodeine and morphine, and 23-4,600 ng/mL for C6G, M3G and M6G, with exceptions for norcodeine in muscle (3-300 ng/mL), morphine in muscle, fat and brain (3-300 ng/mL) and M6G in fat (46-4,600 ng/mL). Within-run and between-run accuracy (88.1-114.1%) and precision (CV 0.6-12.7%), matrix effects (CV 0.3-13.5%) and recovery (57.8-94.1%) were validated at two concentration levels; 3 and 150 ng/mL for codeine, norcodeine and morphine, and 46 and 2,300 ng/mL for C6G, M3G and M6G. Freeze-thaw and long-term stability (6 months at -80°C) was assessed, showing no significant changes in analyte concentrations (-12 to +8%). The method was applied in two authentic forensic autopsy cases implicating codeine in both therapeutic and presumably lethal concentration levels.

  7. Markers for blood-brain barrier integrity

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    Saunders, Norman R; Dziegielewska, Katarzyna M; Møllgård, Kjeld;

    2015-01-01

    In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain......, and cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth-century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well...... known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction...

  8. AIDS and the blood-brain barrier

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    Ivey, Nathan S.; MacLean, Andrew G.; Lackner, Andrew A.

    2009-01-01

    The blood-brain barrier (BBB) plays a critical role in normal physiology of the central nervous system by regulating what reaches the brain from the periphery. The BBB also plays a major role in neurologic disease including neuropathologic sequelae associated with infection by human immunodeficiency virus (HIV) in humans and the closely related simian immunodeficiency virus (SIV) in macaques. In this review, we provide an overview of the function, structure and components of the BBB, followed...

  9. A neurovascular blood-brain barrier in vitro model.

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    Zehendner, Christoph M; White, Robin; Hedrich, Jana; Luhmann, Heiko J

    2014-01-01

    The cerebral microvasculature possesses certain cellular features that constitute the blood-brain barrier (BBB) (Abbott et al., Neurobiol Dis 37:13-25, 2010). This dynamic barrier separates the brain parenchyma from peripheral blood flow and is of tremendous clinical importance: for example, BBB breakdown as in stroke is associated with the development of brain edema (Rosenberg and Yang, Neurosurg Focus 22:E4, 2007), inflammation (Kuhlmann et al., Neurosci Lett 449:168-172, 2009; Coisne and Engelhardt, Antioxid Redox Signal 15:1285-1303, 2011), and increased mortality. In vivo, the BBB consists of brain endothelial cells (BEC) that are embedded within a precisely regulated environment containing astrocytes, pericytes, smooth muscle cells, and glial cells. These cells experience modulation by various pathways of intercellular communication and by pathophysiological processes, e.g., through neurovascular coupling (Attwell et al., Nature 468:232-243, 2010), cortical spreading depression (Gursoy-Ozdemir et al., J Clin Invest 113:1447-1455, 2004), or formation of oxidative stress (Yemisci et al., Nat Med 15:1031-1037, 2009). Hence, this interdependent assembly of cells is referred to as the neurovascular unit (NVU) (Zlokovic, Nat Med 16:1370-1371, 2010; Zlokovic, Neuron 57:178-201, 2008). Experimental approaches to investigate the BBB in vitro are highly desirable to study the cerebral endothelium in health and disease. However, due to the complex interactions taking place within the NVU in vivo, it is difficult to mimic this interplay in vitro.Here, we describe a murine blood-brain barrier coculture model consisting of cortical organotypic slice cultures and brain endothelial cells that includes most of the cellular components of the NVU including neurons, astrocytes, and brain endothelial cells. This model allows the experimental analysis of several crucial BBB parameters such as transendothelial electrical resistance or tight junction protein localization by

  10. Metabolic control of muscle blood flow during exercise in humans

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    Boushel, Robert Christopher

    2003-01-01

    and the vasculature that induce vasodilation. A link between muscle metabolic events and microvascular control of blood flow is illustrated by local dilation of terminal arterioles during contraction of muscle fibers and conduction of vasodilation upstream. Endothelial-derived vasodilator mechanisms are known...... to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow...

  11. The blood-brain barrier in psychoneuroimmunology.

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    Banks, William A

    2009-05-01

    The term ''psychoneuroimmunology'' connotes separate compartments that interact. The blood-brain barrier (BBB) is both the dividing line, physical and physiologic, between the immune system and the central nervous system (CNS) and the locale for interaction. The BBB restricts unregulated mixing of immune substances in the blood with those in the CNS, directly transports neuroimmune-active substances between the blood and CNS, and itself secretes neuroimmune substances. These normal functions of the BBB can be altered by neuroimmune events. As such, the BBB is an important conduit in the communication between the immune system and the CNS.

  12. Molecular Mechanisms for Exercise Training-Induced Changes in Vascular Structure and Function: Skeletal Muscle, Cardiac Muscle, and the Brain.

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    Olver, T Dylan; Ferguson, Brian S; Laughlin, M Harold

    2015-01-01

    Compared with resting conditions, during incremental exercise, cardiac output in humans is elevated from ~5 to 25 L min(-1). In conjunction with this increase, the proportion of cardiac output directed toward skeletal muscle increases from ~20% to 85%, while blood flow to cardiac muscle increases 500% and blood flow to specific brain structures increases nearly 200%. Based on existing evidence, researchers believe that blood flow in these tissues is matched to the increases in metabolic rate during exercise. This phenomenon, the matching of blood flow to metabolic requirement, is often referred to as functional hyperemia. This chapter summarizes mechanical and metabolic factors that regulate functional hyperemia as well as other exercise-induced signals, which are also potent stimuli for chronic adaptations in vascular biology. Repeated exposure to exercise-induced increases in shear stress and the induction of angiogenic factors alter vascular cell gene expression and mediate changes in vascular volume and blood flow control. The magnitude and regulation of this coordinated response appear to be tissue specific and coupled to other factors such as hypertrophy and hyperplasia. The cumulative effects of these adaptations contribute to increased exercise capacity, reduced relative challenge of a given submaximal exercise bout and ameliorated vascular outcomes in patient populations with pathological conditions. In the subsequent discussion, this chapter explores exercise as a regulator of vascular biology and summarizes the molecular mechanisms responsible for exercise training-induced changes in vascular structure and function in skeletal and cardiac muscle as well as the brain.

  13. The relationship between exercise-induced muscle fatigue, arterial blood flow and muscle perfusion after 56 days local muscle unloading.

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    Weber, Tobias; Ducos, Michel; Mulder, Edwin; Beijer, Åsa; Herrera, Frankyn; Zange, Jochen; Degens, Hans; Bloch, Wilhelm; Rittweger, Jörn

    2014-05-01

    In the light of the dynamic nature of habitual plantar flexor activity, we utilized an incremental isokinetic exercise test (IIET) to assess the work-related power deficit (WoRPD) as a measure for exercise-induced muscle fatigue before and after prolonged calf muscle unloading and in relation to arterial blood flow and muscle perfusion. Eleven male subjects (31 ± 6 years) wore the HEPHAISTOS unloading orthosis unilaterally for 56 days. It allows habitual ambulation while greatly reducing plantar flexor activity and torque production. Endpoint measurements encompassed arterial blood flow, measured in the femoral artery using Doppler ultrasound, oxygenation of the soleus muscle assessed by near-infrared spectroscopy, lactate concentrations determined in capillary blood and muscle activity using soleus muscle surface electromyography. Furthermore, soleus muscle biopsies were taken to investigate morphological muscle changes. After the intervention, maximal isokinetic torque was reduced by 23·4 ± 8·2% (PBlood flow, tissue oxygenation, lactate concentrations and EMG median frequency kinematics during the exercise test were comparable before and after the intervention, whereas the increase of RMS in response to IIET was less following the intervention (P = 0·03). In conclusion, following submaximal isokinetic muscle work exercise-induced muscle fatigue is unaffected after prolonged local muscle unloading. The observation that arterial blood flow was maintained may underlie the unchanged fatigability.

  14. An Electrical Muscle Stimulation Suit for Increasing Blood Pressure

    Science.gov (United States)

    2008-09-01

    being painful . The arterial blood pressure increases from baseline were reg- istered with noninvasive Portapres® equipment (FMS, Amsterdam, The...thighs and over the gluteal and abdominal muscles to create a positive and negative pole over the muscle areas. For better electrical contact... pain . Each subject was instructed to have the investigator lower the intensity or stop the stimulation if muscle contraction pain was experienced

  15. Vasodilator interactions in skeletal muscle blood flow regulation

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    Hellsten, Ylva; Nyberg, Michael Permin; Jensen, Lasse Gliemann;

    2012-01-01

    that this remaining hyperemia may be explained by cAMP and cGMP independent smooth muscle relaxation, such as effects of endothelial derived hyperpolarization factors (EDHFs) or through metabolic modulation of sympathetic effects. The nature and role of EDHF as well as potential novel mechanisms in muscle blood flow...

  16. Hormones and the blood-brain barrier.

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    Hampl, Richard; Bičíková, Marie; Sosvorová, Lucie

    2015-03-01

    Hormones exert many actions in the brain, and brain cells are also hormonally active. To reach their targets in brain structures, hormones must overcome the blood-brain barrier (BBB). The BBB is a unique device selecting desired/undesired molecules to reach or leave the brain, and it is composed of endothelial cells forming the brain vasculature. These cells differ from other endothelial cells in their almost impermeable tight junctions and in possessing several membrane structures such as receptors, transporters, and metabolically active molecules, ensuring their selection function. The main ways how compounds pass through the BBB are briefly outlined in this review. The main part concerns the transport of major classes of hormones: steroids, including neurosteroids, thyroid hormones, insulin, and other peptide hormones regulating energy homeostasis, growth hormone, and also various cytokines. Peptide transporters mediating the saturable transport of individual classes of hormones are reviewed. The last paragraph provides examples of how hormones affect the permeability and function of the BBB either at the level of tight junctions or by various transporters.

  17. Regulation of the skeletal muscle blood flow in humans

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    Mortensen, Stefan; Saltin, Bengt

    2014-01-01

    In humans, skeletal muscle blood flow is regulated by an interaction between several locally formed vasodilators including nitric oxide (NO) and prostaglandins. In plasma, ATP is a potent vasodilator that stimulates the formation of NO and prostaglandins and very importantly can offset local...... concentration does not increase during exercise. In the skeletal muscle interstitium, there is a marked increase in the concentration of ATP and adenosine and this increase is tightly coupled to the increase in blood flow. The sources of interstitial ATP and adenosine are thought to be skeletal muscle cells...... hyperaemia whereas the role of ATP remains uncertain due to lack of specific purinergic receptor blockers for human use. The purpose of this review is to address the interaction between vasodilator systems and to discuss the multiple proposed roles of ATP in human skeletal muscle blood flow regulation...

  18. Genomic studies of mood disorders - the brain as a muscle?

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    Niculescu, Alexander B.

    2005-01-01

    Recent genomic studies showing abnormalities in the fibroblast growth factor system in the postmortem brains of people with major depressive disorder support previous indications of a role for growth factors in mood disorders. Similar molecular pathways, volumetric changes, and the effects of exercise on mood suggest a superficial analogy, and perhaps a deeper relationship, between muscle and brain functioning.

  19. Reduced blood flow to contracting skeletal muscle in ageing humans

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    Nyberg, Michael Permin; Hellsten, Ylva

    2016-01-01

    The ability to sustain a given absolute submaximal workload declines with advancing age likely due to a lower level of blood flow and O2 delivery to the exercising muscles. Given that physical inactivity mimics many of the physiological changes associated with ageing, separating the physiological...... consequences of ageing and physical inactivity can be challenging; yet, observations from cross-sectional and longitudinal studies on the effects of physical activity have provided some insight. Physical activity has the potential to offset the age-related decline in blood flow to contracting skeletal muscle...... the O2 demand of the active skeletal muscle of aged individuals during conditions where systemic blood flow is not limited by cardiac output seems to a large extent to be related to the level of physical activity. This article is protected by copyright. All rights reserved....

  20. 65zinc uptake from blood into brain and other tissues in the rat

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    Pullen, R.G.; Franklin, P.A.; Hall, G.H. (Sunderland Polytechnic, Tyne Wear (England))

    1990-10-01

    Zinc is essential for normal growth, development and brain function although little is known about brain zinc homeostasis. Therefore, in this investigation we have studied 65Zn uptake from blood into brain and other tissues and have measured the blood-brain barrier permeability to 65Zn in the anaesthetized rat in vivo. Adult male Wistar rats within the weight range 500-600 g were used. 65ZnCl2 and (125I)albumin, the latter serving as a vascular marker, were injected in a bolus of normal saline I.V. Sequential arterial blood samples were taken during experiments that lasted between 5 min and 5 hr. At termination, samples from the liver, spleen, pancreas, lung, heart, muscle, kidney, bone, testis, ileum, blood cells, csf, and whole brain were taken and analysed for radio-isotope activity. Data have been analysed by Graphical Analysis which suggests 65Zn uptake from blood by all tissues sampled was unidirectional during this experimental period except brain, where at circulation times less than 30 min, 65Zn fluxes were bidirectional. In addition to the blood space, the brain appears to contain a rapidly exchanging compartment(s) for 65Zn of about 4 ml/100g which is not csf.

  1. Glial and neuronal control of brain blood flow

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    Attwell, David; Buchan, Alastair M; Charpak, Serge

    2010-01-01

    Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...... in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches....

  2. Blood-brain barrier permeability imaging using perfusion computed tomography

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    Avsenik Jernej

    2015-06-01

    Full Text Available Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with pathologies such as acute stroke, tumors, inflammatory and neurodegenerative diseases.

  3. Blood-brain barrier permeability imaging using perfusion computed tomography

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    Avsenik Jernej; Bisdas Sotirios; Popovic Katarina Surlan

    2015-01-01

    Background. The blood-brain barrier represents the selective diffusion barrier at the level of the cerebral microvascular endothelium. Other functions of blood-brain barrier include transport, signaling and osmoregulation. Endothelial cells interact with surrounding astrocytes, pericytes and neurons. These interactions are crucial to the development, structural integrity and function of the cerebral microvascular endothelium. Dysfunctional blood-brain barrier has been associated with patholog...

  4. Decreasing systolic blood pressure with isometric muscle training: a CAT

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    Alexis Espinoza Salinas

    2014-09-01

    Full Text Available INTRODUCTION Hypertension is a major risk factor for cardiovascular diseases such as coronary heart disease or heart failure. One of the interventions for the management of this disorder is isometric muscle training on upper and lower limbs. PURPOSE To prove the validity and applicability of results regarding the effectiveness of isometric training in hypertensive subjects. We also attempt to answer the following question: what is the effectiveness of isometric muscle training on the decrease of systolic blood pressure in hypertensive patients? METHODS Critical appraisal of the systematic review and meta-analysis “Isometric exercise training for blood pressure management”. RESULTS Isometric training reduces systolic blood pressure in normotensive and medicated hypertensive subjects, with a standardized mean difference of 6.77 mm Hg (95% confidence interval: 7.93-5.62. CONCLUSION It is reasonable to recommend isometric muscle training with the aim of lowering systolic blood pressure, considering the impact of the results of the articles analyzed and the applicability of this type of training.

  5. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Somik [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yin, Hongshan [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Cardiovascular Medicine, Third Affiliated Hospital, Hebei Medical University, Shijiazhuang 050051, Hebei (China); Nam, Deokhwa [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Li, Yong [Department of Pediatric Surgery, Center for Stem Cell Research and Regenerative Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030 (United States); Ma, Ke, E-mail: kma@houstonmethodist.org [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States)

    2015-02-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1{sup −/−} mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation.

  6. Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro

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    Vandenhaute Elodie

    2012-06-01

    Full Text Available Abstract Background The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS is the only confirmed, homologous model of malignant hyperthermia (MH in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome. Methods In the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n mutant ryr1/hal alleles, respectively, and tested in vitro for their influence on the permeability of BBB endothelial monolayers. Results Enlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated

  7. Glial and neuronal control of brain blood flow

    DEFF Research Database (Denmark)

    Attwell, David; Buchan, Alastair M; Charpak, Serge

    2010-01-01

    Blood flow in the brain is regulated by neurons and astrocytes. Knowledge of how these cells control blood flow is crucial for understanding how neural computation is powered, for interpreting functional imaging scans of brains, and for developing treatments for neurological disorders. It is now...

  8. Blood-brain barrier dysfunction in Parkinsonian midbrain in vivo

    NARCIS (Netherlands)

    Kortekaas, R; Leenders, KL; van Oostrom, JCH; Vaalburg, W; Bart, J; Willemsen, ATM; Hendrikse, NH

    2005-01-01

    Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood-borne chemicals by the blood-brain barrier which includes

  9. Relation between muscle and brain activity during isometric contractions of the first dorsal interosseus muscle

    NARCIS (Netherlands)

    van Duinen, Hiske; Renken, Remco; Maurits, Natasha M.; Zijdewind, Inge

    2008-01-01

    We studied the relationship between muscle activity (electromyography, EMG), force, and brain activity during isometric contractions of the index finger, on a group and individual level. Ten subjects contracted their right or left index finger at 5, 15, 30, 50, and 70% of their maximal force. Subjec

  10. Adipose tissue and skeletal muscle blood flow during mental stress

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    Linde, B.; Hjemdahl, P.; Freyschuss, U.; Juhlin-Dannfelt, A.

    1989-01-01

    Mental stress (a modified Stroop color word conflict test (CWT)) increased adipose tissue blood flow (ATBF; 133Xe clearance) by 70% and reduced adipose tissue vascular resistance (ATR) by 25% in healthy male volunteers. The vasculatures of adipose tissue (abdomen as well as thigh), skeletal muscle of the calf (133Xe clearance), and the entire calf (venous occlusion plethysmography) responded similarly. Arterial epinephrine (Epi) and glycerol levels were approximately doubled by stress. Beta-Blockade by metoprolol (beta 1-selective) or propranolol (nonselective) attenuated CWT-induced tachycardia similarly. Metoprolol attenuated stress-induced vasodilation in the calf and tended to do so in adipose tissue. Propranolol abolished vasodilation in the calf and resulted in vasoconstriction during CWT in adipose tissue. Decreases in ATR, but not in skeletal muscle or calf vascular resistances, were correlated to increases in arterial plasma glycerol (r = -0.42, P less than 0.05), whereas decreases in skeletal muscle and calf vascular resistances, but not in ATR, were correlated to increases in arterial Epi levels (r = -0.69, P less than 0.01; and r = -0.43, P less than 0.05, respectively). The results suggest that mental stress increases nutritive blood flow in adipose tissue and skeletal muscle considerably, both through the elevation of perfusion pressure and via vasodilatation. Withdrawal of vasoconstrictor nerve activity, vascular beta 2-adrenoceptor stimulation by circulating Epi, and metabolic mechanisms (in adipose tissue) may contribute to the vasodilatation.

  11. The Blood-Brain Barrier: An Engineering Perspective

    Directory of Open Access Journals (Sweden)

    Andrew eWong

    2013-08-01

    Full Text Available It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier that can lead to changes in permeability, modulation of immune cell transport, and trafficking of pathogens into the brain. Therefore advances in our understanding of the structure and function of the blood-brain barrier are key to advances in treatment of a wide range of central nervous system diseases. Over the past 10 years it has become recognized that the blood-brain barrier is a complex dynamic system that involves biomechanical and biochemical signaling between the vascular system and the brain. Here we reconstruct the structure, function, and transport properties of the blood-brain barrier from an engineering perspective. New insight into the physics of the blood-brain barrier could ultimately lead to clinical advances in the treatment of central nervous system diseases.

  12. Barrier mechanisms in the Drosophila blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Samantha Jane Hindle

    2014-12-01

    Full Text Available The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated function of all layers of the compound barrier structure, analogous to signaling between the layers of the vertebrate neurovascular unit. These findings strengthen the notion that many blood-brain barrier mechanisms are conserved between vertebrates and invertebrates, and suggest that novel findings in invertebrate model organisms will have a significant impact on the understanding of vertebrate BBB functions. In this vein, important roles in coordinating localized and systemic signaling to dictate organism development and growth are beginning to show how the blood-brain barrier can govern whole animal physiologies. This includes novel functions of blood-brain barrier gap junctions in orchestrating synchronized neuroblast proliferation, and of blood-brain barrier secreted antagonists of insulin receptor signaling. These advancements and others are pushing the field forward in exciting new directions. In this review, we provide a synopsis of invertebrate blood-brain barrier anatomy and physiology, with a focus on insights from the past 5 years, and highlight important areas for future study.

  13. Blood-Brain Glucose Transfer: Repression in Chronic Hyperglycemia

    Science.gov (United States)

    Gjedde, Albert; Crone, Christian

    1981-10-01

    Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.

  14. Mathematical modelling of blood-brain barrier failure and edema

    Science.gov (United States)

    Waters, Sarah; Lang, Georgina; Vella, Dominic; Goriely, Alain

    2015-11-01

    Injuries such as traumatic brain injury and stroke can result in increased blood-brain barrier permeability. This increase may lead to water accumulation in the brain tissue resulting in vasogenic edema. Although the initial injury may be localised, the resulting edema causes mechanical damage and compression of the vasculature beyond the original injury site. We employ a biphasic mixture model to investigate the consequences of blood-brain barrier permeability changes within a region of brain tissue and the onset of vasogenic edema. We find that such localised changes can indeed result in brain tissue swelling and that the type of damage that results (stress damage or strain damage) depends on the ability of the brain to clear edema fluid.

  15. Blood-brain interfaces and bilirubin-induced neurological diseases.

    Science.gov (United States)

    Ghersi-Egea, J F; Gazzin, S; Strazielle, N

    2009-01-01

    The endothelium of the brain microvessels and the choroid plexus epithelium form highly specialized cellular barriers referred to as blood-brain interfaces through which molecular exchanges take place between the blood and the neuropil or the cerebrospinal fluid, respectively. Within the brain, the ependyma and the pia-glia limitans modulate exchanges between the neuropil and the cerebrospinal fluid. All these interfaces are key elements of neuroprotection and fulfill trophic functions; both properties are critical to harmonious brain development and maturation. By analogy to hepatic bilirubin detoxification pathways, we review the transport and metabolic mechanisms which in all these interfaces may participate in the regulation of bilirubin cerebral bioavailability in physiologic conditions, both in adult and in developing brain. We specifically address the role of ABC and OATP transporters, glutathione-S-transferases, and the potential involvement of glucuronoconjugation and oxidative metabolic pathways. Regulatory mechanisms are explored which are involved in the induction of these pathways and represent potential pharmacological targets to prevent bilirubin accumulation into the brain. We then review the possible alteration of the neuroprotective and trophic barrier functions in the course of bilirubin-induced neurological dysfunctions resulting from hyperbilirubinemia. Finally, we highlight the role of the blood-brain and blood-CSF barriers in regulating the brain biodisposition of candidate drugs for the treatment or prevention of bilirubin-induced brain injury.

  16. Study Links Stuttering to Less Blood Flow in Brain

    Science.gov (United States)

    ... medlineplus.gov/news/fullstory_162922.html Study Links Stuttering to Less Blood Flow in Brain The more ... to speech may put people at risk for stuttering, a small study suggests. There are also signs ...

  17. Blood-brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis.

    Science.gov (United States)

    Kim, Soo Young; Buckwalter, Marion; Soreq, Hermona; Vezzani, Annamaria; Kaufer, Daniela

    2012-11-01

    The protection of the brain from blood-borne toxins, proteins, and cells is critical to the brain's normal function. Accordingly, a compromise in the blood-brain barrier (BBB) function accompanies many neurologic disorders, and is tightly associated with brain inflammatory processes initiated by both infiltrating leukocytes from the blood, and activation of glial cells. Those inflammatory processes contribute to determining the severity and prognosis of numerous neurologic disorders, and can both cause, and result from BBB dysfunction. In this review we examine the role of BBB and inflammatory responses, in particular activation of transforming grown factor β (TGFβ) signaling, in epilepsy, stroke, and Parkinson's disease.

  18. Barrier mechanisms in the Drosophila blood-brain barrier

    OpenAIRE

    Samantha Jane Hindle; Roland Jerome Bainton

    2014-01-01

    The invertebrate blood-brain barrier field is growing at a rapid pace and, in recent years, studies have shown a physiologic and molecular complexity that has begun to rival its vertebrate counterpart. Novel mechanisms of paracellular barrier maintenance through GPCR signaling were the first demonstrations of the complex adaptive mechanisms of barrier physiology. Building upon this work, the integrity of the invertebrate blood-brain barrier has recently been shown to require coordinated funct...

  19. Increasing oxime efficacy by blood-brain barrier modulation

    NARCIS (Netherlands)

    Joosen, M.J.A.; Schans, M.J. van der; Dijk, C.G.M. van; Kuijpers, W.C.; Wortelboer, H.M.; Helden, H.P.M. van

    2011-01-01

    One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures.

  20. Effect of extraluminal ATP application on vascular tone and blood flow in skeletal muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin; Al-Khazraji, Baraa K; Mortensen, Stefan P;

    2013-01-01

    During skeletal muscle contractions, the concentration of ATP increases in muscle interstitial fluid as measured by microdialysis probes. This increase is associated with the magnitude of blood flow, suggesting that interstitial ATP may be important for contraction-induced vasodilation. However...... in interstitial ATP concentrations increases muscle blood flow, indicating that the contraction-induced increase in skeletal muscle interstitial [ATP] is important for exercise hyperemia. The vasodilator effect of ATP application is mediated by NO and prostanoid formation....

  1. The Blood-Brain Barrier: An Engineering Perspective

    OpenAIRE

    Andrew eWong; Mao eYe; Amanda eLevy; Jeffrey eRothstein; Dwight eBergles; Peter Charles Searson

    2013-01-01

    It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich’s first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and it remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of the blood-brain barrier...

  2. Blood-Brain Transfer of Pittsburgh Compound B in Humans

    Directory of Open Access Journals (Sweden)

    Albert eGjedde

    2013-11-01

    Full Text Available In the labeled form, the Pittsburgh compound B (2-(4’-{N-methyl-[11C]}methyl-aminophenyl-6-hydroxybenzothiazole,[11C]PiB, is used as a biomarker for positron emission tomography (PET of brain □-amyloiddeposition in Alzheimer’s disease (AD. The permeability of [11C]PiB in the blood-brain barrier is held tobe high but the permeability-surface area product and extraction fractions in patients or healthy volunteersare not known. We used PET to determine the clearance associated with the unidrectional blood-braintransfer of [11C]PiB and the corresponding cerebral blood flow rates in frontal lobe, whole cerebral cortex,and cerebellum of patients with Alzheimer’s disease and healthy volunteers. Regional cerebral blood flowrates differed significantly between the two groups, but regional and whole-brain permeability-surface areaproducts were identical, in agreement with the observation that numerically, but insignificantly, unidirectionalblood-brain clearances are lower and extraction fractions higher in the patients. The evidence of unchangedpermeability-surface area products in the patients implies that blood flow changes can be deduced from theunidirectional blood-brain clearances of [11C]PiB in the patients.

  3. Matrix metalloproteinases in the brain and blood-brain barrier: Versatile breakers and makers.

    Science.gov (United States)

    Rempe, Ralf G; Hartz, Anika Ms; Bauer, Björn

    2016-09-01

    Matrix metalloproteinases are versatile endopeptidases with many different functions in the body in health and disease. In the brain, matrix metalloproteinases are critical for tissue formation, neuronal network remodeling, and blood-brain barrier integrity. Many reviews have been published on matrix metalloproteinases before, most of which focus on the two best studied matrix metalloproteinases, the gelatinases MMP-2 and MMP-9, and their role in one or two diseases. In this review, we provide a broad overview of the role various matrix metalloproteinases play in brain disorders. We summarize and review current knowledge and understanding of matrix metalloproteinases in the brain and at the blood-brain barrier in neuroinflammation, multiple sclerosis, cerebral aneurysms, stroke, epilepsy, Alzheimer's disease, Parkinson's disease, and brain cancer. We discuss the detrimental effects matrix metalloproteinases can have in these conditions, contributing to blood-brain barrier leakage, neuroinflammation, neurotoxicity, demyelination, tumor angiogenesis, and cancer metastasis. We also discuss the beneficial role matrix metalloproteinases can play in neuroprotection and anti-inflammation. Finally, we address matrix metalloproteinases as potential therapeutic targets. Together, in this comprehensive review, we summarize current understanding and knowledge of matrix metalloproteinases in the brain and at the blood-brain barrier in brain disorders.

  4. Blood-brain barrier transport of drugs for the treatment of brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2009-06-01

    The central nervous system is a sanctuary protected by barriers that regulate brain homeostasis and control the transport of endogenous compounds into the brain. The blood-brain barrier, formed by endothelial cells of the brain capillaries, restricts access to brain cells allowing entry only to amino acids, glucose and hormones needed for normal brain cell function and metabolism. This very tight regulation of brain cell access is essential for the survival of neurons which do not have a significant capacity to regenerate, but also prevents therapeutic compounds, small and large, from reaching the brain. As a result, various strategies are being developed to enhance access of drugs to the brain parenchyma at therapeutically meaningful concentrations to effectively manage disease.

  5. The Blood-Brain Barrier and Methamphetamine: Open Sesame?

    Directory of Open Access Journals (Sweden)

    Patric eTurowski

    2015-05-01

    Full Text Available The chemical and electrical microenvironment of neurons within the central nervous system is protected and segregated from the circulation by the vascular blood–brain barrier. This barrier operates on the level of endothelial cells and includes regulatory crosstalk with neighbouring pericytes, astrocytes and neurons. Within this neurovascular unit, the endothelial cells form a formidable, highly regulated barrier through the presence of inter-endothelial tight junctions, the absence of fenestrations, and the almost complete absence of fluid-phase transcytosis. The potent psychostimulant drug methamphetamine transiently opens the vascular blood–brain barrier through either or both the modulation of inter-endothelial junctions and the induction of fluid-phase transcytosis. Direct action of methamphetamine on the vascular endothelium induces acute opening of the blood-brain barrier. In addition, striatal effects of methamphetamine and resultant neuroinflammatory signalling can indirectly lead to chronic dysfunction of the blood-brain barrier. Breakdown of the blood-brain barrier may exacerbate the neuronal damage that occurs during methamphetamine abuse. However, this process also constitutes a rare example of agonist-induced breakdown of the blood-brain barrier and the adjunctive use of methamphetamine may present an opportunity to enhance delivery of chemotherapeutic agents to the underlying neural tissue.

  6. Mapping blood flow directionality in the human brain.

    Science.gov (United States)

    Park, Sung-Hong; Do, Won-Joon; Choi, Seung Hong; Zhao, Tiejun; Bae, Kyongtae Ty

    2016-07-01

    Diffusion properties of tissue are often expressed on the basis of directional variance, i.e., diffusion tensor imaging. In comparison, common perfusion-weighted imaging such as arterial spin labeling yields perfusion in a scalar quantity. The purpose of this study was to test the feasibility of mapping cerebral blood flow directionality using alternate ascending/descending directional navigation (ALADDIN), a recently-developed arterial spin labeling technique with sensitivity to blood flow directions. ALADDIN was applied along 3 orthogonal directions to assess directional blood flow in a vector form and also along 6 equally-spaced directions to extract blood flow tensor matrix (P) based on a blood flow ellipsoid model. Tensor elements (eigenvalues, eigenvectors, etc) were calculated to investigate characteristics of the blood flow tensor, in comparison with time-of-flight MR angiogram. While the directions of the main eigenvectors were heterogeneous throughout the brain, regional clusters of blood flow directionality were reproducible across subjects. The technique could show heterogeneous blood flow directionality within and around brain tumor, which was different from that of the contralateral normal side. The proposed method is deemed to provide information of blood flow directionality, which has not been demonstrated before. The results warrant further studies to assess changes in the directionality map as a function of scan parameters, to understand the signal sources, to investigate the possibility of mapping local blood perfusion directionality, and to evaluate its usefulness for clinical diagnosis.

  7. Iron uptake and transport at the blood-brain barrier

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart; Thomsen, Louiza Bohn; Moos, Torben

    . The mRNA expression of the iron-related molecules was also investigated in isolated brain capillaries from iron deficiency, iron reversible and normal rats. We also performed iron transport studies to analyze the routes by which iron is transported through the brain capillary endothelial cells: i) We......The mechanism by which iron is transported across the blood-brain barrier (BBB) remains controversial, and in this study we aimed to further clarify mechanisms by which iron is transported into the brain. We analyzed and compared the mRNA and protein expression of a variety of proteins involved...... in the transport of iron (transferrin receptor, divalent metal transporter I (DMT1), steap 2, steap 3, ceruloplasmin, hephaestin and ferroportin) in both primary rat brain capillary endothelial cells (BCEC) and immortalized rat brain capillary endothelial cell line (RBE4) grown in co-culture with defined polarity...

  8. The blood-brain barrier: an engineering perspective

    OpenAIRE

    Wong, Andrew D.; Ye, Mao; Levy, Amanda F.; Rothstein, Jeffrey D.; Bergles, Dwight E.; Searson, Peter C.

    2013-01-01

    It has been more than 100 years since Paul Ehrlich reported that various water-soluble dyes injected into the circulation did not enter the brain. Since Ehrlich's first experiments, only a small number of molecules, such as alcohol and caffeine have been found to cross the blood-brain barrier, and this selective permeability remains the major roadblock to treatment of many central nervous system diseases. At the same time, many central nervous system diseases are associated with disruption of...

  9. Exercise intensity and muscle hypertrophy in blood flow-restricted limbs and non-restricted muscles: a brief review.

    Science.gov (United States)

    Abe, Takashi; Loenneke, Jeremy P; Fahs, Christopher A; Rossow, Lindy M; Thiebaud, Robert S; Bemben, Michael G

    2012-07-01

    Although evidence for high-intensity resistance training-induced muscle hypertrophy has accumulated over the last several decades, the basic concept of the training can be traced back to ancient Greece: Milo of Croton lifted a bull-calf daily until it was fully grown, which would be known today as progressive overload. Now, in the 21st century, different types of training are being tested and studied, such as low-intensity exercise combined with arterial as well as venous blood flow restriction (BFR) to/from the working muscles. Because BFR training requires the use of a cuff that is placed at the proximal ends of the arms and/or legs, the BFR is only applicable to limb muscles. Consequently, most previous BFR training studies have focused on the physiological adaptations of BFR limb muscles. Muscle adaptations in non-BFR muscles of the hip and trunk are lesser known. Recent studies that have reported both limb and trunk muscle adaptations following BFR exercise training suggest that low-intensity (20-30% of 1RM) resistance training combined with BFR elicits muscle hypertrophy in both BFR limb and non-BFR muscles. However, the combination of leg muscle BFR with walk training elicits muscle hypertrophy only in the BFR leg muscles. In contrast to resistance exercise with BFR, the exercise intensity may be too low during BFR walk training to cause muscle hypertrophy in the non-BFR gluteus maximus and other trunk muscles. Other mechanisms including hypoxia, local and systemic growth factors and muscle cell swelling may also potentially affect the hypertrophic response of non-BFR muscles to BFR resistance exercise.

  10. Epstein Barr Virus and Blood Brain Barrier in Multiple Sclerosis

    Science.gov (United States)

    2014-01-01

    Multiple sclerosis (MS) is a chronic, autoimmune neurodegenerative disease. Epstein-Barr virus (EBV) infection is associated with MS pathogenesis. However, mechanism for the EBV-MS connection is unclear. The blood brain barrier (BBB) is a separation of circulating blood and the brain extracellular fluid in the central nervous system. BBB contains both endothelial cells as well as astrocytes. Interestingly EBV is able to infect both kinds of cells. Because EBV is able to transfer infection from one cell type to another cell type, it is thus hypothesized that EBV uses

  11. Transport characteristics of tramadol in the blood-brain barrier.

    Science.gov (United States)

    Kitamura, Atsushi; Higuchi, Kei; Okura, Takashi; Deguchi, Yoshiharu

    2014-10-01

    Tramadol is a centrally acting analgesic whose action is mediated by both agonistic activity at opioid receptors and inhibitory activity on neuronal reuptake of monoamines. The purpose of this study was to characterize the blood-brain barrier (BBB) transport of tramadol by means of microdialysis studies in rat brain and in vitro studies with human immortalized brain capillary endothelial cells (hCMEC/D3). The Kp,uu,brain value of tramadol determined by rat brain microdialysis was greater than unity, indicating that tramadol is actively taken up into the brain across the BBB. Tramadol was transported into hCMEC/D3 cells in a concentration-dependent manner. The uptake was inhibited by type II cations (pyrilamine, verapamil, etc.), but not by substrates of organic cation transporter OCTs or OCTN2. It was also inhibited by a metabolic inhibitor but was independent of extracellular sodium or membrane potential. The uptake was altered by changes of extracellular pH, and by ammonium chloride-induced intracellular acidification, suggesting that transport of tramadol is driven by an oppositely directed proton gradient. Thus, our in vitro and in vivo results suggest that tramadol is actively transported, at least in part, from blood to the brain across the BBB by proton-coupled organic cation antiporter.

  12. P-glycoprotein mediates brain-to-blood efflux transport of buprenorphine across the blood-brain barrier.

    Science.gov (United States)

    Suzuki, Toyofumi; Zaima, Chika; Moriki, Yoshiaki; Fukami, Toshiro; Tomono, Kazuo

    2007-01-01

    The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood-brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [3H]BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [3H]BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [3H]BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 x 10- 2 min- 1) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [3H]BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part.

  13. Acupuncture - effects on muscle blood flow and aspects of treatment in the clinicla context

    OpenAIRE

    2004-01-01

    The overall aim of this thesis was to elucidate and investigate psychophysiological aspects and effects of acupuncture and needle stimulation. Within this framework emphasis was directed toward the effects of needle stimulation (acupuncture) on muscle blood flow in the tibialis anterior and trapezius muscles in healthy subjects and patients suffering from chronic muscle pain. This study also included evaluation of a new application of photoplethysmography in noninvasive monitoring of muscle b...

  14. Vascular Function and Regulation of Blood Flow in Resting and Contracting Skeletal Muscle

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    in the regulation of exercise hyperemia. Furthermore, blood flow to contracting leg skeletal muscles is reduced both in essential hypertension and with aging. The potential difference in vasoactive system(s) responsible for the reduction in blood flow in the two conditions is in agreement with the suggestion......The precise matching of blood flow, oxygen delivery and metabolism is essential as it ensures that any increase in muscle work is precisely matched by increases in oxygen delivery. Therefore, understanding the control mechanisms of skeletal muscle blood flow regulation is of great biological...... importance. The present work provides new insight in to vasodilator interactions important for exercise hyperemia and sheds light on mechanisms important for vascular function and regulation of skeletal muscle blood flow in essential hypertension (high blood pressure) and aging and identifies mechanisms...

  15. Relationship between muscle oxygenation by NIRS and blood lactate

    Energy Technology Data Exchange (ETDEWEB)

    Xu Guodong [School of Physical Education, Jianghan University, Hubei Wuhan 430056 (China); Mao Zongzhen; Ye Yanjie; Lv Kunru, E-mail: xguodong@wipe.edu.cn [School of Health Sciences, Wuhan Institute of Physical Education, Hubei Wuhan 430079 (China)

    2011-01-01

    The aim of the study was to investigate the relationship of muscle oxygenation in term of oxy-hemoglobin concentration change ({Delta}HbO{sub 2}) by NIRS and blood lactate (BLA) in local skeletal muscle and evaluate the capability of NIRS in the research of exercise physiology Twenty-three athlete in the national fin-swimming team took the increasing load training on the power bicycle while their {Delta}HbO{sub 2} and BLA were simultaneously recorded. The initial powers used in the training were set as 100 w for males and 40 w for females. During the experiment, the power kept constant for 3 min before each abrupt increment of 30 w until the limit of the athlete's capability. Statistical analysis and data visualization were performed. Following the increasing load training, {Delta}HbO{sub 2} step-likely increased in the phase of aerobic metabolism but linearly decreased in the phase of anaerobic metabolism. The variation tendency of BLA was the same as {Delta}HbO{sub 2} and the concurrency of crucial turning points between {Delta}HbO{sub 2} and BLA was revealed. This relationship between {Delta}HbO{sub 2} and BLA presented in the increasing load training suggested that {Delta}HbO{sub 2} might be capable for taking the place of the invasively measured parameter BLA. Considering that {Delta}HbO{sub 2} can be noninvasively measured by NIRS, {Delta}HbO{sub 2} has the potential in the evaluation of athletes' physiological function and training effect on the athletes and accordingly NIRS can be well used in this field.

  16. Gliomas and the vascular fragility of the blood brain barrier

    Directory of Open Access Journals (Sweden)

    Luiz Gustavo eDubois

    2014-12-01

    Full Text Available Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB. By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM, characterized by a highly heterogeneous cell population (including tumor stem cells, extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the blood brain barrier and the concerns that arise when this barrier is affected.

  17. Blood and Brain Glutamate Levels in Children with Autistic Disorder

    Science.gov (United States)

    Hassan, Tamer H.; Abdelrahman, Hadeel M.; Fattah, Nelly R. Abdel; El-Masry, Nagda M.; Hashim, Haitham M.; El-Gerby, Khaled M.; Fattah, Nermin R. Abdel

    2013-01-01

    Despite of the great efforts that move forward to clarify the pathophysiologic mechanisms in autism, the cause of this disorder, however, remains largely unknown. There is an increasing body of literature concerning neurochemical contributions to the pathophysiology of autism. We aimed to determine blood and brain levels of glutamate in children…

  18. Blood-brain distribution of morphine-6-glucuronide in sheep

    DEFF Research Database (Denmark)

    Villesen, H H; Foster, D J R; Upton, R N;

    2006-01-01

    At present there are few data regarding the rate and extent of brain-blood partitioning of the opioid active metabolite of morphine, morphine-6-glucuronide (M6G). In this study the cerebral kinetics of M6G were determined, after a short-term intravenous infusion, in chronically instrumented consc...

  19. Cerebral autoregulation control of blood flow in the brain

    CERN Document Server

    Payne, Stephen

    2016-01-01

    This Brief provides a comprehensive introduction to the control of blood flow in the brain. Beginning with the basic physiology of autoregulation, the author goes on to discuss measurement techniques, mathematical models, methods of analysis, and relevant clinical conditions, all within this single volume. The author draws together this disparate field, and lays the groundwork for future research directions. The text gives an up-to-date review of the state of the art in cerebral autoregulation, which is particularly relevant as cerebral autoregulation moves from the laboratory to the bedside. Cerebral Autoregulation will be useful to researchers in the physical sciences such as mathematical biology, medical physics, and biomedical engineering whose work is concerned with the brain. Researchers in the medical sciences and clinicians dealing with the brain and blood flow, as well as industry professionals developing techniques such as ultrasound, MRI, and CT will also find this Brief of interest.

  20. Postmortem Quetiapine Reference Concentrations in Brain and Blood

    DEFF Research Database (Denmark)

    Skov, Louise; Johansen, Sys Stybe; Linnet, Kristian

    2015-01-01

    and related to concentrations in postmortem blood. For cases, where quetiapine was unrelated to the cause of death (N 5 36), the 10–90 percentiles for quetiapine concentrations in brain tissue were 0.030 – 1.54 mg/kg (median 0.48 mg/kg, mean 0.79 mg/kg). Corresponding blood 10 –90 percentile values were 0.......007 – 0.39 mg/kg (median 0.15 mg/kg, mean 0.19 mg/kg), giving brainblood ratio 10 –90 percentiles of 2.31 – 6.54 (median 3.87, mean 4.32). Both correspond well to the limited amount of data found in the literature. For cases where quetiapine was a contributing factor to death (N 5 5), the median value.......08 –6.05, which correspond to those of the nontoxic concentrations. A single case, where quetiapine was ruled as the sole cause of death, a suicide by quetiapine overdose, had an even higher value of 25.74 mg/kg in brain tissue. The blood concentration was 8.99 mg/kg, giving a brain–blood ratio of 2...

  1. The application of blood flow measurements to the study of aging muscle.

    Science.gov (United States)

    McCully, K K; Posner, J D

    1995-11-01

    Blood flow to skeletal muscle is a potentially important factor in the reduction of muscle function associated with aging (sarcopenia). The main influence of reduced blood flow capacity on muscle function is in limiting oxidative metabolism. Direct measures of blood flow include: intravital-microscopy, plethysmography, radioactive microspheres, 133Xenon washout, thermodilution, and Doppler ultrasound. Indirect measurement of blood flow includes arm-to-ankle pressure index and the rate of phosphocreatine recovery after exercise. Several new methodologies have been developed to evaluate muscle blood flow, including color-Doppler imaging, magnetic resonance imaging/angiography (MRI/MRA), and near-infrared spectroscopy (NIRS). As adaptations of traditional techniques, these methods promise more precise information under less invasive conditions. MRI is an expensive and technically challenging method able to measure vessel location, blood flow, and wall diameter in blood vessels throughout the cardiac cycle. Color-Doppler provides excellent temporal resolution blood flow throughout the cardiac cycle, along with some anatomical information. NIRS is an inexpensive and portable technology that can measure changes in oxygen saturation and provide information on tissue oxygen delivery in studies of frailer and more difficult-to-study subjects. Muscle blood flow is not thought to limit oxidative metabolism under normal conditions in young individuals. However, it is not clear what happens to muscle blood flow in healthy older individuals. Reduced capillary density, less maximal blood flow, and a slower hyperemic flow response have been reported in some, but not all, studies. Further studies with the newer methodologies are needed to re-examine age-related changes in muscle blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors

    Directory of Open Access Journals (Sweden)

    Yadollah Omidi

    2012-02-01

    Full Text Available Introduction: Entry of blood circulating agents into the brain is highly selectively controlled by specific transport machineries at the blood brain barrier (BBB, whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods: Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results: Brain capillary endothelial cells (BCECs form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics. Conclusion: The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent.

  3. Neuro-inflammation, blood-brain barrier, seizures and autism

    Directory of Open Access Journals (Sweden)

    Theoharides Theoharis C

    2011-11-01

    Full Text Available Abstract Many children with Autism Spectrum Diseases (ASD present with seizure activity, but the pathogenesis is not understood. Recent evidence indicates that neuro-inflammation could contribute to seizures. We hypothesize that brain mast cell activation due to allergic, environmental and/or stress triggers could lead to focal disruption of the blood-brain barrier and neuro-inflammation, thus contributing to the development of seizures. Treating neuro-inflammation may be useful when anti-seizure medications are ineffective.

  4. Alpha synuclein is transported into and out of the brain by the blood-brain barrier.

    Science.gov (United States)

    Sui, Yu-Ting; Bullock, Kristin M; Erickson, Michelle A; Zhang, Jing; Banks, W A

    2014-12-01

    Alpha-synuclein (α-Syn), a small protein with multiple physiological and pathological functions, is one of the dominant proteins found in Lewy Bodies, a pathological hallmark of Lewy body disorders, including Parkinson's disease (PD). More recently, α-Syn has been found in body fluids, including blood and cerebrospinal fluid, and is likely produced by both peripheral tissues and the central nervous system. Exchange of α-Syn between the brain and peripheral tissues could have important pathophysiologic and therapeutic implications. However, little is known about the ability of α-Syn to cross the blood-brain barrier (BBB). Here, we found that radioactively labeled α-Syn crossed the BBB in both the brain-to-blood and the blood-to-brain directions at rates consistent with saturable mechanisms. Low-density lipoprotein receptor-related protein-1 (LRP-1), but not p-glycoprotein, may be involved in α-Syn efflux and lipopolysaccharide (LPS)-induced inflammation could increase α-Syn uptake by the brain by disrupting the BBB.

  5. Blood flow and oxygenation in peritendinous tissue and calf muscle during dynamic exercise in humans

    DEFF Research Database (Denmark)

    Boushel, R; Langberg, Henning; Green, Stefan Mathias;

    2000-01-01

    1. Circulation around tendons may act as a shunt for muscle during exercise. The perfusion and oxygenation of Achilles' peritendinous tissue was measured in parallel with that of calf muscle during exercise to determine (1) whether blood flow is restricted in peritendinous tissue during exercise......, and (2) whether blood flow is coupled to oxidative metabolism. 2. Seven individuals performed dynamic plantar flexion from 1 to 9 W. Radial artery and popliteal venous blood were sampled for O2, peritendinous blood flow was determined by 133Xe-washout, calf blood flow by plethysmography, cardiac output...... by dye dilution, arterial pressure by an arterial catheter-transducer, and muscle and peritendinous O2 saturation by spatially resolved spectroscopy (SRS). 3. Calf blood flow rose 20-fold with exercise, reaching 44 +/- 7 ml (100 g)-1 min-1 (mean +/- s.e.m. ) at 9 W, while Achilles' peritendinous flow...

  6. Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

    OpenAIRE

    2011-01-01

    Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute—(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which c...

  7. Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation.

    Science.gov (United States)

    Wolff, Gretchen; Davidson, Sarah J; Wrobel, Jagoda K; Toborek, Michal

    2015-08-07

    Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 ± 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression.

  8. BLOOD-BRAIN BARRIER DYSFUNCTION IN DISORDERS OF THE DEVELOPING BRAIN

    Directory of Open Access Journals (Sweden)

    Raffaella eMoretti

    2015-02-01

    Full Text Available ABSTRACTDisorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult.The blood brain barrier (BBB protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response.The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g. perinatal stroke, traumatic brain injury or chronic (e.g. perinatal infectious diseases actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data.

  9. Blood-brain barrier dysfunction in disorders of the developing brain

    Science.gov (United States)

    Moretti, Raffaella; Pansiot, Julien; Bettati, Donatella; Strazielle, Nathalie; Ghersi-Egea, Jean-François; Damante, Giuseppe; Fleiss, Bobbi; Titomanlio, Luigi; Gressens, Pierre

    2015-01-01

    Disorders of the developing brain represent a major health problem. The neurological manifestations of brain lesions can range from severe clinical deficits to more subtle neurological signs or behavioral problems and learning disabilities, which often become evident many years after the initial damage. These long-term sequelae are due at least in part to central nervous system immaturity at the time of the insult. The blood-brain barrier (BBB) protects the brain and maintains homeostasis. BBB alterations are observed during both acute and chronic brain insults. After an insult, excitatory amino acid neurotransmitters are released, causing reactive oxygen species (ROS)-dependent changes in BBB permeability that allow immune cells to enter and stimulate an inflammatory response. The cytokines, chemokines and other molecules released as well as peripheral and local immune cells can activate an inflammatory cascade in the brain, leading to secondary neurodegeneration that can continue for months or even years and finally contribute to post-insult neuronal deficits. The role of the BBB in perinatal disorders is poorly understood. The inflammatory response, which can be either acute (e.g., perinatal stroke, traumatic brain injury) or chronic (e.g., perinatal infectious diseases) actively modulates the pathophysiological processes underlying brain injury. We present an overview of current knowledge about BBB dysfunction in the developing brain during acute and chronic insults, along with clinical and experimental data. PMID:25741233

  10. Gliomas and the vascular fragility of the blood brain barrier

    Science.gov (United States)

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  11. Saturable brain-to-blood transport of endomorphins.

    Science.gov (United States)

    Kastin, A J; Fasold, M B; Smith, R R; Horner, K A; Zadina, J E

    2001-07-01

    Opiate-modulating tetrapeptides such as tyrosine-melanocyte-stimulating hormone-release inhibiting factor-1 (Tyr-MIF-1; Tyr-Pro-Leu-Gly-NH2) and Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) are saturably transported from brain to blood. We examined whether two recently described endogenous opiate tetrapeptides with similar structures, the mu-specific endomorphins, also are transported across the blood-brain barrier (BBB). We found that the efflux rates of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) were each self-inhibited by an excess of the respective endomorphin, thereby defining saturable transport. Cross-inhibition of the transport of each endomorphin by the other indicated shared transport. By contrast, no inhibition of the efflux of either endomorphin resulted from coadministration of Tyr-MIF-1, indicating that peptide transport system-1 (PTS-1) was not involved. Tyr-W-MIF-1, which is partially transported by PTS-1, significantly (Pendomorphin-1 and tended (P=0.051) to decrease the transport of endomorphin-2, consistent with its role as both an opiate and antiopiate. Although involved in modulation of pain, coinjection of calcitonin gene-related peptide or constriction of the sciatic nerve did not appear to inhibit endomorphin efflux. Thus, the results demonstrate the existence of a new efflux system across the BBB which saturably transports endomorphins from brain to blood.

  12. Blood-Brain Barrier Breakdown in the Aging Human Hippocampus

    Science.gov (United States)

    Montagne, Axel; Barnes, Samuel R.; Sweeney, Melanie D.; Halliday, Matthew R.; Sagare, Abhay P.; Zhao, Zhen; Toga, Arthur W.; Jacobs, Russell E.; Liu, Collin Y.; Amezcua, Lilyana; Harrington, Michael G.; Chui, Helena C.; Law, Meng; Zlokovic, Berislav V.

    2014-01-01

    Summary The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer’s disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced magnetic resonance imaging protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment. PMID:25611508

  13. The vasopressin receptor of the blood-brain barrier in the rat hippocampus is linked to calcium signalling

    DEFF Research Database (Denmark)

    Hess, J.; Jensen, Claus V.; Diemer, Nils Henrik

    1991-01-01

    Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2......Neuropathology, vasopressin receptor, VI subtype, blood-brain barrier, cerebral endothelium, hippocampus, Fura-2...

  14. Muscle fatigue in fibromyalgia is in the brain, not in the muscles

    DEFF Research Database (Denmark)

    Bandak, Elisabeth; Amris, Kirstine; Bliddal, Henning

    2013-01-01

    To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC).......To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC)....

  15. Noninvasive optical quantification of absolute blood flow, blood oxygenation, and oxygen consumption rate in exercising skeletal muscle

    Science.gov (United States)

    Gurley, Katelyn; Shang, Yu; Yu, Guoqiang

    2012-07-01

    This study investigates a method using novel hybrid diffuse optical spectroscopies [near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS)] to obtain continuous, noninvasive measurement of absolute blood flow (BF), blood oxygenation, and oxygen consumption rate (\\Vdot O2) in exercising skeletal muscle. Healthy subjects (n=9) performed a handgrip exercise to increase BF and \\Vdot O2 in forearm flexor muscles, while a hybrid optical probe on the skin surface directly monitored oxy-, deoxy-, and total hemoglobin concentrations ([HbO2], [Hb], and THC), tissue oxygen saturation (StO2), relative BF (rBF), and relative oxygen consumption rate (r\\Vdot O2). The rBF and r\\Vdot O2 signals were calibrated with absolute baseline BF and \\Vdot O2 obtained through venous and arterial occlusions, respectively. Known problems with muscle-fiber motion artifacts in optical measurements during exercise were mitigated using a novel gating algorithm that determined muscle contraction status based on control signals from a dynamometer. Results were consistent with previous findings in the literature. This study supports the application of NIRS/DCS technology to quantitatively evaluate hemodynamic and metabolic parameters in exercising skeletal muscle and holds promise for improving diagnosis and treatment evaluation for patients suffering from diseases affecting skeletal muscle and advancing fundamental understanding of muscle and exercise physiology.

  16. Blood-brain barrier permeability and brain uptake mechanism of kainic acid and dihydrokainic acid.

    Science.gov (United States)

    Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen H; Bunch, Lennart; Pickering, Darryl S

    2015-03-01

    The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. The two ionotropic glutamate receptor agonists kainic acid (KA) and dihydrokainic acid (DHK) have been used as research tools in various in vivo central nervous system disease models in rodents, as well as being templates in the design of novel ligands affecting the glutamatergic system. Both molecules are highly polar but yet capable of crossing the blood-brain barrier (BBB). We used an in situ rat brain perfusion technique to determine the brain uptake mechanism and permeability across the BBB. To determine KA and DHK concentrations in the rat brain, simple and rapid sample preparation and liquid chromatography mass spectrometer methods were developed. According to our results the BBB permeability of KA and DHK is low, 0.25 × 10(-6) and 0.28 × 10(-6) cm/s for KA and DHK, respectively. In addition, the brain uptake is mediated by passive diffusion, and not by active transport. Furthermore, the non-specific plasma and brain protein binding of KA and DHK was determined to be low, which means that the unbound drug volume of distribution in brain is also low. Therefore, even though the total KA and DHK concentrations in the brain are low after systemic dosing, the concentrations in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy.

  17. Quorum Sensing Peptides Selectively Penetrate the Blood-Brain Barrier.

    Science.gov (United States)

    Wynendaele, Evelien; Verbeke, Frederick; Stalmans, Sofie; Gevaert, Bert; Janssens, Yorick; Van De Wiele, Christophe; Peremans, Kathelijne; Burvenich, Christian; De Spiegeleer, Bart

    2015-01-01

    Bacteria communicate with each other by the use of signaling molecules, a process called 'quorum sensing'. One group of quorum sensing molecules includes the oligopeptides, which are mainly produced by Gram-positive bacteria. Recently, these quorum sensing peptides were found to biologically influence mammalian cells, promoting i.a. metastasis of cancer cells. Moreover, it was found that bacteria can influence different central nervous system related disorders as well, e.g. anxiety, depression and autism. Research currently focuses on the role of bacterial metabolites in this bacteria-brain interaction, with the role of the quorum sensing peptides not yet known. Here, three chemically diverse quorum sensing peptides were investigated for their brain influx (multiple time regression technique) and efflux properties in an in vivo mouse model (ICR-CD-1) to determine blood-brain transfer properties: PhrCACET1 demonstrated comparatively a very high initial influx into the mouse brain (Kin = 20.87 μl/(g×min)), while brain penetrabilities of BIP-2 and PhrANTH2 were found to be low (Kin = 2.68 μl/(g×min)) and very low (Kin = 0.18 μl/(g×min)), respectively. All three quorum sensing peptides were metabolically stable in plasma (in vitro) during the experimental time frame and no significant brain efflux was observed. Initial tissue distribution data showed remarkably high liver accumulation of BIP-2 as well. Our results thus support the potential role of some quorum sensing peptides in different neurological disorders, thereby enlarging our knowledge about the microbiome-brain axis.

  18. Nanoparticle-mediated brain drug delivery: Overcoming blood-brain barrier to treat neurodegenerative diseases.

    Science.gov (United States)

    Saraiva, Cláudia; Praça, Catarina; Ferreira, Raquel; Santos, Tiago; Ferreira, Lino; Bernardino, Liliana

    2016-08-10

    The blood-brain barrier (BBB) is a vital boundary between neural tissue and circulating blood. The BBB's unique and protective features control brain homeostasis as well as ion and molecule movement. Failure in maintaining any of these components results in the breakdown of this specialized multicellular structure and consequently promotes neuroinflammation and neurodegeneration. In several high incidence pathologies such as stroke, Alzheimer's (AD) and Parkinson's disease (PD) the BBB is impaired. However, even a damaged and more permeable BBB can pose serious challenges to drug delivery into the brain. The use of nanoparticle (NP) formulations able to encapsulate molecules with therapeutic value, while targeting specific transport processes in the brain vasculature, may enhance drug transport through the BBB in neurodegenerative/ischemic disorders and target relevant regions in the brain for regenerative processes. In this review, we will discuss BBB composition and characteristics and how these features are altered in pathology, namely in stroke, AD and PD. Additionally, factors influencing an efficient intravenous delivery of polymeric and inorganic NPs into the brain as well as NP-related delivery systems with the most promising functional outcomes will also be discussed.

  19. Targeted liposomes for drug delivery across the blood-brain barrier

    NARCIS (Netherlands)

    van Rooy, I.

    2011-01-01

    Our brain is protected by the blood-brain barrier (BBB). This barrier is formed by specialized endothelial cells of the brain vasculature and prevents toxic substances from entering the brain. The downside of this barrier is that many drugs that have been developed to cure brain diseases cannot cros

  20. Cerebellar brain inhibition in the target and surround muscles during voluntary tonic activation.

    Science.gov (United States)

    Panyakaew, Pattamon; Cho, Hyun Joo; Srivanitchapoom, Prachaya; Popa, Traian; Wu, Tianxia; Hallett, Mark

    2016-04-01

    Motor surround inhibition is the neural mechanism that selectively favours the contraction of target muscles and inhibits nearby muscles to prevent unwanted movements. This inhibition was previously reported at the onset of a movement, but not during a tonic contraction. Cerebellar brain inhibition (CBI) is reduced in active muscles during tonic activation; however, it has not been studied in the surround muscles. CBI was evaluated in the first dorsal interosseus (FDI) muscle as the target muscle, and the abductor digiti minimi, flexor carpi radialis and extensor carpi radialis muscles as surround muscles, during rest and tonic activation of the FDI muscle in 21 subjects. Cerebellar stimulation was performed under magnetic resonance imaging-guided neuronavigation targeting lobule VIII of the cerebellar hemisphere. Stimulus intensities for cerebellar stimulation were based on the resting motor cortex threshold (RMT) and adjusted for the depth difference between the cerebellar and motor cortices. We used 90-120% of the adjusted RMT as the conditioning stimulus intensity during rest. The intensity that generated the best CBI at rest in the FDI muscle was selected for use during tonic activation. During selective tonic activation of the FDI muscle, CBI was significantly reduced only for the FDI muscle, and not for the surround muscles. Unconditioned motor evoked potential sizes were increased in all muscles during FDI muscle tonic activation as compared with rest, despite background electromyography activity increasing only for the FDI muscle. Our study suggests that the cerebellum may play an important role in selective tonic finger movement by reducing its inhibition in the motor cortex only for the relevant agonist muscle.

  1. Effect of blood flow on muscle lactate release studied in perfused rat hindlimb

    DEFF Research Database (Denmark)

    Pilegaard, H; Bangsbo, Jens; Henningsen, P;

    1995-01-01

    The influence of blood flow on muscle lactate and H+ release as well as muscle glyconeogenesis was studied in the perfused rat hindlimb. After 2 min of supramaximal stimulation the perfusate flow rate was 7 (F7), 12 (F12), or 18 (F18) ml/min for 30 min. Perfusate samples were drawn frequently...... between H+ and lactate release was larger (P flow in each of the muscles. The present data suggest that 1) in the range of blood...... flow rates from 0.61 to 0.92 ml.min-1.g-1, lactate and H+ release are independent of the flow rate, whereas at a lower flow rate (0.36 ml.min-1.g-1) release of these substances is decreased; 2) low blood flow influences lactate efflux more than H+ release; and 3) muscle glyconeogenesis from lactate...

  2. Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

    Directory of Open Access Journals (Sweden)

    Strazielle Nathalie

    2008-03-01

    Full Text Available Abstract Background Prostaglandin E2 (PGE2 is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation. Methods The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection. Results The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma. Conclusion The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.

  3. Blood flow response to electrically induced twitch and tetanic lower-limb muscle contractions.

    NARCIS (Netherlands)

    Janssen, T.W.; Hopman, M.T.E.

    2003-01-01

    OBJECTIVES: To compare the effect of electric stimulation (ES)-induced twitch with tetanic leg muscle contractions on blood flow responses and to assess blood flow responses in the contralateral inactive leg. DESIGN: Intervention with within-subject comparisons. SETTING: University research laborato

  4. Does blood flow restriction result in skeletal muscle damage? A critical review of available evidence.

    Science.gov (United States)

    Loenneke, J P; Thiebaud, R S; Abe, T

    2014-12-01

    Blood flow restriction (BFR) alone or in combination with exercise has been shown to result in muscle hypertrophy and strength gain across a variety of populations. Although there are numerous studies in the literature showing beneficial muscular effects following the application of BFR, questions have been raised over whether BFR may lead to or even increase the incidence of muscle damage. The purpose of this review is to examine the proposed mechanisms behind muscle damage and critically review the available BFR literature. The available evidence does not support the hypothesis that BFR in combination with low-intensity exercise increases the incidence of muscle damage. Instead, the available literature suggests that minimal to no muscle damage is occurring with this type of exercise. This conclusion is drawn from the following observations: (a) no prolonged decrements in muscle function; (b) no prolonged muscle swelling; (c) muscle soreness ratings similar to a submaximal low load control; and (d) no elevation in blood biomarkers of muscle damage.

  5. Impact of migraine attacks on the blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    GAO Hong-mei; LI Le; ZHANG Ke-ling; CHEN Xu-hui; TIAN Shu-qing; ZHANG Zhong-ling

    2010-01-01

    Background Cortical spreading depression can cause migraine attack, and up-regulate matrix metalloproteinase-9 (MMP-9) expression in animal. This study aimed to determine the impact on the structure and function of the blood-brain barrier by measuring plasma MMP-9 levels in patients at the acute and late stages of migraine attacks in order to elucidate the pathological mechanisms involved.Methods We recruited a case-control cohort of 38 adult migraine patients and 20 age- and gender-matched healthy control subjects. Five milliliter blood samples were collected at the acute and late stages of migraine (days 1-7), and also from the control subjects. Solid phase double antibody sandwich enzyme-linked immunosorbent assay was used to determine plasma MMP-9 levels. Statistical analysis was performed using the SAS version 9.1.Results Initial plasma MMP-9 levels of migraine patients were significantly higher than those of controls ((12.612±0.016)μg/L vs. (6.069±0.023) μg/L, respectively, P 0.05); in addition, levels were not correlated with degree of headache pain (P >0.05).Conclusions We hypothesize that migraine could lead to increased plasma MMP-9 levels resulting in blood-brain barrier damage. MMP-9 levels increase during days 1-6 of migraine attacks, peaking on day 3. Therefore, MMP-9 could be used as a biological marker to guide treatment of migraine attacks.

  6. Effects of a disrupted blood-brain barrier on cholesterol homeostasis in the brain.

    Science.gov (United States)

    Saeed, Ahmed A; Genové, Guillem; Li, Tian; Lütjohann, Dieter; Olin, Maria; Mast, Natalia; Pikuleva, Irina A; Crick, Peter; Wang, Yuqin; Griffiths, William; Betsholtz, Christer; Björkhem, Ingemar

    2014-08-22

    The presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism have not been studied previously. Here we used a pericyte-deficient mouse model, Pdgfb(ret/ret), shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brains of the Pdgfb(ret/ret) mice. By dietary treatment with 0.3% deuterium-labeled cholesterol, we could demonstrate a significant flux of cholesterol from the circulation into the brains of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a down-regulation of cholesterol synthesis. Instead, cholesterol synthesis was increased by about 60%. The levels of 24(S)-hydroxycholesterol (24S-OHC) were significantly reduced in the brains of the pericyte-deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet, the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis, and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge, this is the first demonstration that a defective BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed.

  7. A novel transgenic zebrafish model for blood-brain and blood-retinal barrier development

    Directory of Open Access Journals (Sweden)

    Sugimoto Masahiko

    2010-07-01

    Full Text Available Abstract Background Development and maintenance of the blood-brain and blood-retinal barrier is critical for the homeostasis of brain and retinal tissue. Despite decades of research our knowledge of the formation and maintenance of the blood-brain (BBB and blood-retinal (BRB barrier is very limited. We have established an in vivo model to study the development and maintenance of these barriers by generating a transgenic zebrafish line that expresses a vitamin D-binding protein fused with enhanced green fluorescent protein (DBP-EGFP in blood plasma, as an endogenous tracer. Results The temporal establishment of the BBB and BRB was examined using this transgenic line and the results were compared with that obtained by injection of fluorescent dyes into the sinus venosus of embryos at various stages of development. We also examined the expression of claudin-5, a component of tight junctions during the first 4 days of development. We observed that the BBB of zebrafish starts to develop by 3 dpf, with expression of claudin-5 in the central arteries preceding it at 2 dpf. The hyaloid vasculature in the zebrafish retina develops a barrier function at 3 dpf, which endows the zebrafish with unique advantages for studying the BRB. Conclusion Zebrafish embryos develop BBB and BRB function simultaneously by 3 dpf, which is regulated by tight junction proteins. The Tg(l-fabp:DBP-EGFP zebrafish will have great advantages in studying development and maintenance of the blood-neural barrier, which is a new application for the widely used vertebrate model.

  8. Brain injury associated with widely abused amphetamines: neuroinflammation, neurogenesis and blood-brain barrier.

    Science.gov (United States)

    Silva, Ana P; Martins, Tânia; Baptista, Sofia; Gonçalves, Joana; Agasse, Fabienne; Malva, João O

    2010-12-01

    Over the course of the 20(th) century, it became increasingly clear that amphetamine-like psychostimulants carried serious abuse liability that has resulted in sociological use patterns that have been described as epidemics. In fact, drug addiction is a brain disease with a high worldwide prevalence, and is considered the most expensive of the neuropsychiatric disorders. This review goes beyond the previously well-documented evidence demonstrating that amphetamines cause neuronal injury. Cellular and molecular mechanisms involved in the neurotoxicity of psychostimulants drugs have been extensively described giving particular attention to the role of oxidative stress and metabolic compromise. Recently, it was shown that the amphetamine class of drugs of abuse triggers an inflammatory process, emerging as a critical concept to understand the toxic effects of these drugs. Moreover, it has been suggested that psychostimulants compromise the capacity of the brain to generate new neurons (neurogenesis), and can also lead to blood-brain barrier (BBB) dysfunction. Together, these effects may contribute to brain damage, allowing the entry of pathogens into the brain parenchyma and thus decreasing the endogenous brain repair resources. The overall objective of this review is to highlight experimental evidence in an attempt to clarify the role of neuroinflammation in amphetamines-induced brain dysfunction and the effect of these drugs on both neurogenesis and BBB integrity.

  9. Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla

    DEFF Research Database (Denmark)

    Larsson, Henrik B W; Courivaud, Frédéric; Rostrup, Egill;

    2009-01-01

    Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted...

  10. Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

    Directory of Open Access Journals (Sweden)

    Patrícia Fernanda Schuck

    Full Text Available Ethylmalonic acid (EMA accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7'-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers, and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy.

  11. Brain and muscle redox imbalance elicited by acute ethylmalonic acid administration.

    Science.gov (United States)

    Schuck, Patrícia Fernanda; Milanez, Ana Paula; Felisberto, Francine; Galant, Leticia Selinger; Machado, Jéssica Luca; Furlanetto, Camila Brulezi; Petronilho, Fabricia; Dal-Pizzol, Felipe; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2015-01-01

    Ethylmalonic acid (EMA) accumulates in tissues and biological fluids of patients affected by short-chain acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy, illnesses characterized by neurological and muscular symptoms. Considering that the mechanisms responsible for the brain and skeletal muscle damage in these diseases are poorly known, in the present work we investigated the effects of acute EMA administration on redox status parameters in cerebral cortex and skeletal muscle from 30-day-old rats. Animals received three subcutaneous injections of EMA (6 μmol/g; 90 min interval between injections) and were killed 1 h after the last administration. Control animals received saline in the same volumes. EMA administration significantly increased thiobarbituric acid-reactive substances levels in cerebral cortex and skeletal muscle, indicating increased lipid peroxidation. In addition, carbonyl content was increased in EMA-treated animal skeletal muscle when compared to the saline group. EMA administration also significantly increased 2',7'-dihydrodichlorofluorescein oxidation and superoxide production (reactive species markers), and decreased glutathione peroxidase activity in cerebral cortex, while glutathione levels were decreased only in skeletal muscle. On the other hand, respiratory chain complex I-III activity was altered by acute EMA administration neither in cerebral cortex nor in skeletal muscle. The present results show that acute EMA administration elicits oxidative stress in rat brain and skeletal muscle, suggesting that oxidative damage may be involved in the pathophysiology of the brain and muscle symptoms found in patients affected by SCADD and ethylmalonic encephalopathy.

  12. [The blood-brain barrier and neurodegenerative lysosomal storage diseases].

    Science.gov (United States)

    Urayama, Akihiko

    2013-02-01

    Enzyme replacement therapy has been a very effective treatment for several lysosomal storage diseases. However, correcting central nervous system (CNS) storage has been challenging due to the presence of the blood-brain barrier (BBB), which hampers the entry of circulating lysosomal enzymes into the brain. In our previous studies, we discovered that luminally expressed cation-independent mannose 6-phosphate (M6P) receptor is a universal transporter for lysosomal enzymes that contain M6P moieties on the enzyme molecule. This receptor-mediated transport of lysosomal enzymes showed developmental down-regulation that resulted in a failure of delivery of lysosomal enzymes across the BBB in the adult brain. Conceptually, if one can re-induce M6P receptor-mediated transport of lysosomal enzymes in adult BBB, this could provide a novel brain targeting approach for treating abnormal storage in the CNS, regardless of the age of subjects. We found that systemic adrenergic stimuli restored functional transport of β-glucuronidase across the adult BBB. The concept of manipulating BBB transport activity by endogenous characteristics has also been demonstrated by another group who showed effective treatment in a Pompe disease model animal in vivo. It is intriguing that lysosomal enzymes utilize multiple mechanisms for their transport across the BBB. This review explores pharmacological manipulations for the delivery of lysosomal enzymes into the CNS, and the mechanisms of their transport across the BBB, based on existing evidence from studies of β-glucuronidase, sulfamidase, acid α-glucosidase, and arylsulfatase A.

  13. Perlecan and the Blood-Brain Barrier: Beneficial Proteolysis?

    Directory of Open Access Journals (Sweden)

    Jill eRoberts

    2012-08-01

    Full Text Available The cerebral microvasculature is important for maintaining brain homeostasis. This is achieved via the blood-brain barrier (BBB, composed of endothelial cells with specialized tight junctions, astrocytes and a basement membrane. Prominent components of the basement membrane extracellular matrix (ECM include fibronectin, laminin, collagen IV and perlecan, all of which regulate cellular processes via signal transduction through various cell membrane bound ECM receptors. Expression and proteolysis of these ECM components can be rapidly altered during pathological states of the central nervous system. In particular, proteolysis of perlecan, a heparan sulfate proteoglycan, occurs within hours following ischemia induced by experimental stroke. Proteolysis of ECM components following stroke results in the degradation of the basement membrane and further disruption of the BBB. While it is clear that such proteolysis has negative consequences for the BBB, we propose that it also may lead to generation of ECM protein fragments, including the C-terminal domain V (DV of perlecan, that potentially have a positive influence on other aspects of CNS health. Indeed, perlecan DV has been shown to be persistently generated after stroke and beneficial as a neuroprotective molecule and promoter of post-stroke brain repair. This mini-review will discuss beneficial roles of perlecan protein fragment generation within the brain during stroke.

  14. Brain and muscle oxygenation monitoring using near-infrared spectroscopy (NIRS) during all-night sleep

    Science.gov (United States)

    Zhang, Zhongxing; Khatami, Ramin

    2013-03-01

    The hemodynamic changes during natural human sleep are still not well understood. NIRS is ideally suited for monitoring the hemodynamic changes during sleep due to the properties of local measurement, totally safe application and good tolerance to motion. Several studies have been conducted using NIRS in both normal subjects and patients with various sleep disorders during sleep to characterize the hemodynamic changing patterns during different sleep stages and during different symptoms such as obstructive apneas. Here we assessed brain and muscle oxygenation changes in 7 healthy adults during all-night sleep with combined polysomnography measurement to test the notion if hemodynamic changes in sleep are indeed brain specific. We found that muscle and brain showed similar hemodynamic changes during sleep initiation. A decrease in HbO2 and tissue oxygenation index (TOI) while an increase in HHb was observed immediately after sleep onset, and an opposite trend was found after transition with progression to deeper slow-wave sleep (SWS) stage. Spontaneous low frequency oscillations (LFO) and very low frequency oscillations (VLFO) were smaller (Levene's test, psleep (LS) and rapid-eye-movement (REM) sleep in both brain and muscle. Spectral analysis of the NIRS signals measured from brain and muscle also showed reductions in VLFO and LFO powers during SWS with respect to LS and REM sleep. These results indicate a systemic attenuation rather than local cerebral reduction of spontaneous hemodynamic activity in SWS. A systemic physiological mechanism may exist to regulate the hemodynamic changes in brain and muscle during sleep.

  15. Brain energy metabolism and blood flow differences in healthy aging

    DEFF Research Database (Denmark)

    Aanerud, Joel; Borghammer, Per; Chakravarty, M Mallar

    2012-01-01

    Cerebral metabolic rate of oxygen consumption (CMRO(2)), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO(2) during normal aging are still controversial, as some authors...... find decreases of both CBF and CMRO(2) but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO(2) and CBF in 66 healthy volunteers aged 21 to 81......, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions...

  16. Effects of High-Intensity Blood Flow Restriction Exercise on Muscle Fatigue

    Directory of Open Access Journals (Sweden)

    Neto Gabriel R.

    2014-07-01

    Full Text Available Strength training combined with blood flow restriction (BFR have been used to improve the levels of muscle adaptation. The aim of this paper was to investigate the acute effect of high intensity squats with and without blood flow restriction on muscular fatigue levels. Twelve athletes (aged 25.95 ± 0.84 years were randomized into two groups: without Blood Flow Restriction (NFR, n = 6 and With Blood Flow Restriction (WFR, n = 6 that performed a series of free weight squats with 80% 1-RM until concentric failure. The strength of the quadriceps extensors was assessed in a maximum voluntary isometric contraction integrated to signals from the surface electromyogram. The average frequency showed significant reductions in the WFR group for the vastus lateralis and vastus medialis muscles, and intergroup only for the vastus medialis. In conclusion, a set of squats at high intensity with BFR could compromise muscle strength immediately after exercise, however, differences were not significant between groups.

  17. Striatal blood-brain barrier permeability in Parkinson's disease.

    Science.gov (United States)

    Gray, Madison T; Woulfe, John M

    2015-05-01

    In vivo studies have shown that blood-brain barrier (BBB) dysfunction is involved in the course of Parkinson's disease (PD). However, these have lacked either anatomic definition or the ability to recognize minute changes in BBB integrity. Here, using histologic markers of serum protein, iron, and erythrocyte extravasation, we have shown significantly increased permeability of the BBB in the postcommissural putamen of PD patients. The dense innervation of the striatum by PD-affected regions allows for exploitation of this permeability for therapeutic goals. These results are also discussed in the context of the retrograde trans-synaptic hypothesis of PD spread.

  18. Skin and muscle components of forearm blood flow in directly heated resting man.

    Science.gov (United States)

    Detry, J.-M. R.; Brengelmann, G. L.; Rowell, L. B.; Wyss, C.

    1972-01-01

    Changes in forearm muscle blood flow (FMBF) during direct whole-body heating were measured in 17 normal subjects using three different methods. We conclude that FMBF is not increased by direct whole-body heating. Since renal and splanchnic blood flow fall 30% under these conditions, maximal total skin blood flow in 12 previously studied subjects can be estimated from the rise in cardiac output to be 7.6 L/min (3.0-11.1 L/min).

  19. Novel models for studying the blood-brain and blood-eye barriers in Drosophila.

    Science.gov (United States)

    Pinsonneault, Robert L; Mayer, Nasima; Mayer, Fahima; Tegegn, Nebiyu; Bainton, Roland J

    2011-01-01

    In species as varied as humans and flies, humoral/central nervous system barrier structures are a major obstacle to the passive penetration of small molecules including endogenous compounds, environmental toxins, and drugs. In vivo measurement of blood-brain physiologic function in vertebrate animal models is difficult and current ex vivo models for more rapid experimentation using, for example, cultured brain endothelial cells, only partially reconstitute the anatomy and physiology of a fully intact blood-brain barrier (BBB). To address these problems, we and others continue to develop in vivo assays for studying the complex physiologic function of central nervous system (CNS) barriers using the fruit fly Drosophila melanogaster (Dm). These methods involve the introduction of small molecule reporters of BBB physiology into the fly humoral compartment by direct injection. Since these reporters must cross the Dm BBB in order to be visible in the eye, we can directly assess genetic or chemical modulators of BBB function by monitoring retinal fluorescence. This assay has the advantage of utilizing a physiologically intact BBB in a model organism that is economical and highly amenable to genetic manipulation. In combination with other approaches outlined here, such as brain dissection and behavioral assessment, one can produce a fuller picture of BBB biology and physiology. In this chapter, we provide detailed methods for examining BBB biology in the fly, including a Dm visual assay to screen for novel modulators of the BBB.

  20. Delivery of antihuman African trypanosomiasis drugs across the blood-brain and blood-CSF barriers.

    Science.gov (United States)

    Sekhar, Gayathri N; Watson, Christopher P; Fidanboylu, Mehmet; Sanderson, Lisa; Thomas, Sarah A

    2014-01-01

    Human African trypanosomiasis (HAT or sleeping sickness) is a potentially fatal disease caused by the parasite, Trypanosoma brucei sp. The parasites are transmitted by the bite of insect vectors belonging to the genus Glossina (tsetse flies) and display a life cycle strategy that is equally spread between human and insect hosts. T.b. gambiense is found in western and central Africa whereas, T.b. rhodesiense is found in eastern and southern Africa. The disease has two clinical stages: a blood stage after the bite of an infected tsetse fly, followed by a central nervous system (CNS) stage where the parasite penetrates the brain; causing death if left untreated. The blood-brain barrier (BBB) makes the CNS stage difficult to treat because it prevents 98% of all known compounds from entering the brain, including some anti-HAT drugs. Those that do enter the brain are toxic compounds in their own right and have serious side effects. There are only a few drugs available to treat HAT and those that do are stage specific. This review summarizes the incidence, diagnosis, and treatment of HAT and provides a close examination of the BBB transport of anti-HAT drugs and an overview of the latest drugs in development.

  1. Permeability of PEGylated Immunoarsonoliposomes Through In Vitro Blood Brain Barrier-Medulloblastoma Co-culture Models for Brain Tumor Therapy

    NARCIS (Netherlands)

    Al-Shehri, A.; Favretto, M.E.; Ioannou, P.V.; Romero, I.A.; Couraud, P.O.; Weksler, B.B.; Parker, T.L.; Kallinteri, P.

    2015-01-01

    PURPOSE: Owing to restricted access of pharmacological agents into the brain due to blood brain barrier (BBB) there is a need: 1. to develop a more representative 3-D-co-culture model of tumor-BBB interaction to investigate drug and nanoparticle transport into the brain for diagnostic and therapeuti

  2. Brain Mechanisms Underlying Urge Incontinence and its Response to Pelvic Floor Muscle Training

    Science.gov (United States)

    Griffiths, Derek; Clarkson, Becky; Tadic, Stasa D.; Resnick, Neil M.

    2016-01-01

    Purpose Urge urinary incontinence is a major problem, especially in the elderly, and to our knowledge the underlying mechanisms of disease and therapy are unknown. We used biofeedback assisted pelvic floor muscle training and functional brain imaging (functional magnetic resonance imaging) to investigate cerebral mechanisms, aiming to improve the understanding of brain-bladder control and therapy. Materials and Methods Before receiving biofeedback assisted pelvic floor muscle training functionally intact, older community dwelling women with urge urinary incontinence as well as normal controls underwent comprehensive clinical and bladder diary evaluation, urodynamic testing and brain functional magnetic resonance imaging. Evaluation was repeated after pelvic floor muscle training in those with urge urinary incontinence. Functional magnetic resonance imaging was done to determine the brain reaction to rapid bladder filling with urgency. Results Of 65 subjects with urge urinary incontinence 28 responded to biofeedback assisted pelvic floor muscle training with 50% or greater improvement of urge urinary incontinence frequency on diary. However, responders and nonresponders displayed 2 patterns of brain reaction. In pattern 1 in responders before pelvic floor muscle training the dorsal anterior cingulate cortex and the adjacent supplementary motor area were activated as well as the insula. After the training dorsal anterior cingulate cortex/supplementary motor area activation diminished and there was a trend toward medial prefrontal cortex deactivation. In pattern 2 in nonresponders before pelvic floor muscle training the medial prefrontal cortex was deactivated, which changed little after the training. Conclusions In older women with urge urinary incontinence there appears to be 2 patterns of brain reaction to bladder filling and they seem to predict the response and nonresponse to biofeedback assisted pelvic floor muscle training. Moreover, decreased cingulate

  3. Multiscale modeling and simulation of brain blood flow

    Energy Technology Data Exchange (ETDEWEB)

    Perdikaris, Paris, E-mail: parisp@mit.edu [Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 (United States); Grinberg, Leopold, E-mail: leopoldgrinberg@us.ibm.com [IBM T.J Watson Research Center, 1 Rogers St, Cambridge, Massachusetts 02142 (United States); Karniadakis, George Em, E-mail: george-karniadakis@brown.edu [Division of Applied Mathematics, Brown University, Providence, Rhode Island 02912 (United States)

    2016-02-15

    The aim of this work is to present an overview of recent advances in multi-scale modeling of brain blood flow. In particular, we present some approaches that enable the in silico study of multi-scale and multi-physics phenomena in the cerebral vasculature. We discuss the formulation of continuum and atomistic modeling approaches, present a consistent framework for their concurrent coupling, and list some of the challenges that one needs to overcome in achieving a seamless and scalable integration of heterogeneous numerical solvers. The effectiveness of the proposed framework is demonstrated in a realistic case involving modeling the thrombus formation process taking place on the wall of a patient-specific cerebral aneurysm. This highlights the ability of multi-scale algorithms to resolve important biophysical processes that span several spatial and temporal scales, potentially yielding new insight into the key aspects of brain blood flow in health and disease. Finally, we discuss open questions in multi-scale modeling and emerging topics of future research.

  4. Blood-brain barrier-supported neurogenesis in healthy and diseased brain.

    Science.gov (United States)

    Pozhilenkova, Elena A; Lopatina, Olga L; Komleva, Yulia K; Salmin, Vladimir V; Salmina, Alla B

    2017-02-14

    Adult neurogenesis is one of the most important mechanisms contributing to brain development, learning, and memory. Alterations in neurogenesis underlie a wide spectrum of brain diseases. Neurogenesis takes place in highly specialized neurogenic niches. The concept of neurogenic niches is becoming widely accepted due to growing evidence of the important role of the microenvironment established in the close vicinity to stem cells in order to provide adequate control of cell proliferation, differentiation, and apoptosis. Neurogenic niches represent the platform for tight integration of neurogenesis and angiogenesis supported by specific properties of cerebral microvessel endothelial cells contributing to establishment of partially compromised blood-brain barrier (BBB) for the adjustment of local conditions to the current metabolic needs of stem and progenitor cells. Here, we review up-to-date data on microvascular dynamics in activity-dependent neurogenesis, specific properties of BBB in neurogenic niches, endothelial-driven mechanisms of clonogenic activity, and future perspectives for reconstructing the neurogenic niches in vitro.

  5. Cerebrolysin attenuates blood-brain barrier and brain pathology following whole body hyperthermia in the rat.

    Science.gov (United States)

    Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Sharma, Aruna; Johanson, Conrad E

    2010-01-01

    The possibility that Cerebrolysin, a mixture of several neurotrophic factors, has some neuroprotective effects on whole body hyperthermia (WBH) induced breakdown of the blood-brain barrier (BBB), blood-CSF barrier (BCSFB), brain edema formation and neuropathology were examined in a rat model. Rats subjected to a 4 h heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator exhibited profound increases in BBB and BCSFB permeability to Evans blue and radioiodine tracers compared to controls. Hippocampus, caudate nucleus, thalamus and hypothalamus exhibited pronounced increase in water content and brain pathology following 4 h heat stress. Pretreatment with Cerebrolysin (1, 2 or 5 mL/kg i.v.) 24 h before WBH significantly attenuated breakdown of the BBB or BCSFB and brain edema formation. This effect was dose dependent. Interestingly, the cell and tissue injury following WBH in cerebrolysin-treated groups were also considerably reduced. These novel observations suggest that cerebrolysin can attenuate WBH induced BBB and BCSFB damage resulting in neuroprotection.

  6. Evaluation of sedentary women’s ambulatory blood pressure and its relation to muscle strength

    Directory of Open Access Journals (Sweden)

    Ramires Alsamir Tibana

    2012-09-01

    Full Text Available Objective: To compare the ambulatory blood pressure in women with different values of relative muscle strength. Methods: Data from 21 (aged 33.8±8.0 years sedentary women from Vila Telebrasília was collected during the period of November 2010 to July 2011. The volunteers were submitted to the evaluation of the handgrip strength and ambulatory monitoring of blood pressure (AMBP for a 72-hour period. Following the evaluation of handgrip strength to determine the absolute muscle strength, an adjustment in the body mass was made, in order to determine the relative muscle strength. Based on the relative value of muscular strength, the sample was divided into tertiles to compare systolic, diastolic and mean blood pressure during the periods of 24 hours, daytime and night-time, by using an one-way ANOVA, followed by Bonferroni test when appropriate, with a significance level of p<0.05. Results: Significant differences were found for systolic blood pressure between tertile 1 (99.3±12.2 and tertile 3 (106.8±11.1 in the night-time (P<0.05. Values of mean blood pressure were also significantly different between tertile 1 (70.2±6.3 and tertile 3 (80.3 ± 8.8 in the night-time (p<0,05. Conclusion: Women with higher relative muscle strength present lower values of blood pressure during night-time

  7. Cyclodextrins, blood-brain barrier, and treatment of neurological diseases.

    Science.gov (United States)

    Vecsernyés, Miklós; Fenyvesi, Ferenc; Bácskay, Ildikó; Deli, Mária A; Szente, Lajos; Fenyvesi, Éva

    2014-11-01

    Biological barriers are the main defense systems of the homeostasis of the organism and protected organs. The blood-brain barrier (BBB), formed by the endothelial cells of brain capillaries, not only provides nutrients and protection to the central nervous system but also restricts the entry of drugs, emphasizing its importance in the treatment of neurological diseases. Cyclodextrins are increasingly used in human pharmacotherapy. Due to their favorable profile to form hydrophilic inclusion complexes with poorly soluble active pharmaceutical ingredients, they are present as excipients in many marketed drugs. Application of cyclodextrins is widespread in formulations for oral, parenteral, nasal, pulmonary, and skin delivery of drugs. Experimental and clinical data suggest that cyclodextrins can be used not only as excipients for centrally acting marketed drugs like antiepileptics, but also as active pharmaceutical ingredients to treat neurological diseases. Hydroxypropyl-β-cyclodextrin received orphan drug designation for the treatment of Niemann-Pick type C disease. In addition to this rare lysosomal storage disease with neurological symptoms, experimental research revealed the potential therapeutic use of cyclodextrins and cyclodextrin nanoparticles in neurodegenerative diseases, stroke, neuroinfections and brain tumors. In this context, the biological effects of cyclodextrins, their interaction with plasma membranes and extraction of different lipids are highly relevant at the level of the BBB.

  8. Astrocytic modulation of blood brain barrier: perspectives on Parkinson's disease.

    Science.gov (United States)

    Cabezas, Ricardo; Avila, Marcos; Gonzalez, Janneth; El-Bachá, Ramon Santos; Báez, Eliana; García-Segura, Luis Miguel; Jurado Coronel, Juan Camilo; Capani, Francisco; Cardona-Gomez, Gloria Patricia; Barreto, George E

    2014-01-01

    The blood-brain barrier (BBB) is a tightly regulated interface in the Central Nervous System (CNS) that regulates the exchange of molecules in and out from the brain thus maintaining the CNS homeostasis. It is mainly composed of endothelial cells (ECs), pericytes and astrocytes that create a neurovascular unit (NVU) with the adjacent neurons. Astrocytes are essential for the formation and maintenance of the BBB by providing secreted factors that lead to the adequate association between the cells of the BBB and the formation of strong tight junctions. Under neurological disorders, such as chronic cerebral ischemia, brain trauma, Epilepsy, Alzheimer and Parkinson's Diseases, a disruption of the BBB takes place, involving a lost in the permeability of the barrier and phenotypical changes in both the ECs and astrocytes. In this aspect, it has been established that the process of reactive gliosis is a common feature of astrocytes during BBB disruption, which has a detrimental effect on the barrier function and a subsequent damage in neuronal survival. In this review we discuss the implications of astrocyte functions in the protection of the BBB, and in the development of Parkinson's disease (PD) and related disorders. Additionally, we highlight the current and future strategies in astrocyte protection aimed at the development of restorative therapies for the BBB in pathological conditions.

  9. Protective effects of taurine in traumatic brain injury via mitochondria and cerebral blood flow.

    Science.gov (United States)

    Wang, Qin; Fan, Weijia; Cai, Ying; Wu, Qiaoli; Mo, Lidong; Huang, Zhenwu; Huang, Huiling

    2016-09-01

    In mammalian tissues, taurine is an important natural component and the most abundant free amino acid in the heart, retina, skeletal muscle, brain, and leukocytes. This study is to examine the taurine's protective effects on neuronal ultrastructure, the function of the mitochondrial respiratory chain complex, and on cerebral blood flow (CBF). The model of traumatic brain injury (TBI) was made for SD rats by a fluid percussion device, with taurine (200 mg/kg) administered by tail intravenous injection once daily for 7 days after TBI. It was found that CBF was improved for both left and right brain at 30 min and 7 days post-injury by taurine. Reaction time was prolonged relative to the TBI-only group. Neuronal damage was prevented by 7 days taurine. Mitochondrial electron transport chain complexes I and II showed greater activity with the taurine group. The improvement by taurine of CBF may alleviate edema and elevation in intracranial pressure. Importantly taurine improved the hypercoagulable state.

  10. Blood-Brain Barrier P-Glycoprotein Function in Neurodegenerative Disease

    NARCIS (Netherlands)

    Bartels, A. L.

    2011-01-01

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protectio

  11. Multidimensional control using a mobile-phone based brain-muscle-computer interface.

    Science.gov (United States)

    Vernon, Scott; Joshi, Sanjay S

    2011-01-01

    Many well-known brain-computer interfaces measure signals at the brain, and then rely on the brain's ability to learn via operant conditioning in order to control objects in the environment. In our lab, we have been developing brain-muscle-computer interfaces, which measure signals at a single muscle and then rely on the brain's ability to learn neuromuscular skills via operant conditioning. Here, we report a new mobile-phone based brain-muscle-computer interface prototype for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single sEMG signal. Electromyographic activity on the surface of a single face muscle (Auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone. User-modulated power in two separate frequency band serves as two separate and simultaneous control channels for machine control. After signal processing, the Android phone sends commands to external devices via Bluetooth. Users are trained to use the device via biofeedback, with simple cursor-to-target activities on the phone screen.

  12. Nitric oxide and prostaglandins influence local skeletal muscle blood flow during exercise in humans: coupling between local substrate uptake and blood flow

    DEFF Research Database (Denmark)

    Kalliokoski, Kari K; Langberg, Henning; Ryberg, Ann Kathrine;

    2006-01-01

    skeletal muscle. Skeletal muscle blood flow was measured in seven healthy young men using near-infrared spectroscopy and indocyanine green and muscle glucose uptake using positron emission tomography and 2-fluoro-2-deoxy-D-[(18)F]glucose without and with local blockade of NO and PG at rest and during one-legged...... dynamic knee-extension exercise. Local blockade was produced by infusing nitro-L-arginine methyl ester and indomethacin directly in the muscle via a microdialysis catheter. Blood flow and glucose uptake were measured in the region of blockade and in two additional regions of vastus lateralis muscle 1......Synergic action of nitric oxide (NO) and prostaglandins (PG) in the regulation of muscle blood flow during exercise has been demonstrated. In the present study, we investigated whether these vasodilators also regulate local blood flow, flow heterogeneity, and glucose uptake within the exercising...

  13. Muscle and Blood Metabolites during a Soccer Game: Implications for Sprint Performance

    DEFF Research Database (Denmark)

    Krustrup, Peter; Mohr, Magni; Steensberg, Adam

    2006-01-01

    Abstract: Purpose: To examine muscle and blood metabolites during soccer match play and relate it to possible changes in sprint performance. Methods: Thirty-one Danish fourth division players took part in three friendly games. Blood samples were collected frequently during the game, and muscle...... biopsies were taken before and after the game as well as immediately after an intense period in each half. The players performed five 30-m sprints interspersed by 25-s recovery periods before the game and immediately after each half (N = 11) or after an intense exercise period in each half (N = 20......). Results: Muscle lactate was 15.9 +/- 1.9 and 16.9 +/- 2.3 mmol[middle dot]kg-1 d.w. during the first and second halves, respectively, with blood lactate being 6.0 +/- 0.4 and 5.0 +/- 0.4 mM, respectively. Muscle lactate was not correlated with blood lactate (r2 = 0.06-0.25, P >0.05). Muscle glycogen...

  14. Crossing the Blood-Brain Barrier: Recent Advances in Drug Delivery to the Brain.

    Science.gov (United States)

    Patel, Mayur M; Patel, Bhoomika M

    2017-02-01

    CNS disorders are on the rise despite advancements in our understanding of their pathophysiological mechanisms. A major hurdle to the treatment of these disorders is the blood-brain barrier (BBB), which serves as an arduous janitor to protect the brain. Many drugs are being discovered for CNS disorders, which, however fail to enter the market because of their inability to cross the BBB. This is a pronounced challenge for the pharmaceutical fraternity. Hence, in addition to the discovery of novel entities and drug candidates, scientists are also developing new formulations of existing drugs for brain targeting. Several approaches have been investigated to allow therapeutics to cross the BBB. As the molecular structure of the BBB is better elucidated, several key approaches for brain targeting include physiological transport mechanisms such as adsorptive-mediated transcytosis, inhibition of active efflux pumps, receptor-mediated transport, cell-mediated endocytosis, and the use of peptide vectors. Drug-delivery approaches comprise delivery from microspheres, biodegradable wafers, and colloidal drug-carrier systems (e.g., liposomes, nanoparticles, nanogels, dendrimers, micelles, nanoemulsions, polymersomes, exosomes, and quantum dots). The current review discusses the latest advancements in these approaches, with a major focus on articles published in 2015 and 2016. In addition, we also cover the alternative delivery routes, such as intranasal and convection-enhanced diffusion methods, and disruption of the BBB for brain targeting.

  15. Possible involvement of cationic-drug sensitive transport systems in the blood-to-brain influx and brain-to-blood efflux of amantadine across the blood-brain barrier.

    Science.gov (United States)

    Suzuki, Toyofumi; Fukami, Toshiro; Tomono, Kazuo

    2015-03-01

    The purpose of this study was to characterize the brain-to-blood efflux transport of amantadine across the blood-brain barrier (BBB). The apparent in vivo efflux rate constant for [(3) H]amantadine from the rat brain (keff ) was found to be 1.53 × 10(-2) min(-1) after intracerebral microinjection using the brain efflux index method. The efflux of [(3) H]amantadine was inhibited by 1-methyl-4-phenylpyridinium (MPP(+) ), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P-glycoprotein (P-gp), did not affect the efflux transport of [(3) H]amantadine. In addition, in vitro studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [(3) H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P-gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [(3) H]amantadine was determined using an in situ mouse brain perfusion technique. Notably, the brain uptake clearance for [(3) H]amantadine was significantly decreased with the co-perfusion of quinidine or verapamil, which are cationic P-gp inhibitors, while MPP(+) did not have a significant effect. It is thus concluded that while P-gp is not involved, it is possible that rPMAT and the cationic drug-sensitive transport system participate in the brain-to-blood efflux and the blood-to-brain influx of amantadine across the BBB, respectively.

  16. Respiratory muscle blood flow during exercise: effects of sex and ovarian cycle.

    Science.gov (United States)

    Smith, Joshua R; Hageman, K Sue; Harms, Craig A; Poole, David C; Musch, Timothy I

    2017-01-26

    Sex and ovarian cycle have been speculated to modify respiratory muscle(s) blood flow control during exercise, but the findings are inconclusive. We tested the hypotheses that females would have higher respiratory muscle blood flow and vascular conductance (VC) compared to males during exercise and that this difference would be accentuated in proestrus versus ovariectomized (OVA) females. Mean arterial pressure (carotid artery catheter) and respiratory muscle blood flow (radiolabeled microspheres) were measured during moderate-intensity (24m/min, 10% grade) exercise in male (n=9), female (n=9), and OVA female (n=7) rats and near-maximal (60m/min, 5% grade) exercise in male (n=5) and female (n=7) rats. At rest, diaphragm, intercostal, and transversus abdominis blood flow were not different (p=0.33) among groups. During moderate-intensity exercise, diaphragm (M: 124±16; F: 140±14; OVA: 140±20mL/min/100g), intercostal (M: 33±5; F: 34±5; OVA: 30±5mL/min/100g), and transversus abdominis blood flow (M: 24±4; F: 35±7; OVA: 35±9mL/min/100g) significantly increased in all groups compared to rest, but were not different (p=0.12) among groups. From rest to moderate-intensity exercise, diaphragm (p0.13) existed in VC among groups. During near-maximal exercise, diaphragm (M: 304±62; F: 283±17mL/min/100g), intercostal (M: 29±8; F: 40±6mL/min/100g), and transversus abdominis (M: 85±14; F: 86±9mL/min/100g) blood flow and VC were not different (p>0.27) between males and females. These data demonstrate that respiratory muscle blood flow and vascular conductance at rest and during exercise are not affected by sex or ovarian cycle in rats.

  17. Blood flow index using near-infrared spectroscopy and indocyanine green as a minimally invasive tool to assess respiratory muscle blood flow in humans

    DEFF Research Database (Denmark)

    Guenette, Jordan A; Henderson, William R; Dominelli, Paolo B

    2011-01-01

    Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS...... relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R(2)) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P

  18. A quantitative MRI method for imaging blood-brain barrier leakage in experimental traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Wei Li

    Full Text Available Blood-brain barrier (BBB disruption is common following traumatic brain injury (TBI. Dynamic contrast enhanced (DCE MRI can longitudinally measure the transport coefficient Ktrans which reflects BBB permeability. Ktrans measurements however are not widely used in TBI research because it is generally considered to be noisy and possesses low spatial resolution. We improved spatiotemporal resolution and signal sensitivity of Ktrans MRI in rats by using a high-sensitivity surface transceiver coil. To overcome the signal drop off profile of the surface coil, a pre-scan module was used to map the flip angle (B1 field and magnetization (M0 distributions. A series of T1-weighted gradient echo images were acquired and fitted to the extended Kety model with reversible or irreversible leakage, and the best model was selected using F-statistics. We applied this method to study the rat brain one hour following controlled cortical impact (mild to moderate TBI, and observed clear depiction of the BBB damage around the impact regions, which matched that outlined by Evans Blue extravasation. Unlike the relatively uniform T2 contrast showing cerebral edema, Ktrans shows a pronounced heterogeneous spatial profile in and around the impact regions, displaying a nonlinear relationship with T2. This improved Ktrans MRI method is also compatible with the use of high-sensitivity surface coil and the high-contrast two-coil arterial spin-labeling method for cerebral blood flow measurement, enabling more comprehensive investigation of the pathophysiology in TBI.

  19. Use of the Structure of Blood Vessel for Detection of Brain Aneurysm and Route Search to Brain Aneurysm

    Directory of Open Access Journals (Sweden)

    Toshihide Miyagi

    2013-08-01

    Full Text Available In this research, we constructed functions that are necessary for the operation simulation system which assists medical students to inhibit brain aneurysm from exploding. The system reported in this paper is "detection of blood vessels", "detection of brain aneurysm" and "route planning to brain aneurysm". Not only the detection method but also the method to reduce the miss detection is realized for the detection of blood vessel. Finally, the future work will be shown including construction of head model consisting of artery, vein, brain and cranium.

  20. Association between blood pressure levels over time and brain atrophy in the elderly

    NARCIS (Netherlands)

    den Heijer, T; Skoog, [No Value; Oudkerk, M; de Leeuw, FE; de Groot, JC; Hofman, A; Breteler, MMB

    2003-01-01

    The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995-1996, we measured blood

  1. Association between blood pressure levels over time and brain atrophy in the elderly.

    NARCIS (Netherlands)

    Heijer, T.; Skoog, I.; Oudkerk, M.; Leeuw, H.F. de; Groot, J.C. de; Hofman, A.W.I.M.; Breteler, M.H.M.

    2003-01-01

    The relation between blood pressure level and degree of global brain atrophy is equivocal. We evaluated past and present blood pressure levels and change in blood pressure over 20 years in relation to the degree of cortical atrophy on magnetic resonance imaging (MRI). In 1995-1996, we measured blood

  2. Transactivating-transduction protein-polyethylene glycol modified liposomes traverse the blood-spinal cord and blood-brain barriers

    Institute of Scientific and Technical Information of China (English)

    Xianhu Zhou; Chunyuan Wang; Shiqing Feng; Jin Chang; Xiaohong Kong; Yang Liu; Shijie Gao

    2012-01-01

    Naive liposomes can cross the blood-brain barrier and blood-spinal cord barrier in small amounts. Liposomes modified by a transactivating-transduction protein can deliver antibiotics for the treatment of acute bacterial infection-induced brain inflammation. Liposomes conjugated with polyethylene glycol have the capability of long-term circulation. In this study we prepared transactivating-transduction protein-polyethylene glycol-modified liposomes labeled with fluorescein isothiocyanate. Thus, liposomes were characterized by transmembrane, long-term circulation and fluorescence tracing. Uptake, cytotoxicity, and the ability of traversing blood-spinal cord and blood-brain barriers were observed following coculture with human breast adenocarcinoma cells (MCF-7). Results demonstrated that the liposomes had good biocompatibility, and low cytotoxicity when cocultured with human breast adenocarcinoma cells. Liposomes could traverse cell membranes and entered the central nervous system and neurocytes through the blood-spinal cord and blood-brain barriers of rats via the systemic circulation. These results verified that fluorescein isothiocyanate-modified transactivating-transduction protein-polyethylene glycol liposomes have the ability to traverse the blood-spinal cord and blood-brain barriers.

  3. Blood BDNF concentrations reflect brain-tissue BDNF levels across species

    DEFF Research Database (Denmark)

    Klein, Anders B; Williamson, Rebecca; Santini, Martin A;

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... no studies directly comparing blood BDNF levels to brain BDNF levels in different species. We examined blood, serum, plasma and brain-tissue BDNF levels in three different mammalian species: rat, pig, and mouse, using an ELISA method. As a control, we included an analysis of blood and brain tissue from...... conditional BDNF knockout mice and their wild-type littermates. Whereas BDNF could readily be measured in rat blood, plasma and brain tissue, it was undetectable in mouse blood. In pigs, whole-blood levels of BDNF could not be measured with a commercially available ELISA kit, but pig plasma BDNF levels (mean...

  4. Gene networks in skeletal muscle following endurance exercise are co-expressed in blood neutrophils and linked with blood inflammation markers.

    Science.gov (United States)

    Broadbent, James A; Sampson, Dayle; Sabapathy, Surendran; Haseler, Luke J; Wagner, Karl-Heinz; Bulmer, Andrew Cameron; Peake, Jonathan M; Neubauer, Oliver

    2017-01-19

    It remains incompletely understood whether there is an association between the transcriptome profiles of skeletal muscle and blood leukocytes in response to exercise or other physiological stressors. We have previously analyzed the changes in the muscle and blood neutrophil transcriptome in eight trained men before and 3 h, 48 h and 96 h after 2 h cycling and running. Because we collected muscle and blood in the same individuals and under the same conditions, we were able to directly compare gene expression between the muscle and blood neutrophils. Applying weighted gene co-expression network analysis (WGCNA) as an advanced network-driven method to these original datasets enabled us to compare the muscle and neutrophil transcriptomes in a rigorous and systematic manner. Two gene networks were identified that were preserved between skeletal muscle and blood neutrophils, functionally related to mitochondria and post-translational processes. Strong preservation measures (Zsummary > 10) for both muscle-neutrophil gene networks were evident within the post-exercise recovery period. Muscle and neutrophil gene co-expression was strongly correlated in the mitochondria-related network (r = 0.97; p = 3.17E-2). We also identified multiple correlations between muscular gene sub-networks and exercise-induced changes in blood leukocyte counts, inflammation and muscle damage markers. These data reveal previously unidentified gene co-expression between skeletal muscle and blood neutrophils following exercise, showing the value of WGCNA to understand exercise physiology. Furthermore, these findings provide preliminary evidence in support of the notion that blood neutrophil gene networks may potentially help us to track physiological and pathophysiological changes in the muscle.

  5. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    Ying Xing; Chun-yan Wen; Song-tao Li; Zong-xin Xia

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) plays an important role in the repair of central nervous system injury, but cannot directly tra-verse the blood-brain barrier. Liposomes are a new type of non-viral vector, able to carry macromolecules across the blood-brain barrier and into the brain. Here, we investigate whether BDNF could be transported across the blood-brain barrier by tail-vein injection of lipo-somes conjugated to transferrin (Tf) and polyethylene glycol (PEG), and carrying BDNF modiifed with cytomegalovirus promoter (pCMV) or glial ifbrillary acidic protein promoter (pGFAP) (Tf-pCMV-BDNF-PEG and Tf-pGFAP-BDNF-PEG, respectively). Both liposomes were able to traverse the blood-brain barrier, and BDNF was mainly expressed in the cerebral cortex. BDNF expression in the cerebral cortex was higher in the Tf-pGFAP-BDNF-PEG group than in the Tf-pCMV-BDNF-PEG group. This study demonstrates the successful construction of a non-virus targeted liposome, Tf-pGFAP-BDNF-PEG, which crosses the blood-brain barrier and is distributed in the cerebral cortex. Our work provides an experimental basis for BDNF-related targeted drug delivery in the brain.

  6. Non-viral liposome-mediated transfer of brain-derived neurotrophic factor across the blood-brain barrier

    Directory of Open Access Journals (Sweden)

    Ying Xing

    2016-01-01

    Full Text Available Brain-derived neurotrophic factor (BDNF plays an important role in the repair of central nervous system injury, but cannot directly traverse the blood-brain barrier. Liposomes are a new type of non-viral vector, able to carry macromolecules across the blood-brain barrier and into the brain. Here, we investigate whether BDNF could be transported across the blood-brain barrier by tail-vein injection of liposomes conjugated to transferrin (Tf and polyethylene glycol (PEG, and carrying BDNF modified with cytomegalovirus promoter (pCMV or glial fibrillary acidic protein promoter (pGFAP (Tf-pCMV-BDNF-PEG and Tf-pGFAP-BDNF-PEG, respectively. Both liposomes were able to traverse the blood-brain barrier, and BDNF was mainly expressed in the cerebral cortex. BDNF expression in the cerebral cortex was higher in the Tf-pGFAP-BDNF-PEG group than in the Tf-pCMV-BDNF-PEG group. This study demonstrates the successful construction of a non-virus targeted liposome, Tf-pGFAP-BDNF-PEG, which crosses the blood-brain barrier and is distributed in the cerebral cortex. Our work provides an experimental basis for BDNF-related targeted drug delivery in the brain.

  7. Sex, the brain and hypertension: brain oestrogen receptors and high blood pressure risk factors.

    Science.gov (United States)

    Hay, Meredith

    2016-01-01

    Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension.

  8. Transporter protein and drug-conjugated gold nanoparticles capable of bypassing the blood-brain barrier

    Science.gov (United States)

    Zhang, Yanhua; Walker, Janelle Buttry; Minic, Zeljka; Liu, Fangchao; Goshgarian, Harry; Mao, Guangzhao

    2016-05-01

    Drug delivery to the central nervous system (CNS) is challenging due to the inability of many drugs to cross the blood-brain barrier (BBB). Here, we show that wheat germ agglutinin horse radish peroxidase (WGA-HRP) chemically conjugated to gold nanoparticles (AuNPs) can be transported to the spinal cord and brainstem following intramuscular injection into the diaphragm of rats. We synthesized and determined the size and chemical composition of a three-part nanoconjugate consisting of WGA-HRP, AuNPs, and drugs for the treatment of diaphragm paralysis associated with high cervical spinal cord injury (SCI). Upon injection into the diaphragm muscle of rats, we show that the nanoconjugate is capable of delivering the drug at a much lower dose than the unconjugated drug injected systemically to effectively induce respiratory recovery in rats following SCI. This study not only demonstrates a promising strategy to deliver drugs to the CNS bypassing the BBB but also contributes a potential nanotherapy for the treatment of respiratory muscle paralysis resulted from cervical SCI.

  9. Contraction-induced muscle fiber damage is increased in soleus muscle of streptozotocin-diabetic rats and is associated with elevated expression of brain-derived neurotrophic factor mRNA in muscle fibers and activated satellite cells

    NARCIS (Netherlands)

    Copray, S; Liem, R; Brouwer, N; Greenhaff, P; Habens, F; Fernyhough, P

    2000-01-01

    The expression of brain-derived neurotrophic factor (BDNF) is elevated in the soleus muscle of streptozotocin-diabetic rats. To determine whether this diabetes-induced elevation was associated with or enhanced by muscle activity we have induced high-intensity muscle contraction by electrically stimu

  10. Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction

    Directory of Open Access Journals (Sweden)

    Murrin L Charles

    2011-03-01

    Full Text Available Abstract Background Methamphetamine (METH, an addictive psycho-stimulant drug with euphoric effect is known to cause neurotoxicity due to oxidative stress, dopamine accumulation and glial cell activation. Here we hypothesized that METH-induced interference of glucose uptake and transport at the endothelium can disrupt the energy requirement of the blood-brain barrier (BBB function and integrity. We undertake this study because there is no report of METH effects on glucose uptake and transport across the blood-brain barrier (BBB to date. Results In this study, we demonstrate that METH-induced disruption of glucose uptake by endothelium lead to BBB dysfunction. Our data indicate that a low concentration of METH (20 μM increased the expression of glucose transporter protein-1 (GLUT1 in primary human brain endothelial cell (hBEC, main component of BBB without affecting the glucose uptake. A high concentration of 200 μM of METH decreased both the glucose uptake and GLUT1 protein levels in hBEC culture. Transcription process appeared to regulate the changes in METH-induced GLUT1 expression. METH-induced decrease in GLUT1 protein level was associated with reduction in BBB tight junction protein occludin and zonula occludens-1. Functional assessment of the trans-endothelial electrical resistance of the cell monolayers and permeability of dye tracers in animal model validated the pharmacokinetics and molecular findings that inhibition of glucose uptake by GLUT1 inhibitor cytochalasin B (CB aggravated the METH-induced disruption of the BBB integrity. Application of acetyl-L-carnitine suppressed the effects of METH on glucose uptake and BBB function. Conclusion Our findings suggest that impairment of GLUT1 at the brain endothelium by METH may contribute to energy-associated disruption of tight junction assembly and loss of BBB integrity.

  11. Blood vessels and desmin control the positioning of nuclei in skeletal muscle fibers

    DEFF Research Database (Denmark)

    Ralston, E; Lu, Z; Biscocho, N

    2006-01-01

    . Here we show that the nuclei are preferentially localized near blood vessels (BV), particularly in slow-twitch, oxidative fibers. Thus, in rat soleus muscle fibers, 81% of the nuclei appear next to BV. Lack of desmin markedly perturbs the distribution of nuclei along the fibers but does not prevent...

  12. Skeletal muscle signaling and the heart rate and blood pressure response to exercise

    DEFF Research Database (Denmark)

    Mortensen, Stefan P; Svendsen, Jesper H; Ersbøll, Mads

    2013-01-01

    Endurance training lowers heart rate and blood pressure responses to exercise, but the mechanisms and consequences remain unclear. To determine the role of skeletal muscle for the cardioventilatory response to exercise, 8 healthy young men were studied before and after 5 weeks of 1-legged knee...

  13. Combined inhibition of nitric oxide and prostaglandins reduces human skeletal muscle blood flow during exercise

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Langberg, Henning; Gemmer, Carsten;

    2002-01-01

    The vascular endothelium is an important mediator of tissue vasodilatation, yet the role of the specific substances, nitric oxide (NO) and prostaglandins (PG), in mediating the large increases in muscle perfusion during exercise in humans is unclear. Quadriceps microvascular blood flow was quanti...

  14. MR-Guided Unfocused Ultrasound Disruption of the Rat Blood-Brain Barrier

    Science.gov (United States)

    Townsend, Kelly A.; King, Randy L.; Zaharchuk, Greg; Pauly, Kim Butts

    2011-09-01

    Therapeutic ultrasound with microbubbles can temporarily disrupt the blood-brain barrier (BBB) for drug delivery. Contrast-enhanced MRI (CE-MRI) can visualize gadolinium passage into the brain, indicating BBB opening. Previous studies used focused ultrasound, which is appropriate for the targeted delivery of drugs. The purpose of this study was to investigate unfocused ultrasound for BBB opening across the whole brain. In 10 rats, gadolinium-based MR contrast agent (Gd; 0.25 ml) was administered concurrent with ultrasound microbubbles (Optison, 0.25 ml) and circulated for 20 sec before sonication. A 753 kHz planar PZT transducer, diameter 1.8 cm, sonicated each rat brain with supplied voltage of 300, 400, or 500 mVpp for 10 sec in continuous wave mode, or at 500 mVpp at 20% duty cycle at 10 Hz for 30-300 sec. After sonication, coronal T1-weighted FSE CE-MRI images were acquired with a 3in surface coil. The imaging protocol was repeated 3-5 times after treatment. One control animal was given Gd and microbubbles, but not sonicated, and the other was given Gd and sonicated without microbubbles. Signal change in ROIs over the muscle, mesencephalon/ventricles, and the cortex/striatum were measured at 3-5 time points up to 36 min after sonication. Signal intensity was converted to % signal change compared to the initial image. In the controls, CE-MRI showed brightening of surrounding structures, but not the brain. In the continuous wave subjects, cortex/striatum signal did not increase, but ventricle/mesenchephalon signal did. Those that received pulsed sonications showed signal increases in both the cortex/striatum and ventricles/mesenchephalon. In conclusion, after pulsed unfocused ultrasound sonication, the BBB is disrupted across the whole brain, including cortex and deep grey matter, while continuous wave sonication affects only the ventricles and possibly deeper structures, without opening the cortex BBB. As time passes, the timeline of Gd passage into the brain

  15. Blood flow restriction prevents muscle damage but not protein synthesis signaling following eccentric contractions.

    Science.gov (United States)

    Sudo, Mizuki; Ando, Soichi; Poole, David C; Kano, Yutaka

    2015-07-01

    There is a growing body of evidence to suggest that resistance training exercise combined with blood flow restriction (BFR) increases muscle size and strength in humans. Eccentric contraction (ECC) frequently induces severe muscle damage. However, it is not known whether and to what extent muscle damage occurs following ECC + BFR due to the difficulty of conducting definitive invasive studies. The purpose of this study was to examine muscle fiber damage following ECC + BFR at the cellular level. High-intensity ECC was purposefully selected to maximize the opportunity for muscle damage and hypertrophic signaling in our novel in vivo animal model. Male Wistar rats were assigned randomly to the following groups: ECC and ECC + BFR at varying levels of occlusion pressure (140, 160, and 200 Torr). In all conditions, electrical stimulation was applied to the dorsiflexor muscles simultaneously with electromotor-induced plantar flexion. We observed severe histochemical muscle fiber damage (area of damaged fibers/total fiber area analyzed) following ECC (26.4 ± 4.0%). Surprisingly, however, muscle damage was negligible following ECC + BFR140 (2.6 ± 1.2%), ECC+BFR160 (3.0 ± 0.5%), and ECC + BFR200 (0.2 ± 0.1%). Ribosomal S6 kinase 1 (S6K1) phosphorylation, a downstream target of rapamycin (mTOR)-phosphorylation kinase, increased following ECC + BFR200 as well as ECC. In contrast, S6K1 phosphorylation was not altered by BFR alone. The present findings suggest that ECC combined with BFR, even at high exercise intensities, may enhance muscle protein synthesis without appreciable muscle fiber damage.

  16. Role of adenosine in regulating the heterogeneity of skeletal muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Nesterov, Sergey V; Kemppainen, Jukka;

    2007-01-01

    ) muscles during exercise, measured using positron emission tomography. In six healthy young women, BF was measured at rest and then during three incremental low and moderate intermittent isometric one-legged knee-extension exercise intensities without and with theophylline-induced nonselective adenosine...... exercise intensity in the QF muscle group. Adenosine seems to play a role in muscle BF heterogeneity even in the absence of changes in bulk BF at low and moderate one-leg intermittent isometric exercise intensities.......Evidence from both animal and human studies suggests that adenosine plays a role in the regulation of exercise hyperemia in skeletal muscle. We tested whether adenosine also plays a role in the regulation of blood flow (BF) distribution and heterogeneity among and within quadriceps femoris (QF...

  17. A correlation study of the expression of resistin and glycometabolism in muscle tissue after traumatic brain injury in rats

    Institute of Scientific and Technical Information of China (English)

    Jin Peng; Zhu Lielie; Zhang Jiasheng; Xie Songling; Pan Da; Wen Hao; Meng Weiyang

    2014-01-01

    Objective:To investigate the expression pattern of resistin (RSTN) in skeletal muscle tissue and its influence on glycometabolism in rats with traumatic brain injury (TBI).Methods:Seventy-eight SD rats were randomly divided into traumatic group (n=36),RSTN group (n=36) and sham operation group (n=6).Fluid percussion TBI model was developed in traumatic and RSTN groups and the latter received additional 1 mg RSTN antibody treatment for each rat.At respectively 12 h,24 h,72 h,1 w,2 w,and 4 w after operation,venous blood was collected and the right hind leg skeletal muscle tissue was sampled.We used real-time PCR to determine mRNA expression of RSTN in skeletal muscles,western blot to determine RSTN protein expression and ELISA to assess serum insulin as well as fasting blood glucose (FBG) levels.Calculation of the quantitative insulin sensitivity check index (Q value) was also conducted.The above mentioned indicators and their correction were statistically analyzed.Results:Compared with sham operation group,the RSTN expression in the skeletal muscle as well as serum insulin and FBG levels revealed significant elevation (P<0.05),and reduced Q value (P<0.05) in traumatic group.Single factor linear correlation analysis showed a significant negative correlation between RSTN expression and Q values (P<0.001) in traumatic group.Conclusion:The expression of RSTN has been greatly increased in the muscular tissue of TBI rats and it was closely related to the index of glycometabolism.RSTN may play an important role in the process of insulin resistance after TBI.

  18. Blood-Feeding Induces Reversible Functional Changes in Flight Muscle Mitochondria of Aedes aegypti Mosquito

    Science.gov (United States)

    Gonçalves, Renata L. S.; Machado, Ana Carolina L.; Paiva-Silva, Gabriela O.; Sorgine, Marcos H. F.; Momoli, Marisa M.; Oliveira, Jose Henrique M.; Vannier-Santos, Marcos A.; Galina, Antonio; Oliveira, Pedro L.; Oliveira, Marcus F.

    2009-01-01

    Background Hematophagy poses a challenge to blood-feeding organisms since products of blood digestion can exert cellular deleterious effects. Mitochondria perform multiple roles in cell biology acting as the site of aerobic energy-transducing pathways, and also an important source of reactive oxygen species (ROS), modulating redox metabolism. Therefore, regulation of mitochondrial function should be relevant for hematophagous arthropods. Here, we investigated the effects of blood-feeding on flight muscle (FM) mitochondria from the mosquito Aedes aegypti, a vector of dengue and yellow fever. Methodology/Principal Findings Blood-feeding caused a reversible reduction in mitochondrial oxygen consumption, an event that was parallel to blood digestion. These changes were most intense at 24 h after blood meal (ABM), the peak of blood digestion, when oxygen consumption was inhibited by 68%. Cytochromes c and a+a3 levels and cytochrome c oxidase activity of the electron transport chain were all reduced at 24 h ABM. Ultrastructural and molecular analyses of FM revealed that mitochondria fuse upon blood meal, a condition related to reduced ROS generation. Consistently, BF induced a reversible decrease in mitochondrial H2O2 formation during blood digestion, reaching their lowest values at 24 h ABM where a reduction of 51% was observed. Conclusion Blood-feeding triggers functional and structural changes in hematophagous insect mitochondria, which may represent an important adaptation to blood feeding. PMID:19924237

  19. Transcriptional profiling of rat skeletal muscle hypertrophy under restriction of blood flow.

    Science.gov (United States)

    Xu, Shouyu; Liu, Xueyun; Chen, Zhenhuang; Li, Gaoquan; Chen, Qin; Zhou, Guoqing; Ma, Ruijie; Yao, Xinmiao; Huang, Xiao

    2016-12-15

    Blood flow restriction (BFR) under low-intensity resistance training (LIRT) can produce similar effects upon muscles to that of high-intensity resistance training (HIRT) while overcoming many of the restrictions to HIRT that occurs in a clinical setting. However, the potential molecular mechanisms of BFR induced muscle hypertrophy remain largely unknown. Here, using a BFR rat model, we aim to better elucidate the mechanisms regulating muscle hypertrophy as induced by BFR and reveal possible clinical therapeutic targets for atrophy cases. We performed genome wide screening with microarray analysis to identify unique differentially expressed genes during rat muscle hypertrophy. We then successfully separated the differentially expressed genes from BRF treated soleus samples by comparing the Affymetrix rat Genome U34 2.0 array with the control. Using qRT-PCR and immunohistochemistry (IHC) we also analyzed other related differentially expressed genes. Results suggested that muscle hypertrophy induced by BFR is essentially regulated by the rate of protein turnover. Specifically, PI3K/AKT and MAPK pathways act as positive regulators in controlling protein synthesis where ubiquitin-proteasome acts as a negative regulator. This represents the first general genome wide level investigation of the gene expression profile in the rat soleus after BFR treatment. This may aid our understanding of the molecular mechanisms regulating and controlling muscle hypertrophy and provide support to the BFR strategies aiming to prevent muscle atrophy in a clinical setting.

  20. Aquaporin 4 expression and ultrastructure of the blood-brain barrier following cerebral contusion injury

    Institute of Scientific and Technical Information of China (English)

    Xinjun Li; Yangyun Han; Hong Xu; Zhongshu Sun; Zengjun Zhou; Xiaodong Long; Yumin Yang; Linbo Zou

    2013-01-01

    This study aimed to investigate aquaporin 4 expression and the ultrastructure of the blood-brain barrier at 2–72 hours following cerebral contusion injury, and correlate these changes to the formation of brain edema. Results revealed that at 2 hours after cerebral contusion and laceration injury, aquaporin 4 expression significantly increased, brain water content and blood-brain barrier permeability increased, and the number of pinocytotic vesicles in cerebral microvascular endothelial cells increased. In addition, the mitochondrial accumulation was observed. As contusion and laceration injury became aggravated, aquaporin 4 expression continued to increase, brain water content and blood-brain barrier permeability gradually increased, brain capillary endothelial cells and astrocytes swelled, and capillary basement membrane injury gradually increased. The above changes were most apparent at 12 hours after injury, after which they gradually attenuated. Aquaporin 4 expression positively correlated with brain water content and the blood-brain barrier index. Our experimental findings indicate that increasing aquaporin 4 expression and blood-brain barrier permeability after cerebral contusion and laceration injury in humans is involved in the formation of brain edema.

  1. The diffusion permeability to water of the rat blood-brain barrier

    DEFF Research Database (Denmark)

    Bolwig, T G; Lassen, N A

    1975-01-01

    The diffusion permeability to water of the rat blood-brain-barrier (BBB) was studied. Preliminary data obtained with the Oldendorf tissue uptake method (Oldendorf 1970) in seizure experiments suggested that the transfer from blood to brain of labelled water is diffusion-limited. More definite evi...... passage increased from 0.26 to 0.67 when the arterial carbon dioxide tension was changed from 15 to 85 mm Hg, a change increasing the cerebral blood flow about sixfold. This finding suggests that water does not pass the blood-brain barrier as freely as lipophilic gases....

  2. In vitro models of the blood-brain barrier

    DEFF Research Database (Denmark)

    Helms, Hans Christian Cederberg; Abbott, N Joan; Burek, Malgorzata;

    2016-01-01

    components of plasma and xenobiotics. This "blood-brain barrier" function is a major hindrance for drug uptake into the brain parenchyma. Cell culture models, based on either primary cells or immortalized brain endothelial cell lines, have been developed, in order to facilitate in vitro studies of drug...

  3. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    NARCIS (Netherlands)

    Griep, L.M.; Wolbers, F.; Wagenaar, de B.; Braak, ter P.M.; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; Meer, van der A.D.; Berg, van den A.

    2013-01-01

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understo

  4. Penetrating the Blood-Brain Barrier: Promise of Novel Nanoplatforms and Delivery Vehicles.

    Science.gov (United States)

    Ali, Iqbal Unnisa; Chen, Xiaoyuan

    2015-10-27

    Multifunctional nanoplatforms combining versatile therapeutic modalities with a variety of imaging options have the potential to diagnose, monitor, and treat brain diseases. The promise of nanotechnology can only be realized by the simultaneous development of innovative brain-targeting delivery vehicles capable of penetrating the blood-brain barrier without compromising its structural integrity.

  5. Stroke and Drug Delivery--In Vitro Models of the Ischemic Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

    Stroke is a major cause of death and disability worldwide. Both cerebral hypoperfusion and focal cerebral infarcts are caused by a reduction of blood flow to the brain, leading to stroke and subsequent brain damage. At present, only few medical treatments of stroke are available, with the Food...... and Drug Administration-approved tissue plasminogen activator for treatment of acute ischemic stroke being the most prominent example. A large number of potential drug candidates for treatment of ischemic brain tissue have been developed and subsequently failed in clinical trials. A deeper understanding...... of permeation pathways across the barrier in ischemic and postischemic brain endothelium is important for development of new medical treatments. The blood-brain barrier, that is, the endothelial monolayer lining the brain capillaries, changes properties during an ischemic event. In vitro models of the blood-brain...

  6. Magnetic Nanoparticles Cross the Blood-Brain Barrier: When Physics Rises to a Challenge

    Directory of Open Access Journals (Sweden)

    Maria Antònia Busquets

    2015-12-01

    Full Text Available The blood-brain barrier is a physical and physiological barrier that protects the brain from toxic substances within the bloodstream and helps maintain brain homeostasis. It also represents the main obstacle in the treatment of many diseases of the central nervous system. Among the different approaches employed to overcome this barrier, the use of nanoparticles as a tool to enhance delivery of therapeutic molecules to the brain is particularly promising. There is special interest in the use of magnetic nanoparticles, as their physical characteristics endow them with additional potentially useful properties. Following systemic administration, a magnetic field applied externally can mediate the capacity of magnetic nanoparticles to permeate the blood-brain barrier. Meanwhile, thermal energy released by magnetic nanoparticles under the influence of radiofrequency radiation can modulate blood-brain barrier integrity, increasing its permeability. In this review, we present the strategies that use magnetic nanoparticles, specifically iron oxide nanoparticles, to enhance drug delivery to the brain.

  7. Differentiation of smooth muscle progenitor cells in peripheral blood and its application in tissue engineered blood vessels

    Institute of Scientific and Technical Information of China (English)

    Shang-zhe XIE; Ning-tao FANG; Shui LIU; Ping ZHOU; Yi ZHANG; Song-mei WANG; Hong-yang GAO; Luan-feng PAN

    2008-01-01

    Background: A major shortcoming in tissue engineered blood vessels (TEBVs) is the lack of healthy and easily attainable smooth muscle cells (SMCs). Smooth muscle progenitor cells (SPCs), especially from peripheral blood, may offer an alternative cell source for tissue engineering involving a less invasive harvesting technique. Methods: SPCs were isolated from 5-ml fresh rat peripheral blood by density-gradient centrifugation and cultured for 3 weeks in endothelial growth medium-2-MV (EGM-2-MV) medium containing platelet-derived growth factor-BB (PDGF BB). Before seeded on the synthesized scaffold, SPC-derived smooth muscle outgrowth cell (SOC) phenotypes were assessed by immuno-fluorescent staining, Western blot analysis, and reverse transcription polymerase chain reaction (RT-PCR). The cells were seeded onto the silk fibroin-modified poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (SF-PHBHHx) scaffolds by 6×104 cells/cm'2 and cultured under the static con-dition for 3 weeks. The growth and proliferation of the seeded cells on the scaffold were analyzed by 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay, scanning electron microscope (SEM), and 4,6-diamidino-2-phenylindole (DAPI) staining. Results: SOCs displayed specific "hill and valley" morphology, expressed the specific markers of the SMC lineage: protein, and extracellular matrix components elastin and matrix Gla protein (MGP), as well as vascular endothelial growth factor (VEGF). After seeded on the SF-PHBHHx scaffold, the cells showed excellent metabolic activity and proliferation. Conclusion: SPCs isolated from peripheral blood can be differentiated into the SMCs in vitro and have an impressive growth potential in the biodegradable synthesized scaffold. Thus, SPCs may be a promising cell source for constructing TEBVs.

  8. Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain

    Science.gov (United States)

    Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas

    1988-03-01

    Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

  9. Control of abdominal muscles by brain stem respiratory neurons in the cat

    Science.gov (United States)

    Miller, Alan D.; Ezure, Kazuhisa; Suzuki, Ichiro

    1985-01-01

    The nature of the control of abdominal muscles by the brain stem respiratory neurons was investigated in decerebrate unanesthetized cats. First, it was determined which of the brain stem respiratory neurons project to the lumbar cord (from which the abdominal muscles receive part of their innervation), by stimulating the neurons monopolarly. In a second part of the study, it was determined if lumbar-projecting respiratory neurons make monosynaptic connections with abdominal motoneurons; in these experiments, discriminate spontaneous spikes of antidromically acivated expiratory (E) neurons were used to trigger activity from both L1 and L2 nerves. A large projection was observed from E neurons in the caudal ventral respiratory group to the contralateral upper lumber cord. However, cross-correlation experiments found only two (out of 47 neuron pairs tested) strong monosynaptic connections between brain stem neurons and abdominal motoneurons.

  10. Blood-Brain Barrier Changes in High Altitude.

    Science.gov (United States)

    Lafuente, José V; Bermudez, Garazi; Camargo-Arce, Lorena; Bulnes, Susana

    2016-01-01

    Cerebral syndromes related to high-altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB considered to play an important role. A fuller comprehension of these processes is crucial to reduce and prevent BBB alterations during high-altitude exposure.

  11. Nanoscale drug delivery systems and the blood-brain barrier.

    Science.gov (United States)

    Alyautdin, Renad; Khalin, Igor; Nafeeza, Mohd Ismail; Haron, Muhammad Huzaimi; Kuznetsov, Dmitry

    2014-01-01

    The protective properties of the blood-brain barrier (BBB) are conferred by the intricate architecture of its endothelium coupled with multiple specific transport systems expressed on the surface of endothelial cells (ECs) in the brain's vasculature. When the stringent control of the BBB is disrupted, such as following EC damage, substances that are safe for peripheral tissues but toxic to neurons have easier access to the central nervous system (CNS). As a consequence, CNS disorders, including degenerative diseases, can occur independently of an individual's age. Although the BBB is crucial in regulating the biochemical environment that is essential for maintaining neuronal integrity, it limits drug delivery to the CNS. This makes it difficult to deliver beneficial drugs across the BBB while preventing the passage of potential neurotoxins. Available options include transport of drugs across the ECs through traversing occludins and claudins in the tight junctions or by attaching drugs to one of the existing transport systems. Either way, access must specifically allow only the passage of a particular drug. In general, the BBB allows small molecules to enter the CNS; however, most drugs with the potential to treat neurological disorders other than infections have large structures. Several mechanisms, such as modifications of the built-in pumping-out system of drugs and utilization of nanocarriers and liposomes, are among the drug-delivery systems that have been tested; however, each has its limitations and constraints. This review comprehensively discusses the functional morphology of the BBB and the challenges that must be overcome by drug-delivery systems and elaborates on the potential targets, mechanisms, and formulations to improve drug delivery to the CNS.

  12. Ultrasound-induced blood-brain barrier opening.

    Science.gov (United States)

    Konofagou, Elisa E; Tung, Yao-Sheng; Choi, James; Deffieux, Thomas; Baseri, Babak; Vlachos, Fotios

    2012-06-01

    Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amyotrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. In addition, aging greatly increases the risk of neurodegenerative disease. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available. This is mainly due to the impermeability of the blood-brain barrier (BBB) that allows only 5% of the 7000 small-molecule drugs available to treat only a tiny fraction of these diseases. On the other hand, safe and localized opening of the BBB has been proven to present a significant challenge. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. FUS may thus have a huge impact in trans-BBB brain drug delivery. The primary objective in this paper is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS, which are responsible for inducing the BBB disruption. The mechanism of the BBB opening in vivo is monitored through the MRI and passive cavitation detection (PCD), and the safety of BBB disruption is assessed using H&E histology at distinct pressures, pulse lengths and microbubble diameters. It is hereby shown that the BBB can be disrupted safely and transiently under specific acoustic pressures (under 0.45 MPa) and microbubble (diameter under 8 μm) conditions.

  13. Use of diffuse optical spectroscopy to monitor muscle and brain oxygenation dynamics during isometric and isokinetic exercise

    Science.gov (United States)

    Ganesan, Goutham; Cotter, Joshua; Reuland, Warren; Warren, Robert V.; Mirzaei Zarandi, Soroush M.; Cerussi, Albert E.; Tromberg, Bruce J.; Galassetti, Pietro

    2013-03-01

    The use of near-infrared time-resolved spectroscopy (TRS-20, Hamamatsu Corporation) in two resistance type exercise applications in human subjects is described. First, using isometric flexion of the biceps, we compared the magnitude and relevance of tissue hemoglobin concentration and oxygen saturation (stO2) changes when assuming constant scattering versus continuous measurement of reduced scattering coefficients at three wavelengths. It was found that the assumption of constant scattering resulted in significant errors in hemoglobin concentration assessment during sustained isometric contractions. Secondly, we tested the effect of blood flow restriction (BFR) on oxygenation in a muscle (vastus medialis oblique, VMO) and in the prefrontal cortex (PFC) of the brain. The BFR training technique resulted in considerably more fatigability in subjects, and correlated with reduced muscle stO2 between sets of exertion. Additionally, exercise with BFR resulted in greater PFC deoxygenation than a condition with equivalent work performance but no BFR. These experiments demonstrate novel applications for diffuse optical spectroscopy in strength testing and targeted muscle rehabilitation.

  14. Effects of respiratory muscle unloading on leg muscle oxygenation and blood volume during high-intensity exercise in chronic heart failure.

    Science.gov (United States)

    Borghi-Silva, Audrey; Carrascosa, Cláudia; Oliveira, Cristino Carneiro; Barroco, Adriano C; Berton, Danilo C; Vilaça, Debora; Lira-Filho, Edgar B; Ribeiro, Dirceu; Nery, Luiz Eduardo; Neder, J Alberto

    2008-06-01

    Blood flow requirements of the respiratory muscles (RM) increase markedly during exercise in chronic heart failure (CHF). We reasoned that if the RM could subtract a fraction of the limited cardiac output (QT) from the peripheral muscles, RM unloading would improve locomotor muscle perfusion. Nine patients with CHF (left ventricle ejection fraction = 26 +/- 7%) undertook constant-work rate tests (70-80% peak) receiving proportional assisted ventilation (PAV) or sham ventilation. Relative changes (Delta%) in deoxy-hemoglobyn, oxi-Hb ([O2Hb]), tissue oxygenation index, and total Hb ([HbTOT], an index of local blood volume) in the vastus lateralis were measured by near infrared spectroscopy. In addition, QT was monitored by impedance cardiography and arterial O2 saturation by pulse oximetry (SpO2). There were significant improvements in exercise tolerance (Tlim) with PAV. Blood lactate, leg effort/Tlim and dyspnea/Tlim were lower with PAV compared with sham ventilation (P 0.05). Unloaded breathing, however, was related to enhanced leg muscle oxygenation and local blood volume compared with sham, i.e., higher Delta[O2Hb]% and Delta[HbTOT]%, respectively (P < 0.05). We conclude that RM unloading had beneficial effects on the oxygenation status and blood volume of the exercising muscles at similar systemic O2 delivery in patients with advanced CHF. These data suggest that blood flow was redistributed from respiratory to locomotor muscles during unloaded breathing.

  15. Biomarkers of Traumatic Injury Are Transported from Brain to Blood via the Glymphatic System

    OpenAIRE

    2015-01-01

    The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulat...

  16. Smuggling Drugs into the Brain: An Overview of Ligands Targeting Transcytosis for Drug Delivery across the Blood-Brain Barrier

    NARCIS (Netherlands)

    Zuhorn, Inge; Georgieva, Julia V.; Hoekstra, Dick

    2015-01-01

    The blood-brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics in

  17. Alteration of blood-brain barrier integrity by retroviral infection.

    Directory of Open Access Journals (Sweden)

    Philippe V Afonso

    2008-11-01

    Full Text Available The blood-brain barrier (BBB, which forms the interface between the blood and the cerebral parenchyma, has been shown to be disrupted during retroviral-associated neuromyelopathies. Human T Lymphotropic Virus (HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP is a slowly progressive neurodegenerative disease associated with BBB breakdown. The BBB is composed of three cell types: endothelial cells, pericytes and astrocytes. Although astrocytes have been shown to be infected by HTLV-1, until now, little was known about the susceptibility of BBB endothelial cells to HTLV-1 infection and the impact of such an infection on BBB function. We first demonstrated that human cerebral endothelial cells express the receptors for HTLV-1 (GLUT-1, Neuropilin-1 and heparan sulfate proteoglycans, both in vitro, in a human cerebral endothelial cell line, and ex vivo, on spinal cord autopsy sections from HAM/TSP and non-infected control cases. In situ hybridization revealed HTLV-1 transcripts associated with the vasculature in HAM/TSP. We were able to confirm that the endothelial cells could be productively infected in vitro by HTLV-1 and that blocking of either HSPGs, Neuropilin 1 or Glut1 inhibits this process. The expression of the tight-junction proteins within the HTLV-1 infected endothelial cells was altered. These cells were no longer able to form a functional barrier, since BBB permeability and lymphocyte passage through the monolayer of endothelial cells were increased. This work constitutes the first report of susceptibility of human cerebral endothelial cells to HTLV-1 infection, with implications for HTLV-1 passage through the BBB and subsequent deregulation of the central nervous system homeostasis. We propose that the susceptibility of cerebral endothelial cells to retroviral infection and subsequent BBB dysfunction is an important aspect of HAM/TSP pathogenesis and should be considered in the design of future therapeutics strategies.

  18. A streamlined protocol for extracting RNA and genomic DNA from archived human blood and muscle.

    Science.gov (United States)

    Majumdar, Gipsy; Vera, Santiago; Elam, Marshall B; Raghow, Rajendra

    2015-04-01

    We combined the TRIzol method of nucleic acid extraction with QIAamp columns to achieve coextraction of RNA and genomic DNA from peripheral blood mononuclear cells (PBMCs) and biopsied skeletal muscle, both stored at -80 °C for many months. Total RNA was recovered from the upper aqueous phase of TRIzol. The interphase and organic phases were precipitated with ethanol, digested with proteinase K, and filtered through QIAamp MinElute columns to recover DNA. The combined protocol yielded excellent quality and quantity of nucleic acids from archived human PBMCs and muscle and may be easily adapted for other tissues.

  19. Muscle blood flow and muscle metabolism during exercise and heat stress

    DEFF Research Database (Denmark)

    Nielsen, Bodil; Savard, G; Richter, Erik;

    1990-01-01

    The effect of heat stress on blood flow and metabolism in an exercising leg was studied in seven subjects walking uphill (12-17%) at 5 km/h on a treadmill for 90 min or until exhaustion. The first 30 min of exercise were performed in a cool environment (18-21 degrees C); then subjects moved to an...

  20. Distribution of radiolabeled L-glutamate and D-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection

    Energy Technology Data Exchange (ETDEWEB)

    Klin, Yael [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel); Zlotnik, Alexander; Boyko, Matthew; Ohayon, Sharon; Shapira, Yoram [The Division of Anesthesiology, Soroka Medical Center and Ben Gurion University of the Negev, Beer-Sheva (Israel); Teichberg, Vivian I., E-mail: Vivian.teichberg@weizmann.ac.il [Department of Neurobiology, The Weizmann Institute of Science, Rehovot 76100 (Israel)

    2010-09-03

    Research highlights: {yields} Blood glutamate has a half-life time of 2-3 min. {yields} Blood glutamate is submitted to rapid decarboxylation. {yields} Blood glutamate and its metabolites are mainly absorbed in skeletal muscle and liver. {yields} The skeletal muscle and liver are now targets for potential drugs affording brain neuroprotection. -- Abstract: Excess L-glutamate (glutamate) levels in brain interstitial and cerebrospinal fluids (ISF and CSF, respectively) are the hallmark of several neurodegenerative conditions such as stroke, traumatic brain injury or amyotrophic lateral sclerosis. Its removal could prevent the glutamate excitotoxicity that causes long-lasting neurological deficits. As in previous studies, we have established the role of blood glutamate levels in brain neuroprotection, we have now investigated the contribution of the peripheral organs to the homeostasis of glutamate in blood. We have administered naive rats with intravenous injections of either L-[1-{sup 14}C] Glutamic acid (L-[1-{sup 14}C] Glu), L-[G-{sup 3}H] Glutamic acid (L-[G-{sup 3}H] Glu) or D-[2,3-{sup 3}H] Aspartic acid (D-[2,3-{sup 3}H] Asp), a non-metabolized analog of glutamate, and have followed their distribution into peripheral organs. We have observed that the decay of the radioactivity associated with L-[1-{sup 14}C] Glu and L-[G-{sup 3}H] Glu was faster than that associated with glutamate non-metabolized analog, D-[2,3-{sup 3}H] Asp. L-[1-{sup 14}C] Glu was subjected in blood to a rapid decarboxylation with the loss of {sup 14}CO{sub 2}. The three major sequestrating organs, serving as depots for the eliminated glutamate and/or its metabolites were skeletal muscle, liver and gut, contributing together 92% or 87% of total L-[U-{sup 14}C] Glu or D-[2,3-{sup 3}H] Asp radioactivity capture. L-[U-{sup 14}C] Glu and D-[2,3-{sup 3}H] Asp showed a different organ sequestration pattern. We conclude that glutamate is rapidly eliminated from the blood into peripheral tissues

  1. Is peripheral immunity regulated by blood-brain barrier permeability changes?

    Directory of Open Access Journals (Sweden)

    Erin Bargerstock

    Full Text Available S100B is a reporter of blood-brain barrier (BBB integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD. Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient. After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc. and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.

  2. Autoregulation of cerebral blood flow in experimental focal brain ischemia.

    Science.gov (United States)

    Dirnagl, U; Pulsinelli, W

    1990-05-01

    The relationship between systemic arterial pressure (SAP) and neocortical microcirculatory blood-flow (CBF) in areas of focal cerebral ischemia was studied in 15 spontaneously hypertensive rats (SHRs) anesthetized with halothane (0.5%). Ischemia was induced by ipsilateral middle cerebral artery/common carotid artery occlusion and CBF was monitored continuously in the ischemic territory using laser-Doppler flowmetry during manipulation of SAP with I-norepinephrine (hypertension) or nitroprusside (hypotension). In eight SHRs not subjected to focal ischemia, we demonstrated that 0.5% halothane and the surgical manipulations did not impair autoregulation. Autoregulation was partly preserved in ischemic brain tissue with a CBF of greater than 30% of preocclusion values. In areas where ischemic CBF was less than 30% of preocclusion values, autoregulation was completely lost. Changes in SAP had a greater influence on CBF in tissue areas where CBF ranged from 15 to 30% of baseline (9% change in CBF with each 10% change in SAP) than in areas where CBF was less than 15% of baseline (6% change in CBF with each 10% change in SAP). These findings demonstrate that the relationship between CBF and SAP in areas of focal ischemia is highly dependent on the severity of ischemia. Autoregulation is lost in a gradual manner until CBF falls below 30% of normal. In areas without autoregulation, the slope of the CBF/SAP relationship is inversely related to the degree of ischemia.

  3. Alterations of blood brain barrier function in hyperammonemia: an overview.

    Science.gov (United States)

    Skowrońska, Marta; Albrecht, Jan

    2012-02-01

    Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute--(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which couple adjacent cerebral capillary endothelial cells to each other to form the barrier. Ammonia modulates the transcellular passage of low-to medium-size molecules, by affecting their carriers located at the BBB. Ammonia induces interrelated aberrations of the transport of the large neutral amino acids and aromatic amino acids (AAA), whose influx is augmented by exchange with glutamine produced in the course of ammonia detoxification, and maybe also modulated by the extracellularly acting gamma-glutamyl moiety transferring enzyme, gamma-glutamyl-transpeptidase. Impaired AAA transport affects neurotransmission by altering intracerebral synthesis of catecholamines (serotonin and dopamine), and producing "false neurotransmitters" (octopamine and phenylethylamine). Ammonia also modulates BBB transport of the cationic amino acids: the nitric oxide precursor, arginine, and ornithine, which is an ammonia trap, and affects the transport of energy metabolites glucose and creatine. Moreover, ammonia acting either directly or in synergy with liver injury-derived inflammatory cytokines also evokes subtle increases of the transcellular passage of molecules of different size (BBB "leakage"), which appears to be responsible for the vasogenic component of cerebral edema associated with ALF.

  4. Smooth muscle progenitor cells from peripheral blood promote the neovascularization of endothelial colony-forming cells

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Hyung Joon; Seo, Ha-Rim [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Jeong, Hyo Eun [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Choi, Seung-Cheol; Park, Jae Hyung; Yu, Cheol Woong; Hong, Soon Jun [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of); Chung, Seok [Department of Mechanical Engineering, Korea University, Seoul (Korea, Republic of); Lim, Do-Sun, E-mail: dslmd@kumc.or.kr [Department of Cardiology, Cardiovascular Center, College of Medicine, Korea University, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Two distinct vascular progenitor cells are induced from adult peripheral blood. • ECFCs induce vascular structures in vitro and in vivo. • SMPCs augment the in vitro and in vivo angiogenic potential of ECFCs. • Both cell types have synergistic therapeutic potential in ischemic hindlimb model. - Abstract: Proangiogenic cell therapy using autologous progenitors is a promising strategy for treating ischemic disease. Considering that neovascularization is a harmonized cellular process that involves both endothelial cells and vascular smooth muscle cells, peripheral blood-originating endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SMPCs), which are similar to mature endothelial cells and vascular smooth muscle cells, could be attractive cellular candidates to achieve therapeutic neovascularization. We successfully induced populations of two different vascular progenitor cells (ECFCs and SMPCs) from adult peripheral blood. Both progenitor cell types expressed endothelial-specific or smooth muscle-specific genes and markers, respectively. In a protein array focused on angiogenic cytokines, SMPCs demonstrated significantly higher expression of bFGF, EGF, TIMP2, ENA78, and TIMP1 compared to ECFCs. Conditioned medium from SMPCs and co-culture with SMPCs revealed that SMPCs promoted cell proliferation, migration, and the in vitro angiogenesis of ECFCs. Finally, co-transplantation of ECFCs and SMPCs induced robust in vivo neovascularization, as well as improved blood perfusion and tissue repair, in a mouse ischemic hindlimb model. Taken together, we have provided the first evidence of a cell therapy strategy for therapeutic neovascularization using two different types of autologous progenitors (ECFCs and SMPCs) derived from adult peripheral blood.

  5. Calcium-activated potassium channels mediated blood-brain tumor barrier opening in a rat metastatic brain tumor model

    Directory of Open Access Journals (Sweden)

    Ong John M

    2007-03-01

    Full Text Available Abstract Background The blood-brain tumor barrier (BTB impedes the delivery of therapeutic agents to brain tumors. While adequate delivery of drugs occurs in systemic tumors, the BTB limits delivery of anti-tumor agents into brain metastases. Results In this study, we examined the function and regulation of calcium-activated potassium (KCa channels in a rat metastatic brain tumor model. We showed that intravenous infusion of NS1619, a KCa channel agonist, and bradykinin selectively enhanced BTB permeability in brain tumors, but not in normal brain. Iberiotoxin, a KCa channel antagonist, significantly attenuated NS1619-induced BTB permeability increase. We found KCa channels and bradykinin type 2 receptors (B2R expressed in cultured human metastatic brain tumor cells (CRL-5904, non-small cell lung cancer, metastasized to brain, human brain microvessel endothelial cells (HBMEC and human lung cancer brain metastasis tissues. Potentiometric assays demonstrated the activity of KCa channels in metastatic brain tumor cells and HBMEC. Furthermore, we detected higher expression of KCa channels in the metastatic brain tumor tissue and tumor capillary endothelia as compared to normal brain tissue. Co-culture of metastatic brain tumor cells and brain microvessel endothelial cells showed an upregulation of KCa channels, which may contribute to the overexpression of KCa channels in tumor microvessels and selectivity of BTB opening. Conclusion These findings suggest that KCa channels in metastatic brain tumors may serve as an effective target for biochemical modulation of BTB permeability to enhance selective delivery of chemotherapeutic drugs to metastatic brain tumors.

  6. [Ultrastructure of the blood vessels and muscle fibers in the skeletal muscle of rats flown on the Kosmos-605 and Kosmos-782 biosatellites].

    Science.gov (United States)

    Savik, Z F; Rokhlenko, K D

    1981-01-01

    Electron microscopy was used to study ultrastructures of the wall of blood vessels and muscle fibers of the red (soleus) and mixed (gastrocnemius) muscles of rats flown on Cosmos-605 for 22.5 days and on Cosmos-782 for 19,5 days and sacrificed 4-6 hours, 48 hours and 25-27 days postflight. It was demonstrated that the orbital flight did not induce significant changes in the ultrastructure of blood vessels of the soleus and gastrocnemius muscles but caused atrophy of muscle fibers and reduction of the number of functioning capillaries. Readaptation of the soleus vascular system to 1 g led to degradation of permeability of capillary and venular walls and development of edema of the perivascular connective tissue. This may be one of the factors responsible for dystrophic changes in muscle fibers.

  7. Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases.

    Science.gov (United States)

    Stolp, H B; Dziegielewska, K M

    2009-04-01

    The causes of most neurological disorders are not fully understood. Inflammation and blood-brain barrier dysfunction appear to play major roles in the pathology of these diseases. Inflammatory insults that occur during brain development may have widespread effects later in life for a spectrum of neurological disorders. In this review, a new hypothesis suggesting a mechanistic link between inflammation and blood-brain barrier function (integrity), which is universally important in both neurodevelopmental and neurodegenerative diseases, is proposed. The role of inflammation and the blood-brain barrier will be discussed in cerebral palsy, schizophrenia, Parkinson's disease, Alzheimer's disease and multiple sclerosis, conditions where both inflammation and blood-brain barrier dysfunction occur either during initiation and/or progression of the disease. We suggest that breakdown of normal blood-brain barrier function resulting in a short-lasting influx of blood-born molecules, in particular plasma proteins, may cause local damage, such as reduction of brain white matter observed in some newborn babies, but may also be the mechanism behind some neurodegenerative diseases related to underlying brain damage and long-term changes in barrier properties.

  8. Contribution of respiratory muscle blood flow to exercise-induced diaphragmatic fatigue in trained cyclists

    DEFF Research Database (Denmark)

    Vogiatzis, Ioannis; Athanasopoulos, Dimitris; Boushel, Robert Christopher

    2008-01-01

    We investigated whether the greater degree of exercise-induced diaphragmatic fatigue previously reported in highly trained athletes in hypoxia (compared with normoxia) could have a contribution from limited respiratory muscle blood flow. Seven trained cyclists completed three constant load 5 min...... exercise tests at inspired O(2) fractions (FIO2) of 0.13, 0.21 and 1.00 in balanced order. Work rates were selected to produce the same tidal volume, breathing frequency and respiratory muscle load at each FIO2 (63 +/- 1, 78 +/- 1 and 87 +/- 1% of normoxic maximal work rate, respectively). Intercostals......(-1) and 95.1 +/- 7.8 ml (100 ml)(-1) min(-1), respectively). Neither IMBF was different across hypoxia, normoxia and hyperoxia (53.6 +/- 8.5, 49.9 +/- 5.9 and 52.9 +/- 5.9 ml (100 ml)(-1) min(-1), respectively). We conclude that when respiratory muscle energy requirement is not different between...

  9. Genetic analysis of blood vessel formation role of endothelial versus smooth muscle cells.

    Science.gov (United States)

    Carmeliet, P; Collen, D

    1997-11-01

    Formation of new blood vessels is vital during embryogenesis, essential for reproduction and wound healing during adulthood, and required to rescue tissue during ischemia. Neovascularization may, however, also contribute to the pathogenesis of several disorders, including tumorigenesis, diabetic vasculopathy, and chronic inflammation. Initially, blood vessels form as endothelium-lined channels by in situ differentiation of endothelial cells. Subsequently, they sprout and remodel into a highly organized and interconnected vascular network. During further maturation of the blood vessels, a sheet of primitive vascular smooth muscle cells surrounds the endothelium-lined channels, which controls endothelial cell function and provides structural support. Recent molecular analyses have identified candidate molecules that affect these processes. Their in vivo role has been further established by targeted gene manipulation in transgenic mice. This review highlights recent developments in the genetic analysis of blood vessel formation, as deduced from analysis of gene-inactivated mice. (Trends Cardiovasc Med 1997;7:271-281). © 1997, Elsevier Science Inc.

  10. Insulin action in muscle and adipose tissue in type 2diabetes: The significance of blood flow

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Under normal metabolic conditions insulin stimulatesmicrovascular perfusion (capillary recruitment) ofskeletal muscle and subcutaneous adipose tissue andthus increases blood flow mainly after meal ingestionor physical exercise. This helps the delivery of insulinitself but also that of substrates and of other signallingmolecules to multiple tissues beds and facilitatesglucose disposal and lipid kinetics. This effect is impairedin insulin resistance and type 2 diabetes early in thedevelopment of metabolic dysregulation and reflectsearly-onset endothelial dysfunction. Failure of insulinto increase muscle and adipose tissue blood flowresults in decreased glucose handling. In fat depots, ablunted postprandial blood flow response will result inan insufficient suppression of lipolysis and an increasedspill over of fatty acids in the circulation, leading toa more pronounced insulin resistant state in skeletalmuscle. This defect in blood flow response is apparenteven in the prediabetic state, implying that it is afacet of insulin resistance and exists long before overthyperglycaemia develops. The following review intendsto summarize the contribution of blood flow impairmentto the development of the atherogenic dysglycemia anddyslipidaemia.

  11. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

    OpenAIRE

    Boado, Ruben J.; Pardridge, William M.

    2011-01-01

    The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB). Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV) administration. Recent progress in the “Trojan Horse Liposome” (THL) technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brai...

  12. Hyperammonemia,brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paravrtamol intoxication

    Institute of Scientific and Technical Information of China (English)

    Camila Scorticati; Juan P. Prestifilippo; Francisco X. Eizayaga; José L. Castro; Salvador Romay; Maria A. Fernández; Abraham Lemberg; Juan C. Perazzo

    2004-01-01

    AIM: To study the blood-brain barrier integrity, brain edema,animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication.METHODS: Adults male Wistar rats were divided into four groups. Group Ⅰ: sham operation; Ⅱ: Prehepatic portal hypertension, produced by partial portal vein ligation; Ⅲ:Acetaminophen intoxication and Ⅳ: Prehepatic portal hypertension plus acetaminophen. Acetaminophen was administered to produce acute hepatic injury. Portal pressure, liver serum enzymes and ammonia plasma levels were determined. Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity. Reflexes and behavioral tests were recorded.RESULTS: Portal hypertension was significantly elevated in groups Ⅱ and Ⅳ. Liver enzymes and ammonia plasma levels were increased in groups Ⅱ, Ⅳ and Ⅳ. Prehepatic portal hypertension (group Ⅱ), acetaminophen intoxication (group Ⅲ) and both (group Ⅳ) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia. Cortical edema was present in rats with acute hepatic injury in groups Ⅲ and Ⅳ. Behavioral test (rota rod) was altered in group Ⅳ.CONCLUSION: These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (cytotoxic). Group Ⅳ, with behavioral altered test, can be considered as a model for study at an early stage of portal-systemic encephalopathy.

  13. WR-2721 entry into the brain across a modified blood-brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Lamperti, A.; Conger, A.D.; Jenkins, O.; Cohen, G.; Rizzo, A.; Davis, M.E.; Sodicoff, M.

    1988-08-01

    Radioprotection of the CNS by WR-2721 has not been possible because of its inability to cross the blood-brain barrier (BBB) and so gain access to the neural tissue. Modification of the BBB using hypertonic arabinose (1.8 m), injected via the internal carotid artery (ica), permitted entry of ip-injected (/sup 14/C)WR-2721 into the ipsilateral cerebral hemisphere. The BBB-modified hemisphere had a 5.34-fold increased uptake compared to nonmodified controls. Delivery as a bolus via the ica further enhanced uptake after BBB opening; WR-2721 was 3.73 times greater than by ip injection. A 20-fold increase of WR-2721 brain uptake has been calculated for ica administration with the BBB opened as compared to the ip route without BBB modification. Toxicity of ip-administered WR-2721 with the BBB open was only 1.4 times greater than non-modified controls and 1.96 times more toxic when delivered via the ica. These data demonstrate significant uptake of WR-2721 into the CNS, a previously unprotected organ, and provide a model for future radioprotective studies.

  14. Skeletal muscle adaptations following blood flow-restricted training during 30 days of muscular unloading.

    Science.gov (United States)

    Cook, Summer B; Brown, Kimberly A; Deruisseau, Keith; Kanaley, Jill A; Ploutz-Snyder, Lori L

    2010-08-01

    This study evaluated the effectiveness of low-load resistance training with a blood flow restriction (LL(BFR)) to attenuate muscle loss and weakness after 30 days of unilateral lower limb suspension (ULLS). Sixteen subjects (ages 18-50 yr) underwent 30 days of ULLS. Measurements of muscle strength, cross-sectional area, and endurance on the knee extensors and plantar flexors were collected before and after ULLS. Plasma concentrations of IGF-1 and IGFBP-3 were also assessed. During ULLS, eight subjects (5 males, 3 females) participated in LL(BFR) three times per week (ULLS + Exercise) while eight subjects (4 males, 4 females) did not exercise (ULLS). The blood flow-restricted exercise consisted of dynamic knee extension at 20% of the subject's isometric maximum voluntary contraction coupled with a suprasystolic blood flow restriction. After 30 days of limb suspension, the ULLS + Exercise group experienced minimal and insignificant losses in knee extensor cross-sectional area and strength (1.2% and 2.0%, respectively; P 0.05). Muscular endurance in the knee extensors improved 31% in the ULLS + Exercise group, while it decreased 24% in the ULLS group (P = 0.01). No changes were seen in hormone concentrations throughout the study. In conclusion, LL(BFR) of the knee extensors is effective in maintaining muscle strength and size during 30 days of ULLS and results in improved knee extensor muscular endurance.

  15. Determination and Difference Analysis of DNA Methylation Content Both in Blood and Muscle Tissue of Pigs

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    In this experiment, DNA samples from parental lines Large White, Landrace, and Meishan pigs, and their hybrids Large White×Landrace, Landrace×Large White, Large White×Meishan, and Meishan×Large White pigs were used for the determination of DNA methylation content in both blood and muscle tissue. The differences about DNA methylation content between parental lines and their hybrids were analyzed. These will offer theoretical support from molecular level for heterosis. High performance liquid chromatography (HPLC) was firstly used to detect DNA methylation content. The average DNA methylation content in 163 DNA samples of muscle tissue was 16.92%, whereas, the average DNA methylation content in 182 samples of blood was 6.49%, the difference between which was especially prominent (P 0.05); and the differences between reciprocal cross hybrids in both hybrid systems were not significant (P > 0.05), but between different hybrid systems, the hybrids had a significant difference (P<0.05). The average methylation content in muscle samples was higher than that in blood samples, and the methylation in different tissues was different.

  16. One-year high fat diet affects muscle-but not brain mitochondria

    DEFF Research Database (Denmark)

    Joergensen, Tenna; Grunnet, Niels; Quistorff, Bjørn

    2015-01-01

    It is well known that few weeks of high fat (HF) diet may induce metabolic disturbances and mitochondrial dysfunction in skeletalmuscle. However, little is known about the effects of long-term HF exposure and effects on brain mitochondria are unknown. Wistarrats were fed either chow (13E% fat......) or HF diet (60E% fat) for 1 year. The HF animals developed obesity, dyslipidemia, insulinresistance, and dysfunction of isolated skeletal muscle mitochondria: state 3 and state 4 were 30% to 50% increased (P ...-brain barrier may play a role in this strikingly different phenotype of mitochondriafrom the two tissues of the same animal....

  17. Blood vessels and desmin control the positioning of nuclei in skeletal muscle fibers.

    Science.gov (United States)

    Ralston, E; Lu, Z; Biscocho, N; Soumaka, E; Mavroidis, M; Prats, C; Lømo, T; Capetanaki, Y; Ploug, T

    2006-12-01

    Skeletal muscle fibers contain hundreds to thousands of nuclei which lie immediately under the plasmalemma and are spaced out along the fiber, except for a small cluster of specialized nuclei at the neuromuscular junction. How the nuclei attain their positions along the fiber is not understood. Here we show that the nuclei are preferentially localized near blood vessels (BV), particularly in slow-twitch, oxidative fibers. Thus, in rat soleus muscle fibers, 81% of the nuclei appear next to BV. Lack of desmin markedly perturbs the distribution of nuclei along the fibers but does not prevent their close association with BV. Consistent with a role for desmin in the spacing of nuclei, we show that denervation affects the organization of desmin filaments as well as the distribution of nuclei. During chronic stimulation of denervated muscles, new BV form, along which muscle nuclei align themselves. We conclude that the positioning of nuclei along muscle fibers is plastic and that BV and desmin intermediate filaments each play a distinct role in the control of this positioning.

  18. Immortalized endothelial cell lines for in vitro blood-brain barrier models: A systematic review.

    Science.gov (United States)

    Rahman, Nurul Adhwa; Rasil, Alifah Nur'ain Haji Mat; Meyding-Lamade, Uta; Craemer, Eva Maria; Diah, Suwarni; Tuah, Ani Afiqah; Muharram, Siti Hanna

    2016-07-01

    Endothelial cells play the most important role in construction of the blood-brain barrier. Many studies have opted to use commercially available, easily transfected or immortalized endothelial cell lines as in vitro blood-brain barrier models. Numerous endothelial cell lines are available, but we do not currently have strong evidence for which cell lines are optimal for establishment of such models. This review aimed to investigate the application of immortalized endothelial cell lines as in vitro blood-brain barrier models. The databases used for this review were PubMed, OVID MEDLINE, ProQuest, ScienceDirect, and SpringerLink. A narrative systematic review was conducted and identified 155 studies. As a result, 36 immortalized endothelial cell lines of human, mouse, rat, porcine and bovine origins were found for the establishment of in vitro blood-brain barrier and brain endothelium models. This review provides a summary of immortalized endothelial cell lines as a guideline for future studies and improvements in the establishment of in vitro blood-brain barrier models. It is important to establish a good and reproducible model that has the potential for multiple applications, in particular a model of such a complex compartment such as the blood-brain barrier.

  19. Signals Analysis and Clinical Validation of Blood and Oxygen Data in Human Brain

    Institute of Scientific and Technical Information of China (English)

    LI Kai-yang; LIU Li-jun; WANG Xiang; QIN Zhao; XIE Ze-ping

    2005-01-01

    With a self-made near-infrared analytical instrument to blood and oxygen parameters in human brain, 80 cases in which 20 are healthy persons and 30are anaesthetised cases and others are patients with heart function lack is taken to examine, and the data of blood and oxygen in brain tissue were collected and analyzed by the method of power spectrum and correlation function. The results indicate that: (1) The average brain oxygen saturation of healthy persons and anaesthetised cases is about 80%, in accord with normal parameter of physiology. Contrastively, the average brain oxygen saturation of patients with heart function lack is 72. 8%, which is obviously less than that of healthy persons and anaesthetised cases. The probability of medical statistics is less than 0. 01. (2) The shapes of wave of brain blood and oxygen for the healthy person and the anaesthetised case reveal small periodical fluctuations with stable shape and base line, and the trend of increase or decrease of blood and oxygen parameters in brain tissue is synchronous and a phase reversal, but for the patient with heart function lack in a brain oxygen lack state, the shapes of wave are irregular. This is a hint that near infrared light passing through tissue can reflect the intuitionistic change of brain blood and oxygen parameters. (3) The power spectra of brain blood and oxygen for the healthy person and the anaesthetised case has a clear main peak, narrow bandwidth and perfect superposition each other, but the power spectra for the patient with heart function lack in a brain oxygen lack state is on the contrary. (4) The average cross correlation coefficient of brain blood and oxygen for healthy persons and anaesthetised cases is -0. 9825±0. 1027 close to -1. But the average cross correlation coefficient for patients with heart function lack in a brain oxygen lack state is merely -0. 8923± 0. 1035 which is obviously greater than -1 and the probability of medical statistics is less than 0. 01

  20. Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair.

    Science.gov (United States)

    Sharma, Aruna; Menon, Preeti; Muresanu, Dafin F; Ozkizilcik, Asya; Tian, Z Ryan; Lafuente, José V; Sharma, Hari S

    2016-01-01

    The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.

  1. Indomethacin in combination with exercise leads to muscle and brain inflammation in mice.

    Science.gov (United States)

    Enos, Reilly T; Davis, J Mark; McClellan, Jamie L; Murphy, E Angela

    2013-08-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used by athletes to reduce exercise-induced inflammation and pain. However, NSAID use has been linked to side effects, including mucosal damage in the gastrointestinal tract resulting in endotoxemia and inflammation. Incidentally, when NSAID use is combined with exercise there is some evidence that this effect may be exacerbated; however, this hypothesis has not been directly tested in a controlled experiment. We examined the combined effect of indomethacin (IND) and exercise on muscle and brain inflammation in mice. Male C57BL/6 mice were randomly assigned to: Exercise 0 mg/Kg IND (Ex-0), Sedentary 0 mg/Kg IND (Sed-0), Exercise 2.5 mg/Kg IND (Ex-2.5), or Sedentary 2.5 mg/Kg IND (Sed-2.5) (n=8-11/group). Mice were given IND (gavage) 1 h before exercise (treadmill run at 25 m/min, 8% grade for 90 min) or rest for 5 consecutive days. Run times and body weight were recorded daily. Muscle and brain were examined for gene expression of inflammatory mediators after 5 days of treatment. While IND and exercise alone had little effect on inflammation, the combination treatment produced substantial increases in the muscle (IL-1β, MCP-1 & TNF-α) and brain (IL-1β & MCP-1) (Pbrain inflammatory mediators. The combination of IND and exercise can lead to inflammation in both the muscle and brain that is associated with serious side effects and impaired performance in mice.

  2. 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...

  3. Blood flow and muscle oxygenation during low, moderate, and maximal sustained isometric contractions.

    Science.gov (United States)

    McNeil, Chris J; Allen, Matti D; Olympico, Eric; Shoemaker, J Kevin; Rice, Charles L

    2015-09-01

    A reduction of blood flow to active muscle will precipitate fatigue, and sustained isometric contractions produce intramuscular and compartmental pressures that can limit flow. The present study explored how blood flow and muscle oxygenation respond to isometric contractions at low, moderate, and maximal intensities. Over two visits, 10 males (26 ± 2 yr; means ± SD) performed 1-min dorsiflexion contractions at 30, 60, and 100% of maximal voluntary contraction (MVC) torque. Doppler ultrasound of the anterior tibial artery was used to record arterial diameter and mean blood velocity and to calculate absolute blood flow. The tissue oxygenation index (TOI) of tibialis anterior was acquired with near-infrared spectroscopy (NIRS). There was a progressive increase in blood flow at 30% MVC (peak of 289 ± 139% resting value), no change from rest until an increase in the final 10 s of exercise at 60% MVC (peak of 197 ± 102% rest), and an initial decrease (59 ± 30% resting value) followed by a progressive increase at 100% MVC (peak of 355 ± 133% rest). Blood flow was greater at 30 and 100% than 60% MVC during the last 30 s of exercise. TOI was ∼63% at rest and, within 30 s of exercise, reached steady-state values of ∼42%, ∼22%, and ∼22% for 30, 60, and 100% MVC, respectively. Even maximal contraction of the dorsiflexors is unable to cause more than a transient decrease of flow in the anterior tibial artery. Unlike dynamic or intermittent isometric exercise, our results indicate blood flow is not linearly graded with intensity or directly coupled with oxygenation during sustained isometric contractions.

  4. Effects of carbofuran and deltamethrin on acetylcholinesterase activity in brain and muscle of the common carp.

    Science.gov (United States)

    Ensibi, Cherif; Hernández-Moreno, David; Míguez Santiyán, M Prado; Daly Yahya, Mohamed Néjib; Rodríguez, Francisco Soler; Pérez-López, Marcos

    2014-04-01

    This work investigated the effect from exposure to insecticides carbofuran and deltamethrin on acetylcholinesterase (AChE) activity in the brain and muscle of common carp (Cyprinus carpio). Both pesticides were evaluated through two separate experiments, and carp were exposed in a semi-static system to three different concentrations of carbofuran (10, 50, and 100 μg/L) and deltamethrin (0.08, 0.4, and 0.8 μg/L) during a month with sampling times at 0, 4, 15, and 30 days (n = 7 from each aquarium). AChE activity was significantly inhibited in both organs of carps exposed to carbofuran at all sampling times depending on dose and time, reaching inhibition values of 73.5 and 67.1%, in brain and muscle tissues respectively, after 30 days with the highest concentration. On the contrary, AChE activity was not significantly affected after deltamethrin exposure at all concentrations and times of the assay. This study shows that the measurement of brain and muscle AChE activity in Cyprinus carpio is a useful biomarker of carbamates exposure and/or effects, but has no application with pyrethroids.

  5. Blood-brain barrier permeability of bioactive withanamides present in Withania somnifera fruit extract.

    Science.gov (United States)

    Vareed, Shaiju K; Bauer, Alison K; Nair, Kavitha M; Liu, Yunbao; Jayaprakasam, Bolleddula; Nair, Muraleedharan G

    2014-08-01

    The neuroprotective effect of Withania somnifera L. Dunal fruit extract, in rodent models, is known. Withanamides, the primary active constituents in W.somnifera fruit extract exhibited neuroprotective effects against β-amyloid-induced cytotoxicity in neuronal cell culture studies. Therefore, we investigated the blood-brain barrier permeability of withanamides in W.somnifera fruit extract in mice using HPLC coupled with high resolution quadrupole time of flight mass spectrometer (Q-TOF/MS) detection. Mice were administered with 250 mg/kg of W.somnifera extract by intraperitoneal injection, and the blood and brain samples analyzed by Q-TOF/MS detection. Four major withanamides were detected in brain and blood of mice administered with W.somnifera extract. The results suggested that the withanamides crossed the blood-brain barrier. These results may help to develop W.somnifera fruit extract as a preventive or therapeutic botanical drug for stress-induced neurological disorders.

  6. Protection of the blood-brain barrier by pentosan against amyloid-β-induced toxicity.

    Science.gov (United States)

    Deli, Mária A; Veszelka, Szilvia; Csiszár, Boglárka; Tóth, Andrea; Kittel, Agnes; Csete, Mária; Sipos, Aron; Szalai, Anikó; Fülöp, Lívia; Penke, Botond; Abrahám, Csongor S; Niwa, Masami

    2010-01-01

    Endothelial cells of brain capillaries forming the blood-brain barrier play an important role in the pathogenesis and therapy of Alzheimer's disease. Amyloid-β (Aβ) peptides are key pathological elements in the development of the disease. A blood-brain barrier model, based on primary rat brain endothelial cells was used in which the barrier properties were induced by glial cells. The effects of amyloid peptides have been tested on cell viability and barrier functions. Aβ showed toxic effects on primary rat brain endothelial cells measured by MTT dye conversion and the lactate dehydrogenase release. Morphologically cytoplasmic vacuolization, disruption of the structure of cytoplasmic organelles and tight junctions could be observed in brain endothelial cells. Treatment with Aβ1-42 decreased the electrical resistance, and increased the permeability of brain endothelial cell monolayers for both fluorescein and albumin. Serum amyloid P component which stabilizes Aβ fibrils in cortical amyloid plaques and cerebrovascular amyloid deposits significantly potentiated the barrier-weakening effect of Aβ1-42. Sulfated polysaccharide pentosan could decrease the toxic effects of Aβ peptides in brain endothelial cells. It could also significantly protect the barrier integrity of monolayers from damaging actions of peptides. Pentosan modified the size, and significantly decreased the number of amyloid aggregates demonstrated by atomic force microscopy. The present data further support the toxic effects of amyloid peptides on brain endothelial cells, and can contribute to the development of molecules protecting the blood-brain barrier in Alzheimer's disease.

  7. Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences

    Directory of Open Access Journals (Sweden)

    Redzic Zoran

    2011-01-01

    Full Text Available Abstract Efficient processing of information by the central nervous system (CNS represents an important evolutionary advantage. Thus, homeostatic mechanisms have developed that provide appropriate circumstances for neuronal signaling, including a highly controlled and stable microenvironment. To provide such a milieu for neurons, extracellular fluids of the CNS are separated from the changeable environment of blood at three major interfaces: at the brain capillaries by the blood-brain barrier (BBB, which is localized at the level of the endothelial cells and separates brain interstitial fluid (ISF from blood; at the epithelial layer of four choroid plexuses, the blood-cerebrospinal fluid (CSF barrier (BCSFB, which separates CSF from the CP ISF, and at the arachnoid barrier. The two barriers that represent the largest interface between blood and brain extracellular fluids, the BBB and the BCSFB, prevent the free paracellular diffusion of polar molecules by complex morphological features, including tight junctions (TJs that interconnect the endothelial and epithelial cells, respectively. The first part of this review focuses on the molecular biology of TJs and adherens junctions in the brain capillary endothelial cells and in the CP epithelial cells. However, normal function of the CNS depends on a constant supply of essential molecules, like glucose and amino acids from the blood, exchange of electrolytes between brain extracellular fluids and blood, as well as on efficient removal of metabolic waste products and excess neurotransmitters from the brain ISF. Therefore, a number of specific transport proteins are expressed in brain capillary endothelial cells and CP epithelial cells that provide transport of nutrients and ions into the CNS and removal of waste products and ions from the CSF. The second part of this review concentrates on the molecular biology of various solute carrier (SLC transport proteins at those two barriers and underlines

  8. Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI.

    Science.gov (United States)

    Vlachos, Fotios; Tung, Yao-Sheng; Konofagou, Elisa

    2011-09-01

    Blood-brain barrier opening using focused ultrasound and microbubbles has been experimentally established as a noninvasive and localized brain drug delivery technique. In this study, the permeability of the opening is assessed in the murine hippocampus after the application of focused ultrasound at three different acoustic pressures and microbubble sizes. Using dynamic contrast-enhanced MRI, the transfer rates were estimated, yielding permeability maps and quantitative K(trans) values for a predefined region of interest. The volume of blood-brain barrier opening according to the K(trans) maps was proportional to both the pressure and the microbubble diameter. A K(trans) plateau of ∼0.05 min(-1) was reached at higher pressures (0.45 and 0.60 MPa) for the larger sized bubbles (4-5 and 6-8 μm), which was on the same order as the K(trans) of the epicranial muscle (no barrier). Smaller bubbles (1-2 μm) yielded significantly lower permeability values. A small percentage (7.5%) of mice showed signs of damage under histological examination, but no correlation with permeability was established. The assessment of the blood-brain barrier permeability properties and their dependence on both the pressure and the microbubble diameter suggests that K(trans) maps may constitute an in vivo tool for the quantification of the efficacy of the focused ultrasound-induced blood-brain barrier opening.

  9. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain

    Science.gov (United States)

    Behrens, Matthias; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2015-01-01

    Background Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects. Methods Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients. Results Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport. PMID:26600019

  10. Volatile Anesthetics Influence Blood-Brain Barrier Integrity by Modulation of Tight Junction Protein Expression in Traumatic Brain Injury

    OpenAIRE

    Thal, Serge C.; Clara Luh; Eva-Verena Schaible; Ralph Timaru-Kast; Jana Hedrich; Luhmann, Heiko J.; Kristin Engelhard; Zehendner, Christoph M.

    2012-01-01

    Disruption of the blood-brain barrier (BBB) results in cerebral edema formation, which is a major cause for high mortalityrnafter traumatic brain injury (TBI). As anesthetic care is mandatory in patients suffering from severe TBI it may be importantrnto elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ) such as zonularnoccludens-1 (ZO-1) and claudin-5 (cl5) play a central role for BBB stability. First, the influence of the volatile anesthet...

  11. Blood-Brain Barrier Effects of the Fusarium Mycotoxins Deoxynivalenol, 3 Acetyldeoxynivalenol, and Moniliformin and Their Transfer to the Brain.

    Directory of Open Access Journals (Sweden)

    Matthias Behrens

    Full Text Available Secondary metabolites produced by Fusarium fungi frequently contaminate food and feed and have adverse effects on human and animal health. Fusarium mycotoxins exhibit a wide structural and biosynthetic diversity leading to different toxicokinetics and toxicodynamics. Several studies investigated the toxicity of mycotoxins, focusing on very specific targets, like the brain. However, it still remains unclear how fast mycotoxins reach the brain and if they impair the integrity of the blood-brain barrier. This study investigated and compared the effects of the Fusarium mycotoxins deoxynivalenol, 3-acetyldeoxynivalenol and moniliformin on the blood-brain barrier. Furthermore, the transfer properties to the brain were analyzed, which are required for risk assessment, including potential neurotoxic effects.Primary porcine brain capillary endothelial cells were cultivated to study the effects of the examined mycotoxins on the blood-brain barrier in vitro. The barrier integrity was monitored by cellular impedance spectroscopy and 14C radiolabeled sucrose permeability measurements. The distribution of the applied toxins between blood and brain compartments of the cell monolayer was analyzed by high performance liquid chromatography-mass spectrometry to calculate transfer rates and permeability coefficients.Deoxynivalenol reduced the barrier integrity and caused cytotoxic effects at 10 μM concentrations. Slight alterations of the barrier integrity were also detected for 3-acetyldeoxynivalenol. The latter was transferred very quickly across the barrier and additionally cleaved to deoxynivalenol. The transfer of deoxynivalenol and moniliformin was slower, but clearly exceeded the permeability of the negative control. None of the compounds was enriched in one of the compartments, indicating that no efflux transport protein is involved in their transport.

  12. Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research.

    Science.gov (United States)

    Walton, Esther; Hass, Johanna; Liu, Jingyu; Roffman, Joshua L; Bernardoni, Fabio; Roessner, Veit; Kirsch, Matthias; Schackert, Gabriele; Calhoun, Vince; Ehrlich, Stefan

    2016-03-01

    Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders.

  13. Associations between Muscle Strength Asymmetry and Impairments in Gait and Posture in Young Brain-Injured Patients

    NARCIS (Netherlands)

    Drijkoningen, D.; Caeyenberghs, K.; Linden, C. van der; Herpe, K. Van; Duysens, J.; Swinnen, S.P.

    2015-01-01

    Traumatic brain injury (TBI) can lead to deficits in gait and posture, which are often asymmetric. A possible factor mediating these deficits may be asymmetry in strength of the leg muscles. However, muscle strength in the lower extremities has rarely been investigated in (young) TBI patients. Here,

  14. Electroconvulsive therapy, hypertensive surge, blood-brain barrier breach, and amnesia

    DEFF Research Database (Denmark)

    Andrade, Chittaranjan; Bolwig, Tom G

    2014-01-01

    Preclinical and clinical evidence show that electroconvulsive therapy (ECT)-induced intraictal surge in blood pressure may result in a small, transient breach in the blood-brain barrier, leading to mild cerebral edema and a possible leach of noxious substances from blood into brain tissues...... of blood pressure during electroconvulsive shocks attenuate electroconvulsive shock-induced amnestic changes; however, the evidence suggests that antihypertensive mechanisms may not necessarily be involved. Clinical studies involving pre-ECT administration of antihypertensive medications do not provide...... convincing evidence of benefits. It is concluded that there is insufficient support, at present, for the hypothesis that the hypertensive surge during ECT and the resultant blood-brain barrier breach contribute meaningfully to ECT-induced cognitive deficits. Future research should address the subset...

  15. Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system.

    Science.gov (United States)

    Plog, Benjamin A; Dashnaw, Matthew L; Hitomi, Emi; Peng, Weiguo; Liao, Yonghong; Lou, Nanhong; Deane, Rashid; Nedergaard, Maiken

    2015-01-14

    The nonspecific and variable presentation of traumatic brain injury (TBI) has motivated an intense search for blood-based biomarkers that can objectively predict the severity of injury. However, it is not known how cytosolic proteins released from traumatized brain tissue reach the peripheral blood. Here we show in a murine TBI model that CSF movement through the recently characterized glymphatic pathway transports biomarkers to blood via the cervical lymphatics. Clinically relevant manipulation of glymphatic activity, including sleep deprivation and cisternotomy, suppressed or eliminated TBI-induced increases in serum S100β, GFAP, and neuron specific enolase. We conclude that routine TBI patient management may limit the clinical utility of blood-based biomarkers because their brain-to-blood transport depends on glymphatic activity.

  16. Reactive actuators and sensors integrated in one device: mimicking brain-muscles feedback communication

    Science.gov (United States)

    Otero, Toribio F.; Martinez, Jose G.

    2013-04-01

    Artificial muscles based on carbon derivative molecular structures are chemical (electro-chemo-mechanical) actuators. The electrochemical reaction drives the film volume variation and the actuation. The applied current controls the movement rate and the charge controls the amplitude of the displacement (Faraday' motors). Any working or surrounding variable influencing the reaction rate will be sensed by the muscle potential, or by the consumed electrical energy, evolution during actuation. Experimental results and full theoretical description of the basic reactive material and of any dual electrochemical sensing-actuator will be presented. During current flow the muscle potential and the consumed electrical energy evolution are influenced by the working variables: temperature, electrolyte concentration, driving current, film volume variation (external pressure, applied strain, hanged masses, obstacles in its way). The working muscle becomes an electrochemical sensor. Only two connecting wires contain actuating (current) and sensing (potential) signals read and controlled, at any time from the computer-generator. One device integrates several sensing and actuating tools working simultaneously mimicking muscles/brain feedback communication.

  17. Motor responses of muscles supplied by cranial nerves to subthalamic nucleus deep brain stimuli.

    Science.gov (United States)

    Costa, João; Valls-Solé, Josep; Valldeoriola, Francesc; Rumià, Jordi; Tolosa, Eduardo

    2007-01-01

    The distribution of human corticobulbar motor excitatory and inhibitory output is not fully understood. In particular, it is unclear whether the pattern of innervation is the same for upper and lower facial muscles, and what is the motor cortical area giving rise to such innervation. We used electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease to activate motor tracts at a subcortical level. We examined the excitatory and inhibitory effects of unilateral single STN deep brain stimulation (sSTN-DBS) in 14 patients by taking recordings from facial, cervical and upper limb muscles on both sides. We measured the latency and amplitude of the motor-evoked potentials (MEPs), and the latency and duration of the silent periods, and compared ipsilateral with contralateral responses and responses obtained in different muscles. Unilateral sSTN-DBS induced strictly contralateral MEPs in the trapezius, deltoid, biceps and thenar muscles. The same stimulus always induced bilateral MEPs in the orbicularis oculi, orbicularis oris, masseter and sternocleidomastoid at a mean latency in the range 6.0-9.1 ms. MEP latencies in the orbicularis oculi and orbicularis oris were significantly longer than in the masseter and sternocleidomastoid (P motor nuclei descend together at the level of the STN. These findings are relevant in the discussion of the innervation of upper and lower facial muscles in humans and in the interpretation of previous results obtained with transcranial cortical stimulation.

  18. Defense at the border : the blood-brain barrier versus bacterial foreigners

    NARCIS (Netherlands)

    van Sorge, Nina M.; Doran, Kelly S.

    2012-01-01

    Bacterial meningitis is among the top ten causes of infectious disease-related deaths worldwide, with up to half of the survivors left with permanent neurological sequelae. The blood-brain barrier (BBB), composed mainly of specialized brain microvascular endothelial cells, maintains biochemical home

  19. The immune system mediates blood-brain barrier damage; Possible implications for pathophysiology of neuropsychiatric illnesses

    NARCIS (Netherlands)

    VanderWerf, YD; DeJongste, MJL; terHorst, GJ

    1995-01-01

    The immune system mediates blood-brain barrier damage; possible implications for pathophysiology of neuropsychiatric illnesses. In this investigation the effects of immune activation on the brain are characterized In order to study this, we used a model for chronic immune activation, the myocardial

  20. Systems pharmacology and blood-brain barrier functionality in Parkinson's disease

    NARCIS (Netherlands)

    Ravenstijn, Paulien Gerarda Maria

    2009-01-01

    Parkinson’s disease is a progressive neurodegenerative disease, which is composed of many components, each caused by interplay of a number of genetic and nongenetic causes. As the blood-brain barrier (BBB) is a key player in the relationship between plasma and brain pharmacokinetics, the influences

  1. Longitudinal assessment of blood-brain barrier leakage during epileptogenesis in rats. A quantitative MRI study.

    NARCIS (Netherlands)

    van Vliet, E.A.; Otte, W.M.; Gorter, J.A.; Dijkhuizen, R.M.; Wadman, W.J.

    2014-01-01

    The blood-brain barrier (BBB) plays an important role in the homeostasis of the brain. BBB dysfunction has been implicated in the pathophysiology of various neurological disorders, including epilepsy in which it may contribute to disease progression. Precise understanding of BBB dynamics during epil

  2. PET tracers for imaging of ABC transporters at the blood-brain barrier : Principles and Strategies

    NARCIS (Netherlands)

    Luurtsema, Gert; Elsinga, Philip; Dierckx, Rudi; Boellaard, Ronald; van Waarde, Aren

    2016-01-01

    ABC transporters at the human blood-brain barrier protect the brain against the entry of harmful compounds but may also limit (or prevent) the cerebral entry of therapeutic drugs (e.g. anti-epileptics, antidepressants and antipsychotics). The efflux function of these transporters may be impaired in

  3. St. John's Wort constituents modulate P-glycoprotein transport activity at the blood-brain barrier.

    NARCIS (Netherlands)

    Ott, M.; Huls, M.; Cornelius, M.G.; Fricker, G.

    2010-01-01

    PURPOSE: The purpose of this study was to investigate the short-term signaling effects of St. John's Wort (SJW) extract and selected SJW constituents on the blood-brain barrier transporter P-glycoprotein and to describe the role of PKC in the signaling. METHODS: Cultured porcine brain capillary endo

  4. The effect of blood brain barrier modulation on oxime efficacy in nerve agent poisoning (Abstract)

    NARCIS (Netherlands)

    Joosen, M.; Schans, M.J. van der; Dijk, C.G.M. van; Kuijpers, WC.; Wortelboer, H.M.; Helden, H.P.M. van

    2012-01-01

    One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood brain barrier (BBB), whereas nerve agents easily do. Enhancing the efficacy of current oximes in the brain, would therefore provide an attractive approach to improve medical countermeasure

  5. Glutamate Efflux at the Blood-Brain Barrier

    DEFF Research Database (Denmark)

    Cederberg-Helms, Hans Christian; Uhd-Nielsen, Carsten; Brodin, Birger

    2014-01-01

    L-Glutamate is considered the most important excitatory amino acid in the mammalian brain. Strict control of its concentration in the brain interstitial fluid is important to maintain neurotransmission and avoid excitotoxicity. The role of astrocytes in handling L-glutamate transport and metaboli...

  6. Smooth Muscle Endothelin B Receptors Regulate Blood Pressure but Not Vascular Function or Neointimal Remodeling.

    Science.gov (United States)

    Miller, Eileen; Czopek, Alicja; Duthie, Karolina M; Kirkby, Nicholas S; van de Putte, Elisabeth E Fransen; Christen, Sibylle; Kimmitt, Robert A; Moorhouse, Rebecca; Castellan, Raphael F P; Kotelevtsev, Yuri V; Kuc, Rhoda E; Davenport, Anthony P; Dhaun, Neeraj; Webb, David J; Hadoke, Patrick W F

    2017-02-01

    The role of smooth muscle endothelinB (ETB) receptors in regulating vascular function, blood pressure (BP), and neointimal remodeling has not been established. Selective knockout mice were generated to address the hypothesis that loss of smooth muscle ETB receptors would reduce BP, alter vascular contractility, and inhibit neointimal remodeling. ETB receptors were selectively deleted from smooth muscle by crossing floxed ETB mice with those expressing cre-recombinase controlled by the transgelin promoter. Functional consequences of ETB deletion were assessed using myography. BP was measured by telemetry, and neointimal lesion formation induced by femoral artery injury. Lesion size and composition (day 28) were analyzed using optical projection tomography, histology, and immunohistochemistry. Selective deletion of ETB was confirmed by genotyping, autoradiography, polymerase chain reaction, and immunohistochemistry. ETB-mediated contraction was reduced in trachea, but abolished from mesenteric veins, of knockout mice. Induction of ETB-mediated contraction in mesenteric arteries was also abolished in these mice. Femoral artery function was unaltered, and baseline BP modestly elevated in smooth muscle ETB knockout compared with controls (+4.2±0.2 mm Hg; P<0.0001), but salt-induced and ETB blockade-mediated hypertension were unaltered. Circulating endothelin-1 was not altered in knockout mice. ETB-mediated contraction was not induced in femoral arteries by incubation in culture medium or lesion formation, and lesion size was not altered in smooth muscle ETB knockout mice. In the absence of other pathology, ETB receptors in vascular smooth muscle make a small but significant contribution to ETB-dependent regulation of BP. These ETB receptors have no effect on vascular contraction or neointimal remodeling.

  7. A review on the mechanisms of blood-flow restriction resistance training-induced muscle hypertrophy.

    Science.gov (United States)

    Pearson, Stephen John; Hussain, Syed Robiul

    2015-02-01

    It has traditionally been believed that resistance training can only induce muscle growth when the exercise intensity is greater than 65% of the 1-repetition maximum (RM). However, more recently, the use of low-intensity resistance exercise with blood-flow restriction (BFR) has challenged this theory and consistently shown that hypertrophic adaptations can be induced with much lower exercise intensities (training being demonstrated by numerous studies, the underlying mechanisms responsible for such effects are not well defined. Metabolic stress has been suggested to be a primary factor responsible, and this is theorised to activate numerous other mechanisms, all of which are thought to induce muscle growth via autocrine and/or paracrine actions. However, it is noteworthy that some of these mechanisms do not appear to be mediated to any great extent by metabolic stress but rather by mechanical tension (another primary factor of muscle hypertrophy). Given that the level of mechanical tension is typically low with BFR resistance exercise (adaptations reported with BFR resistance training. However, despite the low level of mechanical tension, it is plausible that the effects induced by the primary factors (mechanical tension and metabolic stress) are, in fact, additive, which ultimately contributes to the adaptations seen with BFR resistance training. Exercise-induced mechanical tension and metabolic stress are theorised to signal a number of mechanisms for the induction of muscle growth, including increased fast-twitch fibre recruitment, mechanotransduction, muscle damage, systemic and localised hormone production, cell swelling, and the production of reactive oxygen species and its variants, including nitric oxide and heat shock proteins. However, the relative extent to which these specific mechanisms are induced by the primary factors with BFR resistance exercise, as well as their magnitude of involvement in BFR resistance training-induced muscle hypertrophy

  8. Epstein-Barr virus-associated smooth muscle tumour presenting as a parasagittal brain tumour.

    Science.gov (United States)

    Ibebuike, K E; Pather, S; Emereole, O; Ndolo, P; Kajee, A; Gopal, R; Naidoo, S

    2012-11-01

    Dural-based brain tumours, apart from meningiomas, are rare. Epstein-Barr virus (EBV)-associated smooth muscle tumor (SMT) is a documented but rare disease that occurs in immunocompromized patients. These tumours may be located at unusual sites including the brain. We present a 37-year-old patient, positive for the human immunodeficiency virus (HIV), who was admitted after generalized tonic-clonic seizures. MRI and CT scan revealed a dural-based brain tumour, intraoperatively thought to be a meningioma, but with an eventual histological diagnosis of EBV-SMT. Clinically the patient was well postoperatively with a Glasgow coma scale score of 15/15 and no focal neurologic deficit. This case confirms the association between EBV and SMT in patients with HIV/acquired immunodeficiency syndrome (AIDS). It also highlights the need to include EBV-SMT in the differential diagnosis of intracranial mass lesions in patients with HIV/AIDS.

  9. A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

    Science.gov (United States)

    Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

    2016-11-01

    The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes–permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

  10. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature.

    Science.gov (United States)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe; Linnet, Kristian

    2016-09-01

    To interpret postmortem toxicology results, reference concentrations for non-toxic and toxic levels are needed. Usually, measurements are performed in blood, but because of postmortem redistribution phenomena this may not be optimal. Rather, measurement in the target organ of psychoactive drugs, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug-metabolite ratios were similar in brain and blood for most compounds. Duplicate measurements of brain samples showed that the pre-analytical variation in brain (5.9%) was relatively low, supporting the notion that brain tissue is a suitable postmortem specimen. The reported concentrations in both brain and blood can be used as reference values when evaluating postmortem cases.

  11. Role of histaminergic system in blood-brain barrier dysfunction associated with neurological disorders.

    Science.gov (United States)

    Bañuelos-Cabrera, Ivette; Valle-Dorado, María Guadalupe; Aldana, Blanca Irene; Orozco-Suárez, Sandra Adela; Rocha, Luisa

    2014-11-01

    Blood-brain barrier (BBB) disruption has been associated with several acute and chronic brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. This represents a critical situation because damaged integrity of the BBB is related to the influx of immune mediators, plasma proteins and other outside elements from blood to the central nervous system (CNS) that may trigger a cascade of events that leads to neuroinflammation. In this review, evidence that mast cells and the release of factors such as histamine play an important role in the neuroinflammatory process associated with brain disorders such as Alzheimer's disease, Parkinson's disease and epilepsy is presented.

  12. Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins.

    Science.gov (United States)

    Taevernier, Lien; Bracke, Nathalie; Veryser, Lieselotte; Wynendaele, Evelien; Gevaert, Bert; Peremans, Kathelijne; De Spiegeleer, Bart

    2016-09-06

    The cyclic depsipeptide mycotoxins beauvericin and enniatins are capable of reaching the systemic circulation through various routes of exposure and are hence capable of exerting central nervous system (CNS) effects, if they are able to pass the blood-brain barrier (BBB), which was the main objective of this study. Quantification of the mycotoxins was performed using an in-house developed and validated bio-analytical UHPLC-MS/MS method. Prior to the BBB experiments, the metabolic stability of the mycotoxins was evaluated in vitro in mouse serum and brain homogenate. The BBB permeation kinetics of beauvericin and enniatins were studied using an in vivo mice model, applying multiple time regression for studying the blood-to-brain influx. Additionally, capillary depletion was applied to obtain the fraction of the peptides really entering the brain parenchyma and the fraction loosely adhered to the brain capillary wall. Finally, also the brain-to-blood efflux transport kinetics was studied. Metabolic stability data indicated that the investigated mycotoxins were stable during the duration of the in vivo study. The brain influx study showed that beauvericin and enniatins are able to cross the blood-brain barrier in mice: using the Gjedde-Patlak biphasic model, it was shown that all investigated mycotoxins exert a high initial influx rate into the brain (K1 ranging from 11 to 53μL/(g×min)), rapidly reaching a plateau. After penetration, the mycotoxins reached the brain parenchyma (95%) with only a limited amount residing in the capillaries (5%). Negligible efflux (<0.005min(-1)) from the brain was observed in the 15min post-intracerebroventricular injection.

  13. Thenar muscle blood flow and bone mineral in the forearms of lumberjacks.

    Science.gov (United States)

    Karjalainen, P; Alhava, E M; Valtola, J

    1975-02-01

    Forty lumberjacks who had used a chain saw for 0-20 years and who had no general disease affecting the bones were studied by measuring the thenar muscle blood flow of both hands by the 133-Xe local clearance method. Bone mineral in the left forearm in the region of cancellous and cortical bone was assessed by the 241-Am gamma ray attenuation method. Virbration was found to decrease the blood flow in the saw-bearing left hand compared with the right hand of the lumberjacks. The bone mineral density (g/vm-3) was lower in the forearm bones of the lumberjacks than in controls of the same age with healthy bones. Moreover the poorer the thenar muscle blood flow, the greater was the decrease in the mineral density of the distal radius. Measurement of the mineral density of the forearm bones by the gramma ray attenuation method can be used for early detection of bone lesions in traumatic vasospastic disease.

  14. Blood-Brain Barrier Imaging in Human Neuropathologies

    Science.gov (United States)

    Veksler, Ronel; Shelef, Ilan; Friedman, Alon

    2014-01-01

    The blood–brain barrier (BBB) is essential for normal function of the brain, and its role in many brain pathologies has been the focus of numerous studies during the last decades. Dysfunction of the BBB is not only being shown in numerous brain diseases, but animal studies have indicated that it plays a direct key role in the genesis of neurovascular dysfunction and associated neurodegeneration. As such evidence accumulates, the need for robust and clinically applicable methods for minimally invasive assessment of BBB integrity is becoming urgent. This review provides an introduction to BBB imaging methods in the clinical scenario. First, imaging modalities are reviewed, with a focus on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). We then proceed to review image analysis methods, including quantitative and semi-quantitative methods. The advantages and limitations of each approach are discussed, and future directions and questions are highlighted. PMID:25453223

  15. Postmortem Brain and Blood Reference Concentrations of Alprazolam, Bromazepam, Chlordiazepoxide, Diazepam, and their Metabolites and a Review of the Literature

    DEFF Research Database (Denmark)

    Skov, Louise; Holm, Karen Marie Dollerup; Johansen, Sys Stybe

    2016-01-01

    blood and brain tissue in 104 cases. BZDs were judged to be unrelated to the cause of death in 88 cases and contributing to death in 16 cases. No cases were found with cause of death solely attributed to BZD poisoning. All BZDs investigated tended to have higher concentrations in brain than in blood......, the brain, might be considered. Here we present reference concentrations of femoral blood and brain tissue of selected benzodiazepines (BZDs). Using LC-MS/MS, we quantified alprazolam, bromazepam, chlordiazepoxide, diazepam, and the metabolites desmethyldiazepam, oxazepam and temazepam in postmortem femoral...... with median brain-blood ratios ranging from 1.1 to 2.3. A positive correlation between brain and blood concentrations was found with R(2) values from 0.51 to 0.95. Our reported femoral blood concentrations concur with literature values, but sparse information on brain concentration was available. Drug...

  16. SDF-1 controls the muscle and blood vessel formation of the somite.

    Science.gov (United States)

    Abduelmula, Aisha; Huang, Ruijin; Pu, Qin; Tamamura, Hirokazu; Morosan-Puopolo, Gabriela; Brand-Saberi, Beate

    2016-01-01

    Stromal-cell-derived factor-1 (SDF-1), the only ligand of the chemokine receptor CXCR4, is involved in skeletal muscle development. However, its role in the proliferation, differentiation and migration of somite cells is not well understood. Here, we investigated its function during somite development in chicken embryos by using gain-of-function and loss-of-function experiments. Overexpression of SDF-1 was performed by electroporating SDF-1 constructs into the ventrolateral part of the somite, or by injecting SDF-1-expressing cells into the somites of stages HH14-16 chicken embryos. We found that enhanced SDF-1 signaling induced cell proliferation in the somite. This resulted in an increase in number of both myotomal and endothelial cells. In contrast, inhibition of SDF-1/CXCR4 signaling led to a reduction of myotomal cells. Injection of SDF-1 producing cells into the somite induced ectopic localization of myotomal cells in the sclerotome. Although many SDF-1-expressing somite cells colonized the limb, only a few of them developed into muscle cells. This resulted in a reduction of the limb muscle mass. This means that most myogenic progenitors were stopped on their migration towards the limb due to the high concentration of the SDF-1 signal in the somite. Most of the SDF-1-expressing somite cells found in the limb were of endothelial cell fate and they contributed to the increase in limb blood vessels. These results reveal that SDF-1 promotes the proliferation of both myogenic and angiogenic progenitor cells of the somite and controls myotome formation. Furthermore, SDF-1 controls muscle and blood vessel formation in the limb in different ways.

  17. The Trojan Horse Liposome Technology for Nonviral Gene Transfer across the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ruben J. Boado

    2011-01-01

    Full Text Available The application of blood-borne gene therapy protocols to the brain is limited by the presence of the blood-brain barrier (BBB. Viruses have been extensively used as gene delivery systems. However, their efficacy in brain is limited by the lack of transport across the BBB following intravenous (IV administration. Recent progress in the “Trojan Horse Liposome” (THL technology applied to transvascular non-viral gene therapy of the brain presents a promising solution to the trans-vascular brain gene delivery problem. THLs are comprised of immunoliposomes carrying nonviral gene expression plasmids. The tissue target specificity of the THL is provided by peptidomimetic monoclonal antibody (MAb component of the THL, which binds to specific endogenous receptors located on both the BBB and on brain cellular membranes, for example, insulin receptor and transferrin receptor. These MAbs mediate (a receptor-mediated transcytosis of the THL complex through the BBB, (b endocytosis into brain cells and (c transport to the brain cell nuclear compartment. The expression of the transgene in brain may be restricted using tissue/cell specific gene promoters. This manuscript presents an overview on the THL transport technology applied to brain disorders, including lysosomal storage disorders and Parkinson's disease.

  18. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders.

    Science.gov (United States)

    Meng, Qingying; Zhuang, Yumei; Ying, Zhe; Agrawal, Rahul; Yang, Xia; Gomez-Pinilla, Fernando

    2017-02-01

    The complexity of the traumatic brain injury (TBI) pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing), and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

  19. Traumatic Brain Injury Induces Genome-Wide Transcriptomic, Methylomic, and Network Perturbations in Brain and Blood Predicting Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Qingying Meng

    2017-02-01

    Full Text Available The complexity of the traumatic brain injury (TBI pathology, particularly concussive injury, is a serious obstacle for diagnosis, treatment, and long-term prognosis. Here we utilize modern systems biology in a rodent model of concussive injury to gain a thorough view of the impact of TBI on fundamental aspects of gene regulation, which have the potential to drive or alter the course of the TBI pathology. TBI perturbed epigenomic programming, transcriptional activities (expression level and alternative splicing, and the organization of genes in networks centered around genes such as Anax2, Ogn, and Fmod. Transcriptomic signatures in the hippocampus are involved in neuronal signaling, metabolism, inflammation, and blood function, and they overlap with those in leukocytes from peripheral blood. The homology between genomic signatures from blood and brain elicited by TBI provides proof of concept information for development of biomarkers of TBI based on composite genomic patterns. By intersecting with human genome-wide association studies, many TBI signature genes and network regulators identified in our rodent model were causally associated with brain disorders with relevant link to TBI. The overall results show that concussive brain injury reprograms genes which could lead to predisposition to neurological and psychiatric disorders, and that genomic information from peripheral leukocytes has the potential to predict TBI pathogenesis in the brain.

  20. Effects of Yishendaluo decoction on blood-brain barrier integrity in mice with experimental autoimmune encephalomyelitis

    Institute of Scientific and Technical Information of China (English)

    Yanqing Wu; Ying Gao; Lingqun Zhu; Yonghong Gao; Dongmei Zhang; Lixia Lou; Yanfang Yan

    2011-01-01

    This study investigated the effects of Yishendaluo decoction on the loss of blood-brain barrier integrity in mice exhibiting experimental autoimmune encephalomyelitis.To this end,we used real-time fluorescent quantitative PCR to measure the levels of mRNAs specific to the T cell markers CD4 and CD8,and the monocyte marker CD11b.In addition,we used Evans blue dye extravasation in the spinal cord and brain tissues to assess blood-brain barrier permeability.The results indicated that an increase in blood-brain barrier permeability was associated with an increase in CD4,CD8 and CD11b mRNA expression in experimental autoimmune encephalomyelitis mice.Yishendaluo decoction administration significantly reversed inflammatory cell accumulation in cerebral tissues of experimental autoimmune encephalomyelitis mice.

  1. Characterization of an in vitro Rhesus Macaque Blood-Brain Barrier

    Science.gov (United States)

    MacLean, Andrew G.; Orandle, Marlene S.; MacKey, John; Williams, Kenneth C.; Alvarez, Xavier; Lackner, Andrew A.

    2013-01-01

    The blood-brain barrier has been modeled in vitro in a number of species, including rat, cow and human. Coculture of multiple cell types is required for the correct expression of tight junction proteins by microvascular brain endothelial cells (MBEC). Markers of inflammation, especially MHC-II, and cell adhesion molecules, such as VCAM-1, are not expressed on the luminal surface of the barrier under resting conditions. The rhesus macaque model has been used to study early events of HIV-neuropathogenesis in vivo, but a suitable in vitro model has not been available for detailed mechanistic studies. Here we describe an in vitro rhesus macaque blood-brain barrier (BBB) that utilizes autologous MBEC and astrocytes. We believe that this model is highly relevant for examining immunological events at the blood-brain barrier and demonstrate its potential usefulness for examining early events in AIDS neuropathogenesis. PMID:12458041

  2. Simulation of Local Blood Flow in Human Brain under Altered Gravity

    Science.gov (United States)

    Kim, Chang Sung; Kiris, Cetin; Kwak, Dochan

    2003-01-01

    In addition to the altered gravitational forces, specific shapes and connections of arteries in the brain vary in the human population (Cebral et al., 2000; Ferrandez et al., 2002). Considering the geometric variations, pulsatile unsteadiness, and moving walls, computational approach in analyzing altered blood circulation will offer an economical alternative to experiments. This paper presents a computational approach for modeling the local blood flow through the human brain under altered gravity. This computational approach has been verified through steady and unsteady experimental measurements and then applied to the unsteady blood flows through a carotid bifurcation model and an idealized Circle of Willis (COW) configuration under altered gravity conditions.

  3. Evaluation of low level laser therapy irradiation parameters on rat muscle inflammation through systemic blood cytokines

    Science.gov (United States)

    Mantineo, Matias; Pinheiro, João. P.; Morgado, António M.

    2014-02-01

    Low level laser therapy (LLLT) has been used for inflammation treatment. Here, we evaluate the effect of different doses, using continuous (830 and 980 nm) and pulsed illumination (830 nm), in the treatment of inflammation induced in the gastrocnemius muscle of Wistar rats, through cytokines concentration in systemic blood and histological analysis of muscle tissue. Animals were randomly divided into five groups per wavelength (5 animals per group: 10, 20, 30, 40 and 50 mW) plus a control group. LLLT was applied during five days, with constant exposure time and irradiated area (3 minutes; 0.5026 cm2). Blood was collected on days 0, 3 and 6. TNF-α, IL-1β, IL-2 and IL-6 cytokines were quantified by ELISA. Rats were killed on day 6. Muscle inflammatory cells were counted using optical microscopy. Treatment effects occurred for all applied doses (largest effect at 40 mW: 7.2 J, 14 J/cm2 per irradiation), with reduction of proinflammatory TNF-α, IL-1β and IL-6 cytokines and lower number of inflammatory cells. Results were better for 830 nm. Identical methodology was used with pulsed illumination. Average power (40 mW) and duty cycle were kept constant (80%) at five frequencies (5, 25, 50, 100 and 200 Hz). Treatment effects were observed at higher frequencies, with no significant differences between them. However, the treatment effect was lower than for continuous illumination. LLLT effect on inflammation treatment can be monitored by measuring systemic blood cytokines. A larger treatment effect was observed with continuous illumination, where results seem to be compatible with a biphasic dose response.

  4. Intracranial mechanisms for preserving brain blood flow in health and disease.

    Science.gov (United States)

    McBryde, F D; Malpas, S C; Paton, J F R

    2017-01-01

    The brain is an exceptionally energetically demanding organ with little metabolic reserve, and multiple systems operate to protect and preserve the brain blood supply. But how does the brain sense its own perfusion? In this review, we discuss how the brain may harness the cardiovascular system to counter threats to cerebral perfusion sensed via intracranial pressure (ICP), cerebral oxygenation and ischaemia. Since the work of Cushing over 100 years ago, the existence of brain baroreceptors capable of eliciting increases in sympathetic outflow and blood pressure has been hypothesized. In the clinic, this response has generally been thought to occur only in extremis, to perfuse the severely ischaemic brain as cerebral autoregulation fails. We review evidence that pressor responses may also occur with smaller, physiologically relevant increases in ICP. The incoming brain oxygen supply is closely monitored by the carotid chemoreceptors; however, hypoxia and other markers of ischaemia are also sensed intrinsically by astrocytes or other support cells within brain tissue itself and elicit reactive hyperaemia. Recent studies suggest that astrocytic oxygen signalling within the brainstem may directly affect sympathetic nerve activity and blood pressure. We speculate that local cerebral oxygen tension is a major determinant of the mean level of arterial pressure and discuss recent evidence that this may be the case. We conclude that intrinsic intra- and extra-cranial mechanisms sense and integrate information about hypoxia/ischaemia and ICP and play a major role in determining the long-term level of sympathetic outflow and arterial pressure, to optimize cerebral perfusion.

  5. Blood lactate is an important energy source for the human brain

    DEFF Research Database (Denmark)

    G., van Hall; Stromstad, M.; Rasmussen, P.;

    2009-01-01

    Lactate is a potential energy source for the brain. The aim of this study was to establish whether systemic lactate is a brain energy source. We measured in vivo cerebral lactate kinetics and oxidation rates in 6 healthy individuals at rest with and without 90 mins of intravenous lactate infusion...... is taken up and oxidized by the human brain and is an important substrate for the brain both under basal and hyperlactatemic conditions.Journal of Cerebral Blood Flow & Metabolism advance online publication, 1 April 2009; doi:10.1038/jcbfm.2009.35....

  6. Blood flow index using near-infrared spectroscopy and indocyanine green as a minimally invasive tool to assess respiratory muscle blood flow in humans.

    Science.gov (United States)

    Guenette, Jordan A; Henderson, William R; Dominelli, Paolo B; Querido, Jordan S; Brasher, Penelope M; Griesdale, Donald E G; Boushel, Robert; Sheel, A William

    2011-04-01

    Near-infrared spectroscopy (NIRS) in combination with indocyanine green (ICG) dye has recently been used to measure respiratory muscle blood flow (RMBF) in humans. This method is based on the Fick principle and is determined by measuring ICG in the respiratory muscles using transcutaneous NIRS in relation to the [ICG] in arterial blood as measured using photodensitometry. This method is invasive since it requires arterial cannulation, repeated blood withdrawals, and reinfusions. A less invasive alternative is to calculate a relative measure of blood flow known as the blood flow index (BFI), which is based solely on the NIRS ICG curve, thus negating the need for arterial cannulation. Accordingly, the purpose of this study was to determine whether BFI can be used to measure RMBF at rest and during voluntary isocapnic hyperpnea at 25, 40, 55, and 70% of maximal voluntary ventilation in seven healthy humans. BFI was calculated as the change in maximal [ICG] divided by the rise time of the NIRS-derived ICG curve. Intercostal and sternocleidomastoid muscle BFI were correlated with simultaneously measured work of breathing and electromyography (EMG) data from the same muscles. BFI showed strong relationships with the work of breathing and EMG for both respiratory muscles. The coefficients of determination (R(2)) comparing BFI vs. the work of breathing for the intercostal and sternocleidomastoid muscles were 0.887 (P < 0.001) and 0.863 (P < 0.001), respectively, whereas the R(2) for BFI vs. EMG for the intercostal and sternocleidomastoid muscles were 0.879 (P < 0.001) and 0.930 (P < 0.001), respectively. These data suggest that the BFI closely reflects RMBF in conscious humans across a wide range of ventilations and provides a less invasive and less technically demanding alternative to measuring RMBF.

  7. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness

    DEFF Research Database (Denmark)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees......, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy...... metabolism pathways. These metabolic changes could not be attributed to environmental conditions and were confirmed against the expression of their corresponding enzymes. We further conducted muscle strength tests in humans, chimpanzees, and macaques. The results suggest that, while humans are characterized...

  8. [The effect of prostatilen on the contractile activity of the smooth-muscle cells of the blood vessels and bladder in cats].

    Science.gov (United States)

    al-Shchukri, S Kh; Barabanov, S V; Barabanova, V V; Bobkov, Iu A; Gorbachev, A G; Parastaeva, M M

    1996-07-01

    Prostatilene enhanced the functional activity of the bladder and blood vessels' smooth muscle cells. A possibility of activation of the smooth muscle cells contractility with prostatilene by a pharmaco-mechanical association, is discussed.

  9. Near-infrared spectroscopy and indocyanine green derived blood flow index for noninvasive measurement of muscle perfusion during exercise.

    Science.gov (United States)

    Habazettl, Helmut; Athanasopoulos, Dimitris; Kuebler, Wolfgang M; Wagner, Harrieth; Roussos, Charis; Wagner, Peter D; Ungruhe, Juergen; Zakynthinos, Spyros; Vogiatzis, Ioannis

    2010-04-01

    Near-infrared spectroscopy (NIRS) with the tracer indocyanine green (ICG) may be used for measuring muscle blood flow (MBF) during exercise, if arterial ICG concentration is measured simultaneously. Although pulse dye densitometry allows for noninvasive measurement of arterial dye concentration, this technique is sensitive to motion and may not be applicable during exercise. The aim of this study was to evaluate a noninvasive blood flow index (BFI), which is derived solely from the muscle ICG concentration curve. In 10 male cyclists 5 mg ICG were injected into an antecubital vein at rest and during cycling at 30, 60, 70, 80, 90, and 100% of previously determined maximal work load. Simultaneously blood was withdrawn through a photodensitometer at 20 ml/min from the radial artery to measure arterial ICG concentration. To measure muscle tissue ICG concentrations, two sets of NIRS optodes were positioned on the skin, one over the left seventh intercostal space and the other over the left vastus lateralis muscle. MBF was calculated from the arterial and muscle concentration data according to Fick's principle. BFI was calculated solely from the muscle concentration curve as ICG concentration difference divided by rise time between 10 and 90% of peak. During exercise mean BFI values changed similarly to MBF in both intercostal and quadriceps muscles and showed excellent correlations with MBF: r = 0.98 and 0.96, respectively. Individual data showed some scattering among BFI and MBF values but still reasonable correlations of BFI with MBF: r = 0.73 and 0.72 for intercostal and quadriceps muscles, respectively. Interobserver variability, as analyzed by Bland-Altman plots, was considerably less for BFI than MBF. These data suggest that BFI can be used for measuring changes in muscle perfusion from rest to maximal exercise. Although absolute blood flow cannot be determined, BFI has the advantages of being essentially noninvasive and having low interobserver variability.

  10. Exceptional evolutionary divergence of human muscle and brain metabolomes parallels human cognitive and physical uniqueness

    DEFF Research Database (Denmark)

    Bozek, Katarzyna; Wei, Yuning; Yan, Zheng;

    2014-01-01

    Metabolite concentrations reflect the physiological states of tissues and cells. However, the role of metabolic changes in species evolution is currently unknown. Here, we present a study of metabolome evolution conducted in three brain regions and two non-neural tissues from humans, chimpanzees......, macaque monkeys, and mice based on over 10,000 hydrophilic compounds. While chimpanzee, macaque, and mouse metabolomes diverge following the genetic distances among species, we detect remarkable acceleration of metabolome evolution in human prefrontal cortex and skeletal muscle affecting neural and energy...

  11. Disruption in the Blood-Brain Barrier: The Missing Link between Brain and Body Inflammation in Bipolar Disorder?

    Directory of Open Access Journals (Sweden)

    Jay P. Patel

    2015-01-01

    Full Text Available The blood-brain barrier (BBB regulates the transport of micro- and macromolecules between the peripheral blood and the central nervous system (CNS in order to maintain optimal levels of essential nutrients and neurotransmitters in the brain. In addition, the BBB plays a critical role protecting the CNS against neurotoxins. There has been growing evidence that BBB disruption is associated with brain inflammatory conditions such as Alzheimer’s disease and multiple sclerosis. Considering the increasing role of inflammation and oxidative stress in the pathophysiology of bipolar disorder (BD, here we propose a novel model wherein transient or persistent disruption of BBB integrity is associated with decreased CNS protection and increased permeability of proinflammatory (e.g., cytokines, reactive oxygen species substances from the peripheral blood into the brain. These events would trigger the activation of microglial cells and promote localized damage to oligodendrocytes and the myelin sheath, ultimately compromising myelination and the integrity of neural circuits. The potential implications for research in this area and directions for future studies are discussed.

  12. Peptide-Mediated Blood-Brain Barrier Transport of Polymersomes

    NARCIS (Netherlands)

    Georgieva, J.V.; Brinkhuis, R.P.; Stojanov, K.; Weijers, C.A.G.M.; Zuilhof, H.; Rutjes, F.P.J.T.; Hoekstra, D.; Hest, van J.C.M.; Zuhorn, I.S.

    2012-01-01

    A polymeric nanocarrier: Polymersomes tagged with a dodecamer peptide that recognizes gangliosides GM1 and GT1b are shown to cross the blood–brain barrier, both in an in vitro model and in vivo (see picture). The combination of polymeric vesicles with a small GM1-binding peptide and GM1/GT1b ganglio

  13. Role of blood and vascular smooth muscle in the vasoactivity of nitrite.

    Science.gov (United States)

    Liu, Taiming; Schroeder, Hobe J; Barcelo, Lisa; Bragg, Shannon L; Terry, Michael H; Wilson, Sean M; Power, Gordon G; Blood, Arlin B

    2014-10-01

    Recent evidence from humans and rats indicates that nitrite is a vasodilator under hypoxic conditions by reacting with metal-containing proteins to produce nitric oxide (NO). We tested the hypothesis that near-physiological concentrations of nitrite would produce vasodilation in a hypoxia- and concentration-dependent manner in the hind limb of sheep. Anesthetized sheep were instrumented to measure arterial blood pressure and femoral blood flows continuously in both hind limbs. Nitrite was infused into one femoral artery to raise the nitrite concentration in the femoral vein by 10 to 15-fold while the sheep breathed 50%, 14% or 12% oxygen in inspired air. In contrast to reports in humans and rats, the nitrite infusion had no measurable effect on mean femoral blood flows or vascular conductances, regardless of inspired O2 levels. In vitro experiments showed no significant difference in the release of NO from nitrite in sheep and human red blood cells. Further experiments demonstrated nitrite is converted to NO in rat artery homogenates faster than sheep arteries, and that this source of NO production is attenuated in the presence of a heme oxidizer. Finally, western blots indicate that concentrations of the heme-containing protein cytoglobin, but not myoglobin, are markedly lower in sheep arteries compared with rats. Overall, the results demonstrate that nitrite is not a physiological vasodilator in sheep. This is likely due to a lack of conversion of nitrite to NO within the vascular smooth muscle, perhaps due to deficient amounts of the heme-containing protein cytoglobin.

  14. Mercury correlations among blood, muscle, and hair of northern elephant seals during the breeding and molting fasts

    Science.gov (United States)

    Peterson, Sarah; Ackerman, Josh; Costa, Daniel P.

    2016-01-01

    Mercury (Hg) biomonitoring and toxicological risk assessments for marine mammals commonly sample different tissues, making comparisons to toxicity benchmarks and among species and regions difficult. Few studies have examined how life history events, such as fasting, influence the relationship between total Hg (THg) concentrations in different tissues. We evaluated the relationships between THg concentrations in blood, muscle, and hair of female and male northern elephant seals (Mirounga angustirostris) at the start and end of the breeding and molting fasts. The relationships between tissues varied among tissue pairs and differed by sampling period and sex. Blood and muscle were generally related at all time periods; however, hair, an inert tissue, did not strongly represent the metabolically active tissues (blood and muscle) at all times of year. The strongest relationships between THg concentrations in hair and those in blood or muscle were observed during periods of active hair growth (end of the molting period) or during time periods when internal body conditions were similar to those when the hair was grown (end of the breeding fast). Our results indicate that THg concentrations in blood or muscle can be translated to the other tissue type using the equations we developed, but that THg concentrations in hair were generally a poor index of internal THg concentrations except during the end of fasting periods.

  15. A model for investigating the control of muscle blood flow: the masseteric artery in conscious rabbits.

    Science.gov (United States)

    Roatta, S; Mohammed, M; Turturici, M; Milano, L; Passatore, M

    2010-09-01

    The complex interplay of neural, metabolic, myogenic and mechanical mechanisms that regulate blood flow in skeletal muscle (MBF) is still incompletely understood. For the first time, a method is presented for high time-resolution recording of MBF from a purely muscular artery in physiological conditions. Ultrasound perivascular flow probes were implanted (n = 15) mono- or bilaterally around the masseteric branch of the facial artery in nine rabbits and tested up to 16 days after implant. Reliable and stable recordings were achieved in 50% of implants. Blood flow was observed to increase from a resting level of 0.2-0.3 ml min(-1) up to 4.0-6.0 ml min(-1) during spontaneous masticatory activity. In addition, within single masticatory cycles marked back flow transients could be observed (peak flow = -10 ml min(-1)) during powerful masticatory strokes but not during mild mastication. The possibility of (1) surgically removing the sympathetic supply to the relevant vascular bed and of (2) bilaterally monitoring the perfusion of masseter muscles thus allowing to use one side as control side for different types of interventions makes this model a useful tool for disentangling the different mechanisms involved in the control of MBF.

  16. Uptake mechanism of ApoE-modified nanoparticles on brain capillary endothelial cells as a blood-brain barrier model.

    Directory of Open Access Journals (Sweden)

    Sylvia Wagner

    Full Text Available BACKGROUND: The blood-brain barrier (BBB represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. CONCLUSIONS/SIGNIFICANCE: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier.

  17. Restraint stress-induced morphological changes at the blood-brain barrier in adult rats

    Directory of Open Access Journals (Sweden)

    Petra eSántha

    2016-01-01

    Full Text Available Stress is well known to contribute to the development of both neurological and psychiatric diseases. While the role of the blood-brain barrier is increasingly recognised in the development of neurodegenerative disorders, such as Alzheimer’s disease, dysfunction of the blood-brain barrier has been linked to stress-related psychiatric diseases only recently. In the present study the effects of restraint stress with different duration (1, 3 and 21 days were investigated on the morphology of the blood-brain barrier in male adult Wistar rats. Frontal cortex and hippocampus sections were immunostained for markers of brain endothelial cells (claudin-5, occludin and glucose transporter-1 and astroglia (GFAP. Staining pattern and intensity were visualized by confocal microscopy and evaluated by several types of image analysis. The ultrastructure of brain capillaries was investigated by electron microscopy. Morphological changes and intensity alterations in brain endothelial tight junction proteins claudin-5 and occludin were induced by stress. Following restraint stress significant increases in the fluorescence intensity of glucose transporter-1 were detected in brain endothelial cells in the frontal cortex and hippocampus. Significant reductions in GFAP fluorescence intensity were observed in the frontal cortex in all stress groups. As observed by electron microscopy, one-day acute stress induced morphological changes indicating damage in capillary endothelial cells in both brain regions. After 21 days of stress thicker and irregular capillary basal membranes in the hippocampus and edema in astrocytes in both regions were seen. These findings indicate that stress exerts time-dependent changes in the staining pattern of tight junction proteins occludin, claudin-5 and glucose transporter-1 at the level of brain capillaries and in the ultrastructure of brain endothelial cells and astroglial endfeet, which may contribute to neurodegenerative processes

  18. MRI confirms loss of blood-brain barrier integrity in a mouse model of disseminated candidiasis.

    Science.gov (United States)

    Navarathna, Dhammika H M L P; Munasinghe, Jeeva; Lizak, Martin J; Nayak, Debasis; McGavern, Dorian B; Roberts, David D

    2013-09-01

    Disseminated candidiasis primarily targets the kidneys and brain in mice and humans. Damage to these critical organs leads to the high mortality associated with such infections, and invasion across the blood-brain barrier can result in fungal meningoencephalitis. Candida albicans can penetrate a brain endothelial cell barrier in vitro through transcellular migration, but this mechanism has not been confirmed in vivo. MRI using the extracellular vascular contrast agent gadolinium diethylenetriaminepentaacetic acid demonstrated that integrity of the blood-brain barrier is lost during C. albicans invasion. Intravital two-photon laser scanning microscopy was used to provide the first real-time demonstration of C. albicans colonizing the living brain, where both yeast and filamentous forms of the pathogen were found. Furthermore, we adapted a previously described method utilizing MRI to monitor inflammatory cell recruitment into infected tissues in mice. Macrophages and other phagocytes were visualized in kidney and brain by the administration of ultrasmall iron oxide particles. In addition to obtaining new insights into the passage of C. albicans across the brain microvasculature, these imaging methods provide useful tools to study further the pathogenesis of C. albicans infections, to define the roles of Candida virulence genes in kidney versus brain infection and to assess new therapeutic measures for drug development.

  19. Is viscosity important in the production of blood-brain barrier disruption by intracarotid contrast media

    Energy Technology Data Exchange (ETDEWEB)

    Wilcox, J.; Sage, M.R.

    1984-11-01

    A canine model was used to investigate the effects of intracarotid methylglucamine iothalamate (280 mgI/ml) at different viscosities on the normal blood-brain barrier. To alter viscosity, without changing physicochemical parameters, injections were made at either 23/sup 0/C or 37/sup 0/C. The degree of blood-brain barrier damage was assessed using Evans' Blue dye as a visual marker and by contrast enhancement measured by a computed tomographic (CT) scanner. It was found that methylglucamine iothalamate caused more blood-brain barrier damage at 23/sup 0/C than at 37/sup 0/C (p<0.1). Control studies at each temperature using intracarotid injections of physiological saline showed no temperature effect (p>0.1). The implications of these findings are discussed.

  20. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells.

    Science.gov (United States)

    Lippmann, Ethan S; Azarin, Samira M; Kay, Jennifer E; Nessler, Randy A; Wilson, Hannah K; Al-Ahmad, Abraham; Palecek, Sean P; Shusta, Eric V

    2012-08-01

    The blood-brain barrier (BBB) is crucial to the health of the brain and is often compromised in neurological disease. Moreover, because of its barrier properties, this endothelial interface restricts uptake of neurotherapeutics. Thus, a renewable source of human BBB endothelium could spur brain research and pharmaceutical development. Here we show that endothelial cells derived from human pluripotent stem cells (hPSCs) acquire BBB properties when co-differentiated with neural cells that provide relevant cues, including those involved in Wnt/β-catenin signaling. The resulting endothelial cells have many BBB attributes, including well-organized tight junctions, appropriate expression of nutrient transporters and polarized efflux transporter activity. Notably, they respond to astrocytes, acquiring substantial barrier properties as measured by transendothelial electrical resistance (1,450 ± 140 Ω cm2), and they possess molecular permeability that correlates well with in vivo rodent blood-brain transfer coefficients.

  1. Analytical and Biological Methods for Probing the Blood-Brain Barrier

    Science.gov (United States)

    Kuhnline, Sloan; Courtney, D.; Nandi, Pradyot; Linz, Thomas H.; Aldrich, Jane V.; Audus, Kenneth L.; Lunte, Susan M.

    2012-07-01

    The blood-brain barrier (BBB) is an important interface between the peripheral and central nervous systems. It protects the brain against the infiltration of harmful substances and regulates the permeation of beneficial endogenous substances from the blood into the extracellular fluid of the brain. It can also present a major obstacle in the development of drugs that are targeted for the central nervous system. Several methods have been developed to investigate the transport and metabolism of drugs, peptides, and endogenous compounds at the BBB. In vivo methods include intravenous injection, brain perfusion, positron emission tomography, and microdialysis sampling. Researchers have also developed in vitro cell-culture models that can be employed to investigate transport and metabolism at the BBB without the complication of systemic involvement. All these methods require sensitive and selective analytical methods to monitor the transport and metabolism of the compounds of interest at the BBB.

  2. The blood-brain barrier in vitro using primary culture

    DEFF Research Database (Denmark)

    Larsen, Annette Burkhart

    of the thesis involves the establishment and characterization of an in vitro BBB models based on primary cells isolated from the rat brain. Co-culture and triple culture models with astrocytes and pericytes were found to be the superior to mono cultured BCECs with respect to many important BBB characteristics...... obstacle for the treatment of central nervous system (CNS) diseases, as many potentially CNS active drugs are unable to reach their site of action within the brain. In vitro BBB models are, therefore, being developed to investigate the BBB permeability of a drug early in its development. The first part....... In the second part of the thesis, the ability of turning BCECs into protein factories is investigated using a non-viral gene carrier. Transfection and protein synthesis of BCECs cultured with confined BBB properties were found to be feasible without disrupting the BBB properties, although it was not possible...

  3. Pathophysiology of Blood-Brain Barrier in Brain Injury in Cold and Hot Environments: Novel Drug Targets for Neuroprotection.

    Science.gov (United States)

    Sharma, Hari Shanker; Muresanu, Dafin F; Lafuente, José V; Nozari, Ala; Patnaik, Ranjana; Skaper, Stephen D; Sharma, Aruna

    2016-01-01

    The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.

  4. Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier.

    Science.gov (United States)

    Lazear, Helen M; Daniels, Brian P; Pinto, Amelia K; Huang, Albert C; Vick, Sarah C; Doyle, Sean E; Gale, Michael; Klein, Robyn S; Diamond, Michael S

    2015-04-22

    Although interferon-λ [also known as type III interferon or interleukin-28 (IL-28)/IL-29] restricts infection by several viruses, its inhibitory mechanism has remained uncertain. We used recombinant interferon-λ and mice lacking the interferon-λ receptor (IFNLR1) to evaluate the effect of interferon-λ on infection with West Nile virus, an encephalitic flavivirus. Cell culture studies in mouse keratinocytes and dendritic cells showed no direct antiviral effect of exogenous interferon-λ, even though expression of interferon-stimulated genes was induced. We observed no differences in West Nile virus burden between wild-type and Ifnlr1(-/-) mice in the draining lymph nodes, spleen, or blood. We detected increased West Nile virus infection in the brain and spinal cord of Ifnlr1(-/-) mice, yet this was not associated with a direct antiviral effect in mouse neurons. Instead, we observed an increase in blood-brain barrier permeability in Ifnlr1(-/-) mice. Treatment of mice with pegylated interferon-λ2 resulted in decreased blood-brain barrier permeability, reduced West Nile virus infection in the brain without affecting viremia, and improved survival against lethal virus challenge. An in vitro model of the blood-brain barrier showed that interferon-λ signaling in mouse brain microvascular endothelial cells increased transendothelial electrical resistance, decreased virus movement across the barrier, and modulated tight junction protein localization in a protein synthesis- and signal transducer and activator of transcription 1 (STAT1)-independent manner. Our data establish an indirect antiviral function of interferon-λ in which noncanonical signaling through IFNLR1 tightens the blood-brain barrier and restricts viral neuroinvasion and pathogenesis.

  5. Scaling of brain metabolism and blood flow in relation to capillary and neural scaling.

    Science.gov (United States)

    Karbowski, Jan

    2011-01-01

    Brain is one of the most energy demanding organs in mammals, and its total metabolic rate scales with brain volume raised to a power of around 5/6. This value is significantly higher than the more common exponent 3/4 relating whole body resting metabolism with body mass and several other physiological variables in animals and plants. This article investigates the reasons for brain allometric distinction on a level of its microvessels. Based on collected empirical data it is found that regional cerebral blood flow CBF across gray matter scales with cortical volume V as CBF ~ V(-1/6), brain capillary diameter increases as V(1/12), and density of capillary length decreases as V(-1/6). It is predicted that velocity of capillary blood is almost invariant (~V(ε)), capillary transit time scales as V(1/6), capillary length increases as V(1/6+ε), and capillary number as V(2/3-ε), where ε is typically a small correction for medium and large brains, due to blood viscosity dependence on capillary radius. It is shown that the amount of capillary length and blood flow per cortical neuron are essentially conserved across mammals. These results indicate that geometry and dynamics of global neuro-vascular coupling have a proportionate character. Moreover, cerebral metabolic, hemodynamic, and microvascular variables scale with allometric exponents that are simple multiples of 1/6, rather than 1/4, which suggests that brain metabolism is more similar to the metabolism of aerobic than resting body. Relation of these findings to brain functional imaging studies involving the link between cerebral metabolism and blood flow is also discussed.

  6. Scaling of brain metabolism and blood flow in relation to capillary and neural scaling.

    Directory of Open Access Journals (Sweden)

    Jan Karbowski

    Full Text Available Brain is one of the most energy demanding organs in mammals, and its total metabolic rate scales with brain volume raised to a power of around 5/6. This value is significantly higher than the more common exponent 3/4 relating whole body resting metabolism with body mass and several other physiological variables in animals and plants. This article investigates the reasons for brain allometric distinction on a level of its microvessels. Based on collected empirical data it is found that regional cerebral blood flow CBF across gray matter scales with cortical volume V as CBF ~ V(-1/6, brain capillary diameter increases as V(1/12, and density of capillary length decreases as V(-1/6. It is predicted that velocity of capillary blood is almost invariant (~V(ε, capillary transit time scales as V(1/6, capillary length increases as V(1/6+ε, and capillary number as V(2/3-ε, where ε is typically a small correction for medium and large brains, due to blood viscosity dependence on capillary radius. It is shown that the amount of capillary length and blood flow per cortical neuron are essentially conserved across mammals. These results indicate that geometry and dynamics of global neuro-vascular coupling have a proportionate character. Moreover, cerebral metabolic, hemodynamic, and microvascular variables scale with allometric exponents that are simple multiples of 1/6, rather than 1/4, which suggests that brain metabolism is more similar to the metabolism of aerobic than resting body. Relation of these findings to brain functional imaging studies involving the link between cerebral metabolism and blood flow is also discussed.

  7. Muscle disorder

    Science.gov (United States)

    Myopathic changes; Myopathy; Muscle problem ... Blood tests sometimes show abnormally high muscle enzymes. If a muscle disorder might also affect other family members, genetic testing may be done. When someone has symptoms and signs ...

  8. Blood BDNF concentrations reflect brain-tissue BDNF levels across species

    DEFF Research Database (Denmark)

    Klein, Anders B; Williamson, Rebecca; Santini, Martin A

    2011-01-01

    Brain-derived neurotrophic factor (BDNF) is involved in synaptic plasticity, neuronal differentiation and survival of neurons. Observations of decreased serum BDNF levels in patients with neuropsychiatric disorders have highlighted the potential of BDNF as a biomarker, but so far there have been...... positive correlation between frontal cortex and hippocampal BDNF levels in mice (r2=0.81, p=0.0139). Our data support the view that measures of blood and plasma BDNF levels reflect brain-tissue BDNF levels....

  9. Nano carriers for drug transport across the blood-brain barrier.

    Science.gov (United States)

    Li, Xinming; Tsibouklis, John; Weng, Tingting; Zhang, Buning; Yin, Guoqiang; Feng, Guangzhu; Cui, Yingde; Savina, Irina N; Mikhalovska, Lyuba I; Sandeman, Susan R; Howel, Carol A; Mikhalovsky, Sergey V

    2017-01-01

    Effective therapy lies in achieving a therapeutic amount of drug to the proper site in the body and then maintaining the desired drug concentration for a sufficient time interval to be clinically effective for treatment. The blood-brain barrier (BBB) hinders most drugs from entering the central nervous system (CNS) from the blood stream, leading to the difficulty of delivering drugs to the brain via the circulatory system for the treatment, diagnosis and prevention of brain diseases. Several brain drug delivery approaches have been developed, such as intracerebral and intracerebroventricular administration, intranasal delivery and blood-to-brain delivery, as a result of transient BBB disruption induced by biological, chemical or physical stimuli such as zonula occludens toxin, mannitol, magnetic heating and ultrasound, but these approaches showed disadvantages of being dangerous, high cost and unsuitability for most brain diseases and drugs. The strategy of vector-mediated blood-to-brain delivery, which involves improving BBB permeability of the drug-carrier conjugate, can minimize side effects, such as being submicrometre objects that behave as a whole unit in terms of their transport and properties, nanomaterials, are promising carrier vehicles for direct drug transport across the intact BBB as a result of their potential to enter the brain capillary endothelial cells by means of normal endocytosis and transcytosis due to their small size, as well as their possibility of being functionalized with multiple copies of the drug molecule of interest. This review provids a concise discussion of nano carriers for drug transport across the intact BBB, various forms of nanomaterials including inorganic/solid lipid/polymeric nanoparticles, nanoemulsions, quantum dots, nanogels, liposomes, micelles, dendrimers, polymersomes and exosomes are critically evaluated, their mechanisms for drug transport across the BBB are reviewed, and the future directions of this area are fully

  10. Evaluation of blood-brain barrier-stealth nanocomposites for in situ glioblastoma theranostics applications

    Science.gov (United States)

    Su, Chia-Hao; Tsai, Ching-Yi; Tomanek, Boguslaw; Chen, Wei-Yu; Cheng, Fong-Yu

    2016-04-01

    The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy.The blood-brain barrier (BBB) is a physiological structure of the blood vessels in the brain. The BBB efficiently traps most therapeutic drugs in the blood vessels and stops them from entering the brain tissue, resulting in a decreased therapeutic efficiency. In this study, we developed BBB-stealth nanocomposites composed of iron oxide (Fe3O4) nanoparticles (NPs) as a safe nanocarrier for glioblastoma therapy. We showed the antitumor activity of Dox/alg-Fe3O4 NPs using in vitro and in vivo tests. We demonstrated that G23-alg-Fe3O4 NPs crossed the BBB and entered the brain. In situ glioblastoma tumor-bearing mice were used to successfully evaluate the antitumor activity of G23-Dox/alg-Fe3O4 NPs. Magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) confirmed the BBB crossing. The BBB-stealth nanocomposites show great potential for a proof-of-concept clinical trial as a theranostics platform for human brain tumor therapy. Electronic supplementary information (ESI) available: Experimental details. See DOI: 10.1039/c6nr00280c

  11. The Role of P-Glycoprotein in Transport of Danshensu across the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Peng-Fei Yu

    2011-01-01

    Full Text Available Danshensu (3-(3, 4-dihydroxyphenyl lactic acid, a water-soluble active component isolated from the root of Salvia miltiorrhiza Bunge, is widely used for the treatment of cerebrovascular diseases. The present study aims to investigate the role of P-glycoprotein in transport of Danshensu across the blood-brain barrier. Sprague-Dawley rats were pretreated with verapamil at a dose of 20 mg kg−1 (verapamil group or the same volume of normal saline (control group. Ninety minutes later, the animals were administrated with Danshensu (15 mg kg−1 by intravenous injection. At 15 min, 30 min, and 60 min after Danshensu administration, the levels of Danshensu in the blood and brain were detected by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS. The results showed that Danshensu concentrations in the brain of the rats pretreated with verapamil were significantly increased. In addition, the brain-plasma ratios of the group pretreated with verapamil were much higher than that of the control group. There was no difference in Danshensu level in plasma between the verapamil group and control group. The findings indicated that Danshensu can pass the blood-brain barrier, and P-glycoprotein plays an important role in Danshensu transportation in brain.

  12. Targeted blood-to-brain drug delivery --10 key development criteria.

    Science.gov (United States)

    Gaillard, Pieter J; Visser, Corine C; Appeldoorn, Chantal C M; Rip, Jaap

    2012-09-01

    Drug delivery to the brain remains challenging due to the presence of the blood-brain barrier. In this review, 10 key development criteria are presented that are important for successful drug development to treat CNS diseases by targeted drug delivery systems. Although several routes of delivery are being investigated, such as intranasal delivery, direct injections into the brain or CSF, and transient opening of the blood-brain barrier, the focus of this review is on physiological strategies aiming to target endogenous transport mechanisms. Examples from literature, focusing on targeted drug delivery systems that are being commercially developed, will be discussed to illustrate the 10 key development criteria. The first four criteria apply to the targeting of the blood-brain barrier: (1) a proven inherently safe receptor biology, (2) a safe and human applicable ligand, (3) receptor specific binding, and (4) applicable for acute and chronic indications. Next to an efficient and safe targeting strategy, as captured in key criteria 1 to 4, a favorable pharmacokinetic profile is also important (key criterion 5). With regard to the drug carriers, two criteria are important: (6) no modification of active ingredient and (7) able to carry various classes of molecules. The final three criteria apply to the development of a drug from lab to clinic: (8) low costs and straightforward manufacturing, (9) activity in all animal models, and (10) strong intellectual property (IP) protection. Adhering to these 10 key development criteria will allow for a successful brain drug development.

  13. Minocycline ameliorates prenatal valproic acid induced autistic behaviour, biochemistry and blood brain barrier impairments in rats.

    Science.gov (United States)

    Kumar, Hariom; Sharma, Bhupesh

    2016-01-01

    Autism is a neurodevelopment disorder. One percent worldwide population suffers with autism and males suffer more than females. Microglia plays an important role in neurodevelopment, neuropsychiatric and neurodegenerative disorders. The present study has been designed to investigate the role of minocycline in prenatal valproic acid induced autism in rats. Animals with prenatal valproic acid have reduced social interaction (three chamber social behaviour apparatus), spontaneous alteration (Y-Maze), exploratory activity (Hole board test), intestinal motility, serotonin levels (both in prefrontal cortex and ileum) and prefrontal cortex mitochondrial complex activity (complexes I, II, IV). Furthermore, prenatal valproic acid treated animals have shown an increase in locomotion (actophotometer), anxiety (elevated plus maze), brain oxidative stress (thiobarbituric acid reactive species, glutathione, catalase), nitrosative stress (nitrite/nitrate), inflammation (both in brain and ileum myeloperoxidase activity), calcium and blood brain barrier permeability. Treatment with minocycline significantly attenuated prenatal valproic acid induced reduction in social interaction, spontaneous alteration, exploratory activity intestinal motility, serotonin levels and prefrontal cortex mitochondrial complex activity. Furthermore, minocycline has also attenuated prenatal valproic acid induced increase in locomotion, anxiety, brain oxidative and nitrosative stress, inflammation, calcium and blood brain barrier permeability. Thus, it may be concluded that prenatal valproic acid has induced autistic behaviour, biochemistry and blood brain barrier impairment in animals, which were significantly attenuated by minocycline. Minocycline should be explored further for its therapeutic benefits in autism.

  14. The Transferrin Receptor at the Blood-Brain Barrier - exploring the possibilities for brain drug delivery

    NARCIS (Netherlands)

    Visser, Corine

    2005-01-01

    There are many diseases of the central nervous system (CNS), like Parkinson's disease, Alzheimer's disease, depression, schizophrenia, epilepsy, migraine headache, and HIV infection in the brain. However, treatment is difficult since many drugs cannot reach the brain in sufficient quantities due to

  15. A brain-machine-muscle interface for restoring hindlimb locomotion after complete spinal transection in rats.

    Directory of Open Access Journals (Sweden)

    Monzurul Alam

    Full Text Available A brain-machine interface (BMI is a neuroprosthetic device that can restore motor function of individuals with paralysis. Although the feasibility of BMI control of upper-limb neuroprostheses has been demonstrated, a BMI for the restoration of lower-limb motor functions has not yet been developed. The objective of this study was to determine if gait-related information can be captured from neural activity recorded from the primary motor cortex of rats, and if this neural information can be used to stimulate paralysed hindlimb muscles after complete spinal cord transection. Neural activity was recorded from the hindlimb area of the primary motor cortex of six female Sprague Dawley rats during treadmill locomotion before and after mid-thoracic transection. Before spinal transection there was a strong association between neural activity and the step cycle. This association decreased after spinal transection. However, the locomotive state (standing vs. walking could still be successfully decoded from neural recordings made after spinal transection. A novel BMI device was developed that processed this neural information in real-time and used it to control electrical stimulation of paralysed hindlimb muscles. This system was able to elicit hindlimb muscle contractions that mimicked forelimb stepping. We propose this lower-limb BMI as a future neuroprosthesis for human paraplegics.

  16. Brain Functional Connectivity is Different during VoluntaryConcentric and Eccentric Muscle Contraction

    Directory of Open Access Journals (Sweden)

    Wan X Yao

    2016-11-01

    Full Text Available Previous studies report greater activation in the cortical motor network in controlling eccentric contraction (EC than concentric contraction (CC of human skeletal muscles despite lower activation level of the muscle associated with EC. It is unknown, however, whether the strength of functional coupling between the primary motor cortex (M1 and other involved areas in the brain differs as voluntary movements are controlled by a network of regions in the primary, secondary and association cortices. Examining fMRI-based functional connectivity (FC offers an opportunity to measure strength of such coupling. To address the question, we examined functional MRI (fMRI data acquired during EC and CC (20 contractions each with similar movement distance and speed of the right first dorsal interosseous (FDI muscle in 11 young (20-32 years and healthy individuals and estimated FC between the M1 and a number of cortical regions in the motor control network. The major findings from the behavioral and fMRI-based FC analysis were that (1 no significant differences were seen in movement distance, speed and stability between the EC and CC; (2 significantly stronger mean FC was found for CC than EC. Our finding provides novel insights for a better understanding of the control mechanisms underlying voluntary movements produced by EC and CC. The finding is potentially helpful for guiding the development of targeted sport training and/or therapeutic programs for performance enhancement and injury prevention.

  17. Brain-muscle-computer interface: mobile-phone prototype development and testing.

    Science.gov (United States)

    Vernon, Scott; Joshi, Sanjay S

    2011-07-01

    We report prototype development and testing of a new mobile-phone-based brain-muscle-computer interface for severely paralyzed persons, based on previous results from our group showing that humans may actively create specified power levels in two separate frequency bands of a single surface electromyography (sEMG) signal. EMG activity on the surface of a single face muscle site (auricularis superior) is recorded with a standard electrode. This analog electrical signal is imported into an Android-based mobile phone and digitized via an internal A/D converter. The digital signal is split, and then simultaneously filtered with two band-pass filters to extract total power within two separate frequency bands. The user-modulated power in each frequency band serves as two separate control channels for machine control. After signal processing, the Android phone sends commands to external devices via a Bluetooth interface. Users are trained to use the device via visually based operant conditioning, with simple cursor-to-target activities on the phone screen. The mobile-phone prototype interface is formally evaluated on a single advanced Spinal Muscle Atrophy subject, who has successfully used the interface in his home in evaluation trials and for remote control of a television. Development of this new device will not only guide future interface design for community use, but will also serve as an information technology bridge for in situ data collection to quantify human sEMG manipulation abilities for a relevant population.

  18. Longer repetition duration increases muscle activation and blood lactate response in matched resistance training protocols

    Directory of Open Access Journals (Sweden)

    Hugo Cesar Martins-Costa

    2016-03-01

    Full Text Available Abstract This study analyzed the effect of different repetition durations on electromyographic and blood lactate responses of the bench press exercise. Fifteen recreationally trained male volunteers completed two training protocols, matched for intensity (% one-repetition maximum; 1RM, number of sets, number of repetitions, and rest intervals. One of the protocols was performed with a repetition duration of 4 s (2 s concentric: 2 s eccentric; 2:2 protocol, whereas the second protocol had a repetition duration of 6 s (2 s concentric: 4 s eccentric; 2:4 protocol. The results showed higher normalized integrated electromyography (pectoralis major and triceps brachii for the 2:4 protocol. Blood lactate concentration was also higher in the 2:4 protocol across all sets. These results show that adding 2 s to the eccentric action in matched training protocols increases muscle activation and blood lactate response, which reinforces the notion that increasing repetition duration is an alternative load progression in resistance training.

  19. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity.

    Science.gov (United States)

    Unhavaithaya, Yingdee; Orr-Weaver, Terry L

    2012-01-01

    Proper development requires coordination in growth of the cell types composing an organ. Many plant and animal cells are polyploid, but how these polyploid tissues contribute to organ growth is not well understood. We found the Drosophila melanogaster subperineurial glia (SPG) to be polyploid, and ploidy is coordinated with brain mass. Inhibition of SPG polyploidy caused rupture of the septate junctions necessary for the blood-brain barrier. Thus, the increased SPG cell size resulting from polyploidization is required to maintain the SPG envelope surrounding the growing brain. Polyploidization likely is a conserved strategy to coordinate tissue growth during organogenesis, with potential vertebrate examples.

  20. Arginine-Vasopressin Receptor Blocker Conivaptan Reduces Brain Edema and Blood-Brain Barrier Disruption after Experimental Stroke in Mice.

    Directory of Open Access Journals (Sweden)

    Emil Zeynalov

    Full Text Available Stroke is a major cause of morbidity and mortality. Stroke is complicated by brain edema and blood-brain barrier (BBB disruption, and is often accompanied by increased release of arginine-vasopressin (AVP. AVP acts through V1a and V2 receptors to trigger hyponatremia, vasospasm, and platelet aggregation which can exacerbate brain edema. The AVP receptor blockers conivaptan (V1a and V2 and tolvaptan (V2 are used to correct hyponatremia, but their effect on post-ischemic brain edema and BBB disruption remains to be elucidated. Therefore, we conducted this study to investigate if these drugs can prevent brain edema and BBB disruption in mice after stroke.Experimental mice underwent the filament model of middle cerebral artery occlusion (MCAO with reperfusion. Mice were treated with conivaptan, tolvaptan, or vehicle. Treatments were initiated immediately at reperfusion and administered IV (conivaptan or orally (tolvaptan for 48 hours. Physiological variables, neurological deficit scores (NDS, plasma and urine sodium and osmolality were recorded. Brain water content (BWC and Evans Blue (EB extravasation index were evaluated at the end point.Both conivaptan and tolvaptan produced aquaresis as indicated by changes in plasma and urine sodium levels. However plasma and urine osmolality was changed only by conivaptan. Unlike tolvaptan, conivaptan improved NDS and reduced BWC in the ipsilateral hemisphere: from 81.66 ± 0.43% (vehicle to 78.28 ± 0.48% (conivaptan, 0.2 mg, p < 0.05 vs vehicle. Conivaptan also attenuated the EB extravasation from 1.22 ± 0.08 (vehicle to 1.01 ± 0.02 (conivaptan, 0.2 mg, p < 0.05.Continuous IV infusion with conivaptan for 48 hours after experimental stroke reduces brain edema, and BBB disruption. Conivaptan but not tolvaptan may potentially be used in patients to prevent brain edema after stroke.

  1. Volatile anesthetics influence blood-brain barrier integrity by modulation of tight junction protein expression in traumatic brain injury.

    Directory of Open Access Journals (Sweden)

    Serge C Thal

    Full Text Available Disruption of the blood-brain barrier (BBB results in cerebral edema formation, which is a major cause for high mortality after traumatic brain injury (TBI. As anesthetic care is mandatory in patients suffering from severe TBI it may be important to elucidate the effect of different anesthetics on cerebral edema formation. Tight junction proteins (TJ such as zonula occludens-1 (ZO-1 and claudin-5 (cl5 play a central role for BBB stability. First, the influence of the volatile anesthetics sevoflurane and isoflurane on in-vitro BBB integrity was investigated by quantification of the electrical resistance (TEER in murine brain endothelial monolayers and neurovascular co-cultures of the BBB. Secondly brain edema and TJ expression of ZO-1 and cl5 were measured in-vivo after exposure towards volatile anesthetics in native mice and after controlled cortical impact (CCI. In in-vitro endothelial monocultures, both anesthetics significantly reduced TEER within 24 hours after exposure. In BBB co-cultures mimicking the neurovascular unit (NVU volatile anesthetics had no impact on TEER. In healthy mice, anesthesia did not influence brain water content and TJ expression, while 24 hours after CCI brain water content increased significantly stronger with isoflurane compared to sevoflurane. In line with the brain edema data, ZO-1 expression was significantly higher in sevoflurane compared to isoflurane exposed CCI animals. Immunohistochemical analyses revealed disruption of ZO-1 at the cerebrovascular level, while cl5 was less affected in the pericontusional area. The study demonstrates that anesthetics influence brain edema formation after experimental TBI. This effect may be attributed to modulation of BBB permeability by differential TJ protein expression. Therefore, selection of anesthetics may influence the barrier function and introduce a strong bias in experimental research on pathophysiology of BBB dysfunction. Future research is required to investigate

  2. Blood-brain barrier P-glycoprotein function in neurodegenerative disease.

    Science.gov (United States)

    Bartels, A L

    2011-01-01

    Protection of the brain is strengthened by active transport and ABC transporters. P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a substrate from the brain, which is important for maintaining loco-regional homeostasis in the brain and protection against toxic compounds. Importantly, dysfunctional BBB P-gp transport is postulated as an important factor contributing to accumulation of aggregated protein in neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, P-gp is a major factor in mediating resistance to brain entry of numerous exogenous compounds, including toxins that can be involved in PD pathogenesis. This review highlights the role of altered P-gp function in the pathogenesis and progression of neurodegenerative disease. Also the implications of alterations in P-gp function for the treatment of these diseases are discussed.

  3. Effect of combining traction and vibration on back muscles, heart rate and blood pressure.

    Science.gov (United States)

    Wang, Lizhen; Zhao, Meiya; Ma, Jian; Tian, Shan; Xiang, Pin; Yao, Wei; Fan, Yubo

    2014-11-01

    Eighty-five percent of the population has experienced low back pain (LBP), which may result in decreasing muscle strength and endurance, functional capacity of the spine, and so on. Traction and vibration are commonly used to relieve the low back pain. The effect of the combing traction and vibration on back muscles, heart rate (HR) and blood pressure (BP) was investigated in this study. Thirty healthy subjects participated in 12 trials lying supine on the spine-combing bed with different tilt angle (0°, 10°, 20° and 30°) and vibration modes (along with the sagittal and coronal axis with 0 Hz, 2 Hz and 12 Hz separately). EMG was recorded during each trial. Power spectral frequency analysis was applied to evaluate muscle fatigue by the shift of median power frequency (MPF). Pulse pressure (PP) was calculated from BP. HR and PP were used to estimate the effect of the combination of traction and vibration on the cardio-vascular system. It was shown that vibration could increase HR and decrease PP. The combination of traction and vibration (2 Hz vibration along Z-axis and 12 Hz vibration along Y-axis) had no significant effect on the cardio-vascular system. The MPF of lumbar erector spinae (LES) and upper trapezius (UT) decreased significantly when the angle reached 20° under the condition of 2 Hz vibration along Z-axis compared with it of 0°. Furthermore, the MPF also decreased significantly compared with it of static mode at 20° for LES and at 30° for UT. However at 12 Hz vibration along Y-axis, the MPF had significant increase when the angle reached 20° in LES and 30° in UT compared to 0°. For LES, the MPF also had significant difference when the angle was increased from 10° to 20°. Therefore, combining 2 Hz vibration along Z-axis and traction (tilt angles that less than 20°) may to reduce muscle fatigue both for LES and UT compared with either vibration or traction alone. The combination of 12 Hz vibration along Y-axis and traction (tilt angles

  4. Getting into the brain: liposome-based strategies for effective drug delivery across the blood-brain barrier.

    Science.gov (United States)

    Vieira, Débora B; Gamarra, Lionel F

    This review summarizes articles that have been reported in literature on liposome-based strategies for effective drug delivery across the blood-brain barrier. Due to their unique physicochemical characteristics, liposomes have been widely investigated for their application in drug delivery and in vivo bioimaging for the treatment and/or diagnosis of neurological diseases, such as Alzheimer's, Parkinson's, stroke, and glioma. Several strategies have been used to deliver drug and/or imaging agents to the brain. Covalent ligation of such macromolecules as peptides, antibodies, and RNA aptamers is an effective method for receptor-targeting liposomes, which allows their blood-brain barrier penetration and/or the delivery of their therapeutic molecule specifically to the disease site. Additionally, methods have been employed for the development of liposomes that can respond to external stimuli. It can be concluded that the development of liposomes for brain delivery is still in its infancy, although these systems have the potential to revolutionize the ways in which medicine is administered.

  5. Drug Delivery Systems, CNS Protection, and the Blood Brain Barrier

    Directory of Open Access Journals (Sweden)

    Ravi Kant Upadhyay

    2014-01-01

    Full Text Available Present review highlights various drug delivery systems used for delivery of pharmaceutical agents mainly antibiotics, antineoplastic agents, neuropeptides, and other therapeutic substances through the endothelial capillaries (BBB for CNS therapeutics. In addition, the use of ultrasound in delivery of therapeutic agents/biomolecules such as proline rich peptides, prodrugs, radiopharmaceuticals, proteins, immunoglobulins, and chimeric peptides to the target sites in deep tissue locations inside tumor sites of brain has been explained. In addition, therapeutic applications of various types of nanoparticles such as chitosan based nanomers, dendrimers, carbon nanotubes, niosomes, beta cyclodextrin carriers, cholesterol mediated cationic solid lipid nanoparticles, colloidal drug carriers, liposomes, and micelles have been discussed with their recent advancements. Emphasis has been given on the need of physiological and therapeutic optimization of existing drug delivery methods and their carriers to deliver therapeutic amount of drug into the brain for treatment of various neurological diseases and disorders. Further, strong recommendations are being made to develop nanosized drug carriers/vehicles and noninvasive therapeutic alternatives of conventional methods for better therapeutics of CNS related diseases. Hence, there is an urgent need to design nontoxic biocompatible drugs and develop noninvasive delivery methods to check posttreatment clinical fatalities in neuropatients which occur due to existing highly toxic invasive drugs and treatment methods.

  6. The relationship between blood and muscle samples to monitor for residues of the antibiotic enrofloxacin in chickens.

    Science.gov (United States)

    Reyes-Herrera, I; Schneider, M J; Blore, P J; Donoghue, D J

    2011-02-01

    In 2005, the US Food and Drug Administration withdrew approval for use of enrofloxacin in poultry, thus effectively imposing zero tolerance for residues of this antibiotic in poultry. Conventional residue monitoring for most antibiotics, including enrofloxacin, involves removing poultry carcasses from the processing line and collecting muscle tissues for analysis. Because of the loss of valuable edible products and the difficulties and expense of sampling all the carcasses, only a small portion of carcasses are tested for violative residues. Unlike muscle tissue, blood is readily available from all birds at the beginning of processing and may be used to screen for illegal residues in all poultry carcasses. It is unknown, however, if enrofloxacin concentrations in blood are predictive of muscle concentrations. In an effort to evaluate this relationship, 156 broiler chickens, 5 wk of age, were dosed with either 25 or 50 µg/mL of enrofloxacin for 3 or 7 d, respectively, in the drinking water. Blood and muscle samples were collected at 0, 1, 3, 6, 12, and 24 h (n = 6 birds/group) during the first dosing day, every 48 h during the dosing period, and every 12 h during the withdrawal period for up to 60 h after withdrawal. Enrofloxacin residues were determined in all blood and tissue samples during the dosing periods and in most of the withdrawal period for both doses. These results support the potential to use blood to screen for illegal enrofloxacin residues in edible poultry tissues in an effort to protect the human food supply.

  7. Uptake and biodistribution of rizatriptan to blood and brain following different routes of administration in rats.

    Science.gov (United States)

    Wang, Chun; Quan, Li-Hui; Guo, Yi; Liu, Chun-Yu; Liao, Yong-Hong

    2007-06-07

    The objective of the present study was to investigate the biodistribution profiles of rizatriptan in the blood and brain of Wistar rats after peroral, subcutaneous, intranasal and intratracheal administration with a particular view to determining the applicability of inhalation delivery to achieve rapid and high availability of the drug in both blood and the brain. Following the intratracheal administration of the drug (4.0mg/kg) to the rats, the absolute bioavailability was found to be 91.2%, significantly higher than those from intranasal or peroral routes, and T(max) in plasma and brain was attained within 2 min, significantly shorter than the T(max) of intranasal ( approximately 10 min in both plasma and brain), subcutaneous (16.7 min in plasma and 22.5 min in brain) and peroral (30.0 min in plasma and 45.0 min in brain) administration. In addition, other pharmacokinetic parameters associated with rapid onset of action including AUC(plasma/brain) and C(max), of intratracheal instillated rizatriptan appeared also to be comparable or superior to those of other delivered routes. Although AUC(brain)/AUC(plasma) ratios after intranasal delivery (43.4%) differed significantly from the ratios shown after intratracheal instillation (23.2%), the AUC(brain 0-120 min) via the latter routes was slightly but not significantly higher than that from the former routes. The results in the present study indicated that pulmonary delivery of rizatriptan may achieve maximum plasma and brain concentrations significantly more rapidly compared with intranasal, subcutaneous and peroral administration and be a promising delivery method with extremely rapid onset of action in the pain relief of migraine.

  8. Delayed onset muscle soreness and perceived exertion following blood flow restriction exercise.

    Science.gov (United States)

    Brandner, Christopher R; Warmington, Stuart A

    2017-01-11

    The purpose of this study was to determine the perceptual responses to resistance exercise with either heavy-loads (80% 1 repetition maximum [1-RM]), light-loads (20% 1-RM), or light-loads in combination with blood flow restriction (BFR). Despite the use of light-loads, it has been suggested that the adoption of BFR resistance exercise may be limited due to increases in delayed onset muscle soreness (DOMS) and perceived exertion. Seventeen healthy untrained males participated in this balanced, randomized cross-over study. Following four sets of elbow-flexion exercise, participants reported ratings of perceived exertion (RPE), with DOMS also recorded for seven days following each trial. DOMS was significantly greater for low-pressure continuous BFR (until 48 h post-exercise) and high-pressure intermittent BFR (until 72 h post-exercise) compared with traditional heavy-load and light-load resistance exercise. In addition, RPE was higher for heavy-load resistance exercise and high-pressure intermittent BFR compared with low-pressure continuous BFR, with all trials greater than light-load resistance exercise. For practitioners working with untrained participants, this study provides evidence to suggest that in order to minimize the perception of effort and post-exercise muscle soreness associated with BFR resistance exercise, continuous low-pressure application may be more preferential compared with intermittent high-pressure application. Importantly, these perceptual responses are relatively short-lived (∼2 days) and have previously been shown to subside after a few exercise sessions. Combined with smaller initial training volumes (set x repetitions) this may limit RPE and DOMS to strengthen uptake and adherence, and assist in program progression for muscle hypertrophy and gains in strength.

  9. Human Brain Microvascular Endothelial Cells Derived from the BC1 iPS Cell Line Exhibit a Blood-Brain Barrier Phenotype

    OpenAIRE

    Katt, Moriah E.; Xu, Zinnia S.; Gerecht, Sharon; Searson, Peter C.

    2016-01-01

    The endothelial cells that form capillaries in the brain are highly specialized, with tight junctions that minimize paracellular transport and an array of broad-spectrum efflux pumps that make drug delivery to the brain extremely challenging. One of the major limitations in blood-brain barrier research and the development of drugs to treat central nervous system diseases is the lack of appropriate cell lines. Recent reports indicate that the derivation of human brain microvascular endothelial...

  10. A Mixed Approach for Modeling Blood Flow in Brain Microcirculation

    Science.gov (United States)

    Peyrounette, M.; Sylvie, L.; Davit, Y.; Quintard, M.

    2014-12-01

    We have previously demonstrated [1] that the vascular system of the healthy human brain cortex is a superposition of two structural components, each corresponding to a different spatial scale. At small-scale, the vascular network has a capillary structure, which is homogeneous and space-filling over a cut-off length. At larger scale, veins and arteries conform to a quasi-fractal branched structure. This structural duality is consistent with the functional duality of the vasculature, i.e. distribution and exchange. From a modeling perspective, this can be viewed as the superposition of: (a) a continuum model describing slow transport in the small-scale capillary network, characterized by a representative elementary volume and effective properties; and (b) a discrete network approach [2] describing fast transport in the arterial and venous network, which cannot be homogenized because of its fractal nature. This problematic is analogous to modeling problems encountered in geological media, e.g, in petroleum engineering, where fast conducting channels (wells or fractures) are embedded in a porous medium (reservoir rock). An efficient method to reduce the computational cost of fractures/continuum simulations is to use relatively large grid blocks for the continuum model. However, this also makes it difficult to accurately couple both structural components. In this work, we solve this issue by adapting the "well model" concept used in petroleum engineering [3] to brain specific 3-D situations. We obtain a unique linear system of equations describing the discrete network, the continuum and the well model coupling. Results are presented for realistic geometries and compared with a non-homogenized small-scale network model of an idealized periodic capillary network of known permeability. [1] Lorthois & Cassot, J. Theor. Biol. 262, 614-633, 2010. [2] Lorthois et al., Neuroimage 54 : 1031-1042, 2011. [3] Peaceman, SPE J. 18, 183-194, 1978.

  11. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Luisa Ciobanu

    Full Text Available During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine. We showed that the brain/vessels contrast in T(2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.

  12. Theranastic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, Gert; Zandvoort, van Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanop

  13. Theranostic USPIO-loaded microbubbles for mediating and monitoring blood-brain barrier permeation

    NARCIS (Netherlands)

    Lammers, Twan; Koczera, Patrick; Fokong, Stanley; Gremse, Felix; Ehling, Josef; Vogt, Michael; Pich, Andrij; Storm, G; Van Zandvoort, Marc; Kiessling, Fabian

    2015-01-01

    Efficient and safe drug delivery across the blood-brain barrier (BBB) remains one of the major challenges of biomedical and (nano-) pharmaceutical research. Here, it is demonstrated that poly(butyl cyanoacrylate)-based microbubbles (MB), carrying ultrasmall superparamagnetic iron oxide (USPIO) nanop

  14. Dynamic Perfusion CT Assessment of the Blood-Brain Barrier Permeability : First Pass versus Delayed Acquisition

    NARCIS (Netherlands)

    Dankbaar, J. W.; Hom, J.; Schneider, T.; Cheng, S. -C.; Lau, B. C.; van der Schaaf, I.; Virmani, S.; Pohlman, S.; Dillon, W. P.; Wintermark, M.

    2008-01-01

    BACKGROUND AND PURPOSE: The Patlak model has been applied to first-pass perfusion CT (PCT) data to extract information on blood-brain barrier permeability (BBBP) to predict hemorrhagic transformation in patients with acute stroke. However, the Patlak model was originally described for the delayed st

  15. Distribution of dearomatised white spirit in brain, blood, and fat tissue after repeated exposure of rats

    DEFF Research Database (Denmark)

    Lof, A.; Lam, Henrik Rye; Gullstrand, E.

    1999-01-01

    spirit was 1.5 and 5.6 mg/kg in blood; 7.1 and 17.1 mg/kg in brain; 432 and 1452 mg/kg in fat tissue at the exposure levels of 400 and 800 p.p.m., respectively. The concentrations of n-nonane, n-decane, n-undecane, and total white spirit in blood and brain were not affected by the duration of exposure....... Two hours after the end of exposure the n-decane concentration decreased to about 25% in blood and 50% in brain. A similar pattern of elimination was also observed for n-nonane, n-undecane and total white spirit in blood and brain. In fat tissue the concentrations of n-nonane, n-decane, n......-undecane, and total white spirit increased during the 3 weeks of exposure. The time to reach steady-state concentrations is longer than 3 weeks. After the 3 weeks' exposure the fat tissue concentration of n-nonane, n-decane, n-undecane, and total white spirit decreased very slowly compared with the rate of decrease...

  16. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II: Potential mechanisms

    NARCIS (Netherlands)

    van Vliet, E.A.; Otte, W.M.; Wadman, W.J.; Aronica, E.; Kooij, G.; de Vries, H.E.; Dijkhuizen, R.M.; Gorter, J.A.

    2016-01-01

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activit

  17. Blood-brain barrier leakage after status epilepticus in rapamycin-treated rats II : Potential mechanisms

    NARCIS (Netherlands)

    van Vliet, Erwin A; Otte, Wim M; Wadman, Wytse J; Aronica, Eleonora; Kooij, Gijs; de Vries, Helga E; Dijkhuizen, Rick M; Gorter, Jan A

    2016-01-01

    OBJECTIVE: Blood-brain barrier (BBB) leakage may play a pro-epileptogenic role after status epilepticus. In the accompanying contrast-enhanced magnetic resonance imaging (CE-MRI) study we showed that the mammalian target of rapamycin (mTOR) inhibitor rapamycin reduced BBB leakage and seizure activit

  18. Does sumatriptan cross the blood-brain barrier in animals and man?

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer

    2010-01-01

    Sumatriptan, a relatively hydrophilic triptan, based on several animal studies has been regarded to be unable to cross the blood-brain barrier (BBB). In more recent animal studies there are strong indications that sumatriptan to some extent can cross the BBB. The CNS adverse events of sumatriptan...

  19. Early development of arterial spin labeling to measure regional brain blood flow by MRI.

    Science.gov (United States)

    Koretsky, Alan P

    2012-08-15

    Two major avenues of work converged in the late 1980's and early 1990's to give rise to brain perfusion MRI. The development of anatomical brain MRI quickly had as a major goal the generation of angiograms using tricks to label flowing blood in macroscopic vessels. These ideas were aimed at getting information about microcirculatory flow as well. Over the same time course the development of in vivo magnetic resonance spectroscopy had as its primary goal the assessment of tissue function and in particular, tissue energetics. For this the measurement of the delivery of water to tissue was critical for assessing tissue oxygenation and viability. The measurement of the washin/washout of "freely" diffusible tracers by spectroscopic based techniques pointed the way for quantitative approaches to measure regional blood flow by MRI. These two avenues came together in the development of arterial spin labeling (ASL) MRI techniques to measure regional cerebral blood flow. The early use of ASL to measure brain activation to help verify BOLD fMRI led to a rapid development of ASL based perfusion MRI. Today development and applications of regional brain blood flow measurements with ASL continues to be a major area of activity.

  20. Focused Ultrasound-Induced Neurogenesis Requires an Increase in Blood-Brain Barrier Permeability

    Science.gov (United States)

    Mooney, Skyler J.; Shah, Kairavi; Yeung, Sharon; Burgess, Alison; Aubert, Isabelle; Hynynen, Kullervo

    2016-01-01

    Transcranial focused ultrasound technology used to transiently open the blood-brain barrier, is capable of stimulating hippocampal neurogenesis; however, it is not yet known what aspects of the treatment are necessary for enhanced neurogenesis to occur. The present study set out to determine whether the opening of blood-brain barrier, the specific pressure amplitudes of focused ultrasound, and/or the intravenous administration of microbubbles (phospholipid microspheres) are necessary for the enhancement of neurogenesis. Specifically, mice were exposed to burst (10ms, 1Hz burst repetition frequency) focused ultrasound at the frequency of 1.68MHz and with 0.39, 0.78, 1.56 and 3.0MPa pressure amplitudes. These treatments were also conducted with or without microbubbles, at 0.39 + 0.78MPa or 1.56 + 3.0MPa, respectively. Only focused ultrasound at the ~0.78 MPa pressure amplitude with microbubbles promoted hippocampal neurogenesis and was associated with an increase in blood-brain barrier permeability. These results suggest that focused ultrasound -mediated neurogenesis is dependent upon the opening of the blood-brain barrier. PMID:27459643

  1. Blood-brain barrier P-glycoprotein function is not impaired in early Parkinson's disease

    NARCIS (Netherlands)

    Bartels, A. L.; van Berckel, B. N. M.; Lubberink, M.; Luurtsema, G.; Lammertsma, A. A.; Leenders, K. L.

    2008-01-01

    The cause of Parkinson's disease (PD) is unknown. Genetic susceptibility and exposure to environmental toxins contribute to specific neuronal loss in PD. Decreased blood-brain barrier (BBB) P-glycoprotein (P-gp) efflux function has been proposed as a possible causative link between toxin exposure an

  2. Average blood flow and oxygen uptake in the human brain during resting wakefulness

    DEFF Research Database (Denmark)

    Madsen, P L; Holm, S; Herning, M;

    1993-01-01

    tracer between the brain and its venous blood is not reached. As a consequence, normal values for CBF and CMRO2 of 54 ml 100 g-1 min-1 and 3.5 ml 100 g-1 min-1 obtained with the Kety-Schmidt technique are an overestimation of the true values. Using the Kety-Schmidt technique we have performed 57...

  3. Blood Brain Barrier Dysfunction and Delayed Neurological Deficits in Mild Traumatic Brain Injury Induced by Blast Shock Waves

    Directory of Open Access Journals (Sweden)

    Ashok K Shetty

    2014-08-01

    Full Text Available Mild traumatic brain injury (mTBI resulting from exposure to blast shock waves (BSWs is one of the most predominant causes of illnesses among veterans who served in the recent Iraq and Afghanistan wars. Such mTBI can also happen to civilians if exposed to shock waves of bomb attacks by terrorists. While cognitive problems, memory dysfunction, depression, anxiety and diffuse white matter injury have been observed at both early and/or delayed time-points, an initial brain pathology resulting from exposure to BSWs appears to be the dysfunction or disruption of the blood-brain barrier (BBB. Studies in animal models suggest that exposure to relatively milder BSWs (123 kPa initially induces free radical generating enzymes in and around brain capillaries, which enhances oxidative stress resulting in loss of tight junction proteins, edema formation, and leakiness of BBB with disruption or loss of its components pericytes and astrocyte end-feet. On the other hand, exposure to more intense BSWs (145-323 kPa causes acute disruption of the BBB with vascular lesions in the brain. Both of these scenarios lead to apoptosis of endothelial and neural cells and neuroinflammation in and around capillaries, which may progress into chronic traumatic encephalopathy and/or a variety of neurological impairments, depending on brain regions that are afflicted with such lesions. This review discusses studies that examined alterations in the brain milieu causing dysfunction or disruption of the BBB and neuroinflammation following exposure to different intensities of BSWs. Furthermore, potential of early intervention strategies capable of easing oxidative stress, repairing the BBB or blocking inflammation for minimizing delayed neurological deficits resulting from exposure to BSWs is conferred.

  4. Calmodulin Methyltransferase Is Required for Growth, Muscle Strength, Somatosensory Development and Brain Function.

    Science.gov (United States)

    Haziza, Sitvanit; Magnani, Roberta; Lan, Dima; Keinan, Omer; Saada, Ann; Hershkovitz, Eli; Yanay, Nurit; Cohen, Yoram; Nevo, Yoram; Houtz, Robert L; Sheffield, Val C; Golan, Hava; Parvari, Ruti

    2015-08-01

    Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the Ca

  5. Modeling the ischemic blood-brain barrier; the effects of oxygen-glucose deprivation (OGD) on endothelial cells in culture

    DEFF Research Database (Denmark)

    Tornabene, Erica; Helms, Hans Christian Cederberg; Berndt, Philipp;

    Introduction - The blood-brain barrier (BBB) is a physical, transport and metabolic barrier which plays a key role in preventing uncontrolled exchanges between blood and brain, ensuring an optimal environment for neurons activity. This extent interface is created by the endothelial cells forming ...

  6. Blood pH and brain uptake of /sup 14/C-morphine

    Energy Technology Data Exchange (ETDEWEB)

    Schulman, D.S.; Kaufman, J.J.; Eisenstein, M.M.; Rapoport, S.I.

    1984-11-01

    /sup 14/C-Morphine was injected iv in control awake rats or in rats subjected to metabolic alkalosis or acidosis. Ten minutes later, radioactivity was determined within each of seven brain regions, after correction was made for intravascular tracer. In each region, parenchymal radioactivity was correlated positively and significantly (P less than 0.05) with arterial blood pH. Brain radioactivity was twofold to threefold greater in alkalotic rats (mean pH . 7.62) than in acidotic rats (mean pH . 7.16). The results are consistent with the pH-partition hypothesis for drug entry into the brain and indicate that morphine uptake can be increased by elevating the fraction of lipid-soluble uncharged morphine base in blood, by means of alkalosis. The observations may account for an exaggerated morphine-induced analgesia in alkalotic patients.

  7. The rights and wrongs of blood-brain barrier permeability studies

    DEFF Research Database (Denmark)

    Saunders, Norman R; Dreifuss, Jean-Jacques; Dziegielewska, Katarzyna M

    2014-01-01

    . The first person to use this term seems to be Stern in the early 1920s. Studies in embryos by Stern and colleagues, Weed and Wislocki showed results similar to those in adult animals. These were well-conducted experiments made a century ago, thus the persistence of a belief in barrier immaturity is puzzling....... As discussed in this review, evidence for this belief, is of poor experimental quality, often misinterpreted and often not properly cited. The functional state of blood-brain barrier mechanisms in the fetus is an important biological phenomenon with implications for normal brain development. It is also...... important for clinicians to have proper evidence on which to advise pregnant women who may need to take medications for serious medical conditions. Beliefs in immaturity of the blood-brain barrier have held the field back for decades. Their history illustrates the importance of taking account of all...

  8. Statistical distribution of blood serotonin as a predictor of early autistic brain abnormalities

    Directory of Open Access Journals (Sweden)

    Janušonis Skirmantas

    2005-07-01

    Full Text Available Abstract Background A wide range of abnormalities has been reported in autistic brains, but these abnormalities may be the result of an earlier underlying developmental alteration that may no longer be evident by the time autism is diagnosed. The most consistent biological finding in autistic individuals has been their statistically elevated levels of 5-hydroxytryptamine (5-HT, serotonin in blood platelets (platelet hyperserotonemia. The early developmental alteration of the autistic brain and the autistic platelet hyperserotonemia may be caused by the same biological factor expressed in the brain and outside the brain, respectively. Unlike the brain, blood platelets are short-lived and continue to be produced throughout the life span, suggesting that this factor may continue to operate outside the brain years after the brain is formed. The statistical distributions of the platelet 5-HT levels in normal and autistic groups have characteristic features and may contain information about the nature of this yet unidentified factor. Results The identity of this factor was studied by using a novel, quantitative approach that was applied to published distributions of the platelet 5-HT levels in normal and autistic groups. It was shown that the published data are consistent with the hypothesis that a factor that interferes with brain development in autism may also regulate the release of 5-HT from gut enterochromaffin cells. Numerical analysis revealed that this factor may be non-functional in autistic individuals. Conclusion At least some biological factors, the abnormal function of which leads to the development of the autistic brain, may regulate the release of 5-HT from the gut years after birth. If the present model is correct, it will allow future efforts to be focused on a limited number of gene candidates, some of which have not been suspected to be involved in autism (such as the 5-HT4 receptor gene based on currently available clinical and

  9. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L.; Tfelt-Hansen, P.

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access...... to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy Udgivelsesdato: 2008/12...

  10. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L; Tfelt-Hansen, P

    2008-01-01

    Salient aspects of the anatomy and function of the blood-barrier barrier (BBB) are reviewed in relation to migraine pathophysiology and treatment. The main function of the BBB is to limit the access of circulating substances to the neuropile. Smaller lipophilic substances have some access...... to the central nervous system by diffusion, whereas other substances can cross the BBB by carrier-mediated influx transport, receptor-mediated transcytosis and absorptive-mediated transcytosis. Studies of drugs relevant to migraine pathophysiology and treatment have been examined with the pressurized...... vascular beds also. We discuss how this can be related to genuine migraine attacks. Our view is that there exists no clear proof of breakdown or leakage of the BBB during migraine attacks, and that antimigraine drugs need to pass the BBB for efficacy....

  11. Peculiarities of Brain's Blood Flow : Role of Carbon Dioxide

    CERN Document Server

    Gersten, Alexander

    2011-01-01

    Among the major factors controlling the cerebral blood flow (CBF), the effect of PaCO2 is peculiar in that it violates autoregulatory CBF mechanisms and allows to explore the full range of the CBF. This research resulted in a simple physical model, with a four parameter formula, relating the CBF to PaCO2. The parameters can be extracted in an easy manner, directly from the experimental data. With this model earlier experimental data sets of Rhesus monkeys and rats were well fitted. Human data were also fitted with this model. Exact formulae were found, which can be used to transform the fits of one animal to the fits of another one. The merit of this transformation is that it enable us the use of rats data as monkeys data simply by rescaling the PaCO2 values and the CBF data. This transformation makes possible the use of experimental animal data instead of human ones.

  12. Oxygenation and Blood Volume Periodic Waveforms in the Brain

    CERN Document Server

    Gersten, Alexander; Raz, Amir

    2011-01-01

    Results of an experiment are presented whose aim is to explore the relationship between respiration and cerebral oxygenation. Measurements of end tidal CO2 (EtCO2) were taken simultaneously with cerebral oxygen saturation (rSO2) using the INVOS Cerebral Oximeter of Somanetics. Due to the device limitations we could explore only subjects who could perform with a breathing rate of around 2/min or less. Six subjects were used who were experienced in yoga breathing techniques. They performed an identical periodic breathing exercise including periodicity of about 2/min. The results of all six subjects clearly show a periodic change of cerebral oxygenation with the same period as the breathing exercises. Similar periodic changes in blood volume index were observed as well.

  13. Running Pace Decrease during a Marathon Is Positively Related to Blood Markers of Muscle Damage

    Science.gov (United States)

    Del Coso, Juan; Fernández, David; Abián-Vicen, Javier; Salinero, Juan José; González-Millán, Cristina; Areces, Francisco; Ruiz, Diana; Gallo, César; Calleja-González, Julio; Pérez-González, Benito

    2013-01-01

    Background Completing a marathon is one of the most challenging sports activities, yet the source of running fatigue during this event is not completely understood. The aim of this investigation was to determine the cause(s) of running fatigue during a marathon in warm weather. Methodology/Principal Findings We recruited 40 amateur runners (34 men and 6 women) for the study. Before the race, body core temperature, body mass, leg muscle power output during a countermovement jump, and blood samples were obtained. During the marathon (27 °C; 27% relative humidity) running fatigue was measured as the pace reduction from the first 5-km to the end of the race. Within 3 min after the marathon, the same pre-exercise variables were obtained. Results Marathoners reduced their running pace from 3.5 ± 0.4 m/s after 5-km to 2.9 ± 0.6 m/s at the end of the race (P 15% pace reduction) had elevated post-race myoglobin (1318 ± 1411 v 623 ± 391 µg L−1; P<0.05), lactate dehydrogenase (687 ± 151 v 583 ± 117 U L−1; P<0.05), and creatine kinase (564 ± 469 v 363 ± 158 U L−1; P = 0.07) in comparison with marathoners that preserved their running pace reasonably well throughout the race. However, they did not differ in their body mass change (−3.1 ± 1.0 v −3.0 ± 1.0%; P = 0.60) or post-race body temperature (38.7 ± 0.7 v 38.9 ± 0.9 °C; P = 0.35). Conclusions/Significance Running pace decline during a marathon was positively related with muscle breakdown blood markers. To elucidate if muscle damage during a marathon is related to mechanistic or metabolic factors requires further investigation. PMID:23460881

  14. Running pace decrease during a marathon is positively related to blood markers of muscle damage.

    Directory of Open Access Journals (Sweden)

    Juan Del Coso

    Full Text Available BACKGROUND: Completing a marathon is one of the most challenging sports activities, yet the source of running fatigue during this event is not completely understood. The aim of this investigation was to determine the cause(s of running fatigue during a marathon in warm weather. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 40 amateur runners (34 men and 6 women for the study. Before the race, body core temperature, body mass, leg muscle power output during a countermovement jump, and blood samples were obtained. During the marathon (27 °C; 27% relative humidity running fatigue was measured as the pace reduction from the first 5-km to the end of the race. Within 3 min after the marathon, the same pre-exercise variables were obtained. RESULTS: Marathoners reduced their running pace from 3.5 ± 0.4 m/s after 5-km to 2.9 ± 0.6 m/s at the end of the race (P 15% pace reduction had elevated post-race myoglobin (1318 ± 1411 v 623 ± 391 µg L(-1; P<0.05, lactate dehydrogenase (687 ± 151 v 583 ± 117 U L(-1; P<0.05, and creatine kinase (564 ± 469 v 363 ± 158 U L(-1; P = 0.07 in comparison with marathoners that preserved their running pace reasonably well throughout the race. However, they did not differ in their body mass change (-3.1 ± 1.0 v -3.0 ± 1.0%; P = 0.60 or post-race body temperature (38.7 ± 0.7 v 38.9 ± 0.9 °C; P = 0.35. CONCLUSIONS/SIGNIFICANCE: Running pace decline during a marathon was positively related with muscle breakdown blood markers. To elucidate if muscle damage during a marathon is related to mechanistic or metabolic factors requires further investigation.

  15. THE ROLE OF MULTIDRUG RESISTANCE ASSOCIATED PROTEIN (MRP) IN THE BLOOD-BRAIN BARRIER AND OPIOID ANALGESIA

    OpenAIRE

    Su, Wendy; Pasternak, Gavril W.

    2013-01-01

    The blood brain barrier protects the brain from circulating compounds and drugs. The ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) is involved with the barrier, both preventing the influx of agent from the blood into the brain and facilitating the efflux of compounds from the brain into the blood, raising the possibility of a similar role for other transporters. Multidrug resistance associated protein (MRP), a 190 kDa protein similar to Pgp is also ABC transport that has been im...

  16. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  17. Bypassing the blood-brain barrier: delivery of therapeutic agents by macrophages

    Science.gov (United States)

    Hirschberg, Henry; Baek, Seung-Kuk; Kwon, Young Jik; Sun, Chung-Ho; Madsen, Steen J.

    2010-02-01

    Introduction: Failure to eradicate infiltrating glioma cells using conventional treatment regimens results in tumor recurrence and is responsible for the dismal prognosis of patients with glioblastoma multiforme (GBM). This is due to the fact that these migratory cells are protected by the blood-brain barrier (BBB) and the blood brain tumor barrier (BBTB) which prevents the delivery of most anti-cancer agents. We have evaluated the ability of monocytes/macrophages (Mo/Ma) to cross the BBB in rats. This will permit access of anti-cancer agents such as nanoparticles to effectively target the infiltrating tumor cells, and potentially improve the treatment effectiveness for malignant gliomas. Materials and Methods: The infiltration of Mo/Ma into brain tumor spheroids in vitro was determined using fluorescent stained Mo/Ma. Tumors were also established in the brains of inbred rats and ALA-PDT was given 18 days following tumor induction. The degredation of the BBTB and quantification of the number of infiltrating Mo/Ma was examined on histological sections from removed brains. Results & Conclusion: PDT was highly effective in locally opening the BBTB and inducing macrophage migration into the irradiated portions of brain tumors.

  18. Transport of nanoparticles through the blood-brain barrier for imaging and therapeutic applications

    Science.gov (United States)

    Shilo, Malka; Motiei, Menachem; Hana, Panet; Popovtzer, Rachela

    2014-01-01

    A critical problem in the treatment of neurodegenerative disorders and diseases, such as Alzheimer's and Parkinson's, is the incapability to overcome the restrictive mechanism of the blood-brain barrier (BBB) and to deliver important therapeutic agents to the brain. During the last decade, nanoparticles have gained attention as promising drug delivery agents that can transport across the BBB and increase the uptake of appropriate drugs in the brain. In this study we have developed insulin-targeted gold nanoparticles (INS-GNPs) and investigated quantitatively the amount of INS-GNPs that cross the BBB by the receptor-mediated endocytosis process. For this purpose, INS-GNPs and control GNPs were injected into the tail vein of male BALB/c mice. Major organs were then extracted and a blood sample was taken from the mice, and thereafter analyzed for gold content by flame atomic absorption spectroscopy. Results show that two hours post-intravenous injection, the amount of INS-GNPs found in mouse brains is over 5 times greater than that of the control, untargeted GNPs. Results of further experimentation on a rat model show that INS-GNPs can also serve as CT contrast agents to highlight specific brain regions in which they accumulate. Due to the fact that they can overcome the restrictive mechanism of the BBB, this approach could be a potentially valuable tool, helping to confront the great challenge of delivering important imaging and therapeutic agents to the brain for detection and treatment of neurodegenerative disorders and diseases.

  19. Dual role of cerebral blood flow in regional brain temperature control in the healthy newborn infant.

    Science.gov (United States)

    Iwata, Sachiko; Tachtsidis, Ilias; Takashima, Sachio; Matsuishi, Toyojiro; Robertson, Nicola J; Iwata, Osuke

    2014-10-01

    Small shifts in brain temperature after hypoxia-ischaemia affect cell viability. The main determinants of brain temperature are cerebral metabolism, which contributes to local heat production, and brain perfusion, which removes heat. However, few studies have addressed the effect of cerebral metabolism and perfusion on regional brain temperature in human neonates because of the lack of non-invasive cot-side monitors. This study aimed (i) to determine non-invasive monitoring tools of cerebral metabolism and perfusion by combining near-infrared spectroscopy and echocardiography, and (ii) to investigate the dependence of brain temperature on cerebral metabolism and perfusion in unsedated newborn infants. Thirty-two healthy newborn infants were recruited. They were studied with cerebral near-infrared spectroscopy, echocardiography, and a zero-heat flux tissue thermometer. A surrogate of cerebral blood flow (CBF) was measured using superior vena cava flow adjusted for cerebral volume (rSVC flow). The tissue oxygenation index, fractional oxygen extraction (FOE), and the cerebral metabolic rate of oxygen relative to rSVC flow (CMRO₂ index) were also estimated. A greater rSVC flow was positively associated with higher brain temperatures, particularly for superficial structures. The CMRO₂ index and rSVC flow were positively coupled. However, brain temperature was independent of FOE and the CMRO₂ index. A cooler ambient temperature was associated with a greater temperature gradient between the scalp surface and the body core. Cerebral oxygen metabolism and perfusion were monitored in newborn infants without using tracers. In these healthy newborn infants, cerebral perfusion and ambient temperature were significant independent variables of brain temperature. CBF has primarily been associated with heat removal from the brain. However, our results suggest that CBF is likely to deliver heat specifically to the superficial brain. Further studies are required to assess the

  20. Leg crossing with muscle tensing, a physical counter-manoeuvre to prevent syncope, enhances leg blood flow.

    NARCIS (Netherlands)

    Groothuis, J.T.; Dijk, N. van; Woerds, W. ter; Wieling, W.; Hopman, M.T.E.

    2007-01-01

    In patients with orthostatic intolerance, the mechanisms to maintain BP (blood pressure) fail. A physical counter-manoeuvre to postpone or even prevent orthostatic intolerance in these patients is leg crossing combined with muscle tensing. Although the central haemodynamic effects of physical counte

  1. A unique carrier for delivery of therapeutic compounds beyond the blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    Delara Karkan

    Full Text Available BACKGROUND: Therapeutic intervention in many neurological diseases is thwarted by the physical obstacle formed by the blood-brain barrier (BBB that excludes most drugs from entering the brain from the blood. Thus, identifying efficacious modes of drug delivery to the brain remains a "holy grail" in molecular medicine and nanobiotechnology. Brain capillaries, that comprise the BBB, possess an endogenous receptor that ferries an iron-transport protein, termed p97 (melanotransferrin, across the BBB. Here, we explored the hypothesis that therapeutic drugs "piggybacked" as conjugates of p97 can be shuttled across the BBB for treatment of otherwise inoperable brain tumors. APPROACH: Human p97 was covalently linked with the chemotherapeutic agents paclitaxel (PTAX or adriamycin (ADR and following intravenous injection, measured their penetration into brain tissue and other organs using radiolabeled and fluorescent derivatives of the drugs. In order to establish efficacy of the conjugates, we used nude mouse models to assess p97-drug conjugate activity towards glioma and mammary tumors growing subcutaneously compared to those growing intracranially. PRINCIPAL FINDINGS: Bolus-injected p97-drug conjugates and unconjugated p97 traversed brain capillary endothelium within a few minutes and accumulated to 1-2% of the injected by 24 hours. Brain delivery with p97-drug conjugates was quantitatively 10 fold higher than with free drug controls. Furthermore, both free-ADR and p97-ADR conjugates equally inhibited the subcutaneous growth of gliomas growing outside the brain. Evocatively, only p97-ADR conjugates significantly prolonged the survival of animals bearing intracranial gliomas or mammary tumors when compared to similar cumulated doses of free-ADR. SIGNIFICANCE: This study provides the initial proof of concept for p97 as a carrier capable of shuttling therapeutic levels of drugs from the blood to the brain for the treatment of neurological disorders

  2. Fossil skulls reveal that blood flow rate to the brain increased faster than brain volume during human evolution

    Science.gov (United States)

    Seymour, Roger S.; Bosiocic, Vanya; Snelling, Edward P.

    2016-08-01

    The evolution of human cognition has been inferred from anthropological discoveries and estimates of brain size from fossil skulls. A more direct measure of cognition would be cerebral metabolic rate, which is proportional to cerebral blood flow rate (perfusion). The hominin cerebrum is supplied almost exclusively by the internal carotid arteries. The sizes of the foramina that transmitted these vessels in life can be measured in hominin fossil skulls and used to calculate cerebral perfusion rate. Perfusion in 11 species of hominin ancestors, from Australopithecus to archaic Homo sapiens, increases disproportionately when scaled against brain volume (the allometric exponent is 1.41). The high exponent indicates an increase in the metabolic intensity of cerebral tissue in later Homo species, rather than remaining constant (1.0) as expected by a linear increase in neuron number, or decreasing according to Kleiber's Law (0.75). During 3 Myr of hominin evolution, cerebral tissue perfusion increased 1.7-fold, which, when multiplied by a 3.5-fold increase in brain size, indicates a 6.0-fold increase in total cerebral blood flow rate. This is probably associated with increased interneuron connectivity, synaptic activity and cognitive function, which all ultimately depend on cerebral metabolic rate.

  3. Breaking the Blood-Brain Barrier With Mannitol to Aid Stem Cell Therapeutics in the Chronic Stroke Brain.

    Science.gov (United States)

    Tajiri, Naoki; Lee, Jea Young; Acosta, Sandra; Sanberg, Paul R; Borlongan, Cesar V

    2016-01-01

    Blood-brain barrier (BBB) permeabilizers, such as mannitol, can facilitate peripherally delivered stem cells to exert therapeutic benefits on the stroke brain. Although this BBB permeation-aided stem cell therapy has been demonstrated in the acute stage of stroke, such BBB permeation in the chronic stage of the disease remains to be examined. Adult Sprague-Dawley rats initially received sham surgery or experimental stroke via the 1-h middle cerebral artery occlusion (MCAo) model. At 1 month after the MCAo surgery, stroke animals were randomly assigned to receive human umbilical cord stem cells only (2 million viable cells), mannitol only (1.1 mol/L mannitol at 4°C), combined human umbilical cord stem cells (200,000 viable cells) and mannitol (1.1 mol/L mannitol at 4°C), and vehicle (phosphate-buffered saline) only. Stroke animals that received human umbilical cord blood cells alone or combined human umbilical cord stem cells and mannitol exhibited significantly improved motor performance and significantly better brain cell survival in the peri-infarct area compared to stroke animals that received vehicle or mannitol alone, with mannitol treatment reducing the stem cell dose necessary to afford functional outcomes. Enhanced neurogenesis in the subventricular zone accompanied the combined treatment of human umbilical cord stem cells and mannitol. We showed that BBB permeation facilitates the therapeutic effects of a low dose of peripherally transplanted stem cells to effectively cause functional improvement and increase neurogenesis in chronic stroke.

  4. Glucose predictability, blood capillary permeability, and glucose utilization rate in subcutaneous, skeletal muscle, and visceral fat tissues.

    Science.gov (United States)

    Koutny, Tomas

    2013-11-01

    This study suggests an approach for the comparison and evaluation of particular compartments with modest experimental setup costs. A glucose level prediction model was used to evaluate the compartment's glucose transport rate across the blood capillary membrane and the glucose utilization rate by the cells. The glucose levels of the blood, subcutaneous tissue, skeletal muscle tissue, and visceral fat were obtained in experiments conducted on hereditary hypertriglyceridemic rats. After the blood glucose level had undergone a rapid change, the experimenter attempted to reach a steady blood glucose level by manually correcting the glucose infusion rate and maintaining a constant insulin infusion rate. The interstitial fluid glucose levels of subcutaneous tissue, skeletal muscle tissue, and visceral fat were evaluated to determine the reaction delay compared with the change in the blood glucose level, the interstitial fluid glucose level predictability, the blood capillary permeability, the effect of the concentration gradient, and the glucose utilization rate. Based on these data, the glucose transport rate across the capillary membrane and the utilization rate in a particular tissue were determined. The rates obtained were successfully verified against positron emission tomography experiments. The subcutaneous tissue exhibits the lowest and the most predictable glucose utilization rate, whereas the skeletal muscle tissue has the greatest glucose utilization rate. In contrast, the visceral fat is the least predictable and has the shortest reaction delay compared with the change in the blood glucose level. The reaction delays obtained for the subcutaneous tissue and skeletal muscle tissue were found to be approximately equal using a metric based on the time required to reach half of the increase in the interstitial fluid glucose level.

  5. Effects of blood flow restricted low-intensity concentric or eccentric training on muscle size and strength.

    Directory of Open Access Journals (Sweden)

    Tomohiro Yasuda

    Full Text Available We investigated the acute and chronic effects of low-intensity concentric or eccentric resistance training with blood flow restriction (BFR on muscle size and strength. Ten young men performed 30% of concentric one repetition maximal dumbbell curl exercise (four sets, total 75 reps 3 days/week for 6 weeks. One arm was randomly chosen for concentric BFR (CON-BFR exercise only and the other arm performed eccentric BFR (ECC-BFR exercise only at the same exercise load. During the exercise session, iEMG for biceps brachii muscles increased progressively during CON-BFR, which was greater (p<0.05 than that of the ECC-BFR. Immediately after the exercise, muscle thickness (MTH of the elbow flexors acutely increased (p<0.01 with both CON-BFR and ECC-BFR, but was greater with CON-BFR (11.7% (p<0.01 than ECC-BFR (3.9% at 10-cm above the elbow joint. Following 6-weeks of training, MRI-measured muscle cross-sectional area (CSA at 10-cm position and mid-upper arm (12.0% and 10.6%, respectively as well as muscle volume (12.5% of the elbow flexors were increased (p<0.01 with CON-BFR. Increases in muscle CSA and volume were lower in ECC-BFR (5.1%, 0.8% and 2.9%, respectively than in the CON-BFR and only muscle CSA at 10-cm position increased significantly (p<0.05 after the training. Maximal voluntary isometric strength of elbow flexors was increased (p<0.05 in CON-BFR (8.6%, but not in ECC (3.8%. These results suggest that CON-BFR training leads to pronounced acute changes in muscle size, an index of muscle cell swelling, the response to which may be an important factor for promoting muscle hypertrophy with BFR resistance training.

  6. Blood-brain barrier permeability and brain uptake mechanism of kainic Acid and dihydrokainic Acid

    DEFF Research Database (Denmark)

    Gynther, Mikko; Petsalo, Aleksanteri; Hansen, Steen Honoré;

    2015-01-01

    The glutamatergic neurotransmitter system is involved in important neurophysiological processes and thus constitutes a promising target for the treatment of neurological diseases. The two ionotropic glutamate receptor agonists kainic acid (KA) and dihydrokainic acid (DHK) have been used as research...... volume of distribution in brain is also low. Therefore, even though the total KA and DHK concentrations in the brain are low after systemic dosing, the concentrations in the vicinity of the glutamate receptors are sufficient for their activation and thus the observed efficacy....

  7. How hormones influence composition and physiological function of the brain-blood barrier.

    Science.gov (United States)

    Hampl, R; Bičíková, M; Sosvorová, L

    2015-01-01

    Hormones exert many actions in the brain. Their access and effects in the brain are regulated by the blood-brain barrier (BBB). Hormones as other substances may enter the brain and vice versa either by paracellular way requiring breaching tight junctions stitching the endothelial cells composing the BBB, or by passage through the cells (transcellular way). Hormones influence both ways through their receptors, both membrane and intracellular, present on/in the BBB. In the review the main examples are outlined how hormones influence the expression and function of proteins forming the tight junctions, as well as how they regulate expression and function of major protein transporters mediating transport of various substances including hormone themselves.

  8. Focused ultrasound-mediated drug delivery through the blood-brain barrier.

    Science.gov (United States)

    Burgess, Alison; Shah, Kairavi; Hough, Olivia; Hynynen, Kullervo

    2015-05-01

    Despite recent advances in blood-brain barrier (BBB) research, it remains a significant hurdle for the pharmaceutical treatment of brain diseases. Focused ultrasound (FUS) is one method to transiently increase permeability of the BBB to promote drug delivery to specific brain regions. An introduction to the BBB and a brief overview of the methods, which can be used to circumvent the BBB to promote drug delivery, is provided. In particular, we discuss the advantages and limitations of FUS technology and the efficacy of FUS-mediated drug delivery in models of disease. MRI for targeting and evaluating FUS treatments, combined with administration of microbubbles, allows for transient, reproducible BBB opening. The integration of a real-time acoustic feedback controller has improved treatment safety. Successful clinical translation of FUS has the potential to transform the treatment of brain disease worldwide without requiring the development of new pharmaceutical agents.

  9. Disruption of the blood-brain barrier in Parkinson's disease: curse or route to a cure?

    Science.gov (United States)

    Lee, Heyne; Pienaar, Ilse S

    2014-01-01

    The vertebrate blood-brain barrier (BBB) is critical for ensuring the maintenance of brain homeostasis, whilst protecting the brain against toxic insults. Various pathological events disrupt BBB integrity, holding several important clinical implications. In instances where the normal mechanisms controlling passage of substances into the brain are compromised, these could sensitize or even worsen endogenous pathological conditions. Recognition has grown recently that patients diagnosed with Parkinson's disease (PD) present with concurrent medical problems, including cerebrovascular lesions. However, cerebrovascular disturbances may also result from PD-related disease processes; the pathological mechanisms which could entail interaction between environment-derived and genetic factors. The current review addresses the accumulation of studies aimed at better understanding the series of processes affecting the neurovascular unit in human Parkinsonism, due in part to the BBB presenting as a formidable opponent in the effective delivery of therapeutics that have shown promise as therapeutic strategies for treating aspects of PD when tested in vitro.

  10. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis.

    Science.gov (United States)

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle J; Frederiksen, Jette L; Larsson, Henrik B W

    2015-09-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the permeability of the blood-brain barrier in normal-appearing white matter of patients with multiple sclerosis and here, for the first time, we present a study on the capability of blood-brain barrier permeability in predicting conversion from optic neuritis to multiple sclerosis and a direct comparison with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging as part of the diagnostic work-up at time of diagnosis. Eighteen healthy controls were included for comparison. Patients had magnetic resonance imaging and lumbar puncture performed within 4 weeks of onset of optic neuritis. Information on multiple sclerosis conversion was acquired from hospital records 2 years after optic neuritis onset. Logistic regression analysis showed that baseline permeability in normal-appearing white matter significantly improved prediction of multiple sclerosis conversion (according to the 2010 revised McDonald diagnostic criteria) within 2 years compared to T2 lesion count alone. There was no correlation between permeability and T2 lesion count. An increase in permeability in normal-appearing white matter of 0.1 ml/100 g/min increased the risk of multiple sclerosis 8.5 times whereas having more than nine T2 lesions increased the risk 52.6 times. Receiver operating characteristic curve analysis of permeability in normal-appearing white matter gave a cut-off of 0.13 ml/100 g/min, which predicted conversion to multiple sclerosis with a sensitivity of

  11. The role of multidrug resistance-associated protein in the blood-brain barrier and opioid analgesia.

    Science.gov (United States)

    Su, Wendy; Pasternak, Gavril W

    2013-09-01

    The blood-brain barrier protects the brain from circulating compounds and drugs. The ATP-binding cassette (ABC) transporter P-glycoprotein (Pgp) is involved with the barrier, both preventing the influx of agent from the blood into the brain and facilitating the efflux of compounds from the brain into the blood, raising the possibility of a similar role for other transporters. Multidrug resistance-associated protein (MRP), a 190 kDa protein, similar to Pgp is also ABC transporter that has been implicated in the blood-brain barrier. The current study explores its role in opioid action. Immunohistochemically, it is localized in the choroid plexus in rats and can be selectively downregulated by antisense treatment at both the level of mRNA, as shown by RT-PCR, and protein, as demonstrated immunohistochemically. Behaviorally, downregulation of MRP significantly enhances the analgesic potency of systemic morphine in MRP knockout mice and in antisense-treated rats by lowering the blood-brain barrier. Following intracerebroventricular administration, a number of compounds, including some opioids, are rapidly secreted from the brain into the blood where they contribute to the overall analgesic effects by activating peripheral systems. MRP plays a role in this efflux. Downregulating MRP expression leads to a corresponding decrease in the transport and a diminished analgesic response from opioids administered intracerebroventricularly. Thus, the transporter protein MRP plays a role in maintaining the blood-brain barrier and modulates the activity of opioids.

  12. Lycium barbarum extracts protect the brain from blood-brain barrier disruption and cerebral edema in experimental stroke.

    Directory of Open Access Journals (Sweden)

    Di Yang

    Full Text Available BACKGROUND AND PURPOSE: Ischemic stroke is a destructive cerebrovascular disease and a leading cause of death. Yet, no ideal neuroprotective agents are available, leaving prevention an attractive alternative. The extracts from the fruits of Lycium barbarum (LBP, a Chinese anti-aging medicine and food supplement, showed neuroprotective function in the retina when given prophylactically. We aim to evaluate the protective effects of LBP pre-treatment in an experimental stroke model. METHODS: C57BL/6N male mice were first fed with either vehicle (PBS or LBP (1 or 10 mg/kg daily for 7 days. Mice were then subjected to 2-hour transient middle cerebral artery occlusion (MCAO by the intraluminal method followed by 22-hour reperfusion upon filament removal. Mice were evaluated for neurological deficits just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, immunohistochemical analysis, and Western blot experiments. Evans blue (EB extravasation was determined to assess blood-brain barrier (BBB disruption after MCAO. RESULTS: LBP pre-treatment significantly improved neurological deficits as well as decreased infarct size, hemispheric swelling, and water content. Fewer apoptotic cells were identified in LBP-treated brains by TUNEL assay. Reduced EB extravasation, fewer IgG-leaky vessels, and up-regulation of occludin expression were also observed in LBP-treated brains. Moreover, immunoreactivity for aquaporin-4 and glial fibrillary acidic protein were significantly decreased in LBP-treated brains. CONCLUSIONS: Seven-day oral LBP pre-treatment effectively improved neurological deficits, decreased infarct size and cerebral edema as well as protected the brain from BBB disruption, aquaporin-4 up-regulation, and glial activation. The present study suggests that LBP may be used as a prophylactic neuroprotectant in patients at high risk for ischemic stroke.

  13. Relationships among body mass, brain size, gut length, and blood tryptophan and serotonin in young wild-type mice

    OpenAIRE

    2009-01-01

    Abstract Background The blood hyperserotonemia of autism is one of the most consistent biological findings in autism research, but its causes remain unclear. A major difficulty in understanding this phenomenon is the lack of information on fundamental interactions among the developing brain, gut, and blood in the mammalian body. We therefore investigated relationships among the body mass, the brain mass, the volume of the hippocampal complex, the gut length, and the whole-blood levels of tryp...

  14. Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS)

    Science.gov (United States)

    Petrov, Konstantin A; Yagodina, Lilia O; Valeeva, Guzel R; Lannik, Natalya I; Nikitashina, Alexandra D; Rizvanov, Albert A; Zobov, Vladimir V; Bukharaeva, Ellya A; Reznik, Vladimir S; Nikolsky, Eugeny E; Vyskočil, František

    2011-01-01

    BACKGROUND AND PURPOSE The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools. PMID:21232040

  15. Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

    Science.gov (United States)

    Nhan, Tam; Burgess, Alison; Lilge, Lothar; Hynynen, Kullervo

    2014-10-01

    Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01-0.03 min-1. Finally, the model suggests that infusion over a short duration (20-60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.

  16. Compromised Blood-Brain Barrier Competence in Remote Brain Areas in Ischemic Stroke Rats at Chronic Stage

    Science.gov (United States)

    Garbuzova-Davis, Svitlana; Haller, Edward; Williams, Stephanie N.; Haim, Eithan D.; Tajiri, Naoki; Hernandez-Ontiveros, Diana G.; Frisina-Deyo, Aric; Boffeli, Sean M.; Sanberg, Paul R.; Borlongan, Cesario V.

    2014-01-01

    Stroke is a life threatening disease leading to long-term disability in stroke survivors. Cerebral functional insufficiency in chronic stroke might be due to pathological changes in brain areas remote from initial ischemic lesion, i.e. diaschisis. Previously, we showed that the damaged blood-brain barrier (BBB) was implicated in subacute diaschisis. The present study investigated BBB competence in chronic diaschisis using a transient middle cerebral artery occlusion (tMCAO) rat model. Our results demonstrated significant BBB damage mostly in the ipsilateral striatum and motor cortex in rats at 30 days after tMCAO. The BBB alterations were also determined in the contralateral hemisphere via ultrastructural and immunohistochemical analyses. Major BBB pathological changes in contralateral remote striatum and motor cortex areas included: (1) vacuolated endothelial cells containing large autophagosomes, (2) degenerated pericytes displaying mitochondria with cristae disruption, (3) degenerated astrocytes and perivascular edema, (4) Evans Blue extravasation, and (5) appearance of parenchymal astrogliosis. Importantly, discrete analyses of striatal and motor cortex areas revealed significantly higher autophagosome accumulation in capillaries of ventral striatum and astrogliosis in dorsal striatum in both cerebral hemispheres. These widespread microvascular alterations in ipsilateral and contralateral brain hemispheres suggest persistent and/or continued BBB damage in chronic ischemia. The pathological changes in remote brain areas likely indicate chronic ischemic diaschisis, which should be considered in the development of treatment strategies for stroke. PMID:24610730

  17. Nanobiotechnology-based strategies for crossing the blood-brain barrier.

    Science.gov (United States)

    Jain, Kewal K

    2012-08-01

    The blood-brain barrier (BBB) is meant to protect the brain from noxious agents; however, it also significantly hinders the delivery of therapeutics to the brain. Several strategies have been employed to deliver drugs across this barrier and some of these may do structural damage to the BBB by forcibly opening it to allow the uncontrolled passage of drugs. The ideal method for transporting drugs across the BBB should be controlled and should not damage the barrier. Among the various approaches that are available, nanobiotechnology-based delivery methods provide the best prospects for achieving this ideal. This review describes various nanoparticle (NP)-based methods used for drug delivery to the brain and the known underlying mechanisms. Some strategies require multifunctional NPs combining controlled passage across the BBB with targeted delivery of the therapeutic cargo to the intended site of action in the brain. An important application of nanobiotechnology is to facilitate the delivery of drugs and biological therapeutics for brain tumors across the BBB. Although there are currently some limitations and concerns for the potential neurotoxicity of NPs, the future prospects for NP-based therapeutic delivery to the brain are excellent.

  18. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain.

    Science.gov (United States)

    Venkat, Poornima; Chopp, Michael; Chen, Jieli

    2016-06-30

    The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography. The mechanisms and mediators (eg, nitric oxide, astrocytes, and ion channels) that regulate CBF-metabolism coupling have been extensively studied. The neurovascular unit is a conceptual model encompassing the anatomical and metabolic interactions between the neurons, vascular components, and glial cells in the brain. It is compromised under disease states such as stroke, diabetes, hypertension, dementias, and with aging, all of which trigger a cascade of inflammatory responses that exacerbate brain damage. Hence, tight regulation and maintenance of neurovascular coupling is central for brain homeostasis. This review article also discusses the waste clearance pathways in the brain such as the glymphatic system. The glymphatic system is a functional waste clearance pathway that removes metabolic wastes and neurotoxins from the brain along paravascular channels. Disruption of the glymphatic system burdens the brain with accumulating waste and has been reported in aging as well as several neurological diseases.

  19. Study on measurement of free ligand concentration in blood and quantitative analysis of brain benzodiazepine receptor

    Energy Technology Data Exchange (ETDEWEB)

    Hashimoto, Kenji; Goromaru, Tsuyoshi; Inoue, Osamu; Itoh, Takashi; Yamasaki, Toshiro.

    1988-11-01

    We developed the method to determine rapidly the free ligand concentration in the blood as an input function for the purpose of quantitative analysis of binding potential (B/sub max//K/sub d/) of brain benzodiazepine receptor in vivo. It was found that the unmetabolized radioligand in the blood after intravenous administration of /sup 3/H-Ro 15 - 1788 could be extracted by chloroform, whereas the radioactive metabolites could not be extracted. And the plasma protein binding of /sup 3/H-Ro 15 - 1788 was determined using an ultrafiltration method. The biodistribution of /sup 3/H-Ro 15 - 1788 in the cerebral cortex, cerebellum and pons-medulla after intravenous administration of the radiotracer in the control and forced-swimmed mice was examined. And the time course of the free ligand concentration in the blood was determined as described above. Further, the binding potential of benzodiazepine receptor in the mouse brain was analyzed using a simple mathematical model. It was suggested that the binding potential of benzodiazepine receptor in the mouse brain was significantly decreased by forced-swimming. In conclusion, it was found that these methods would be useful for quantitative analysis of clinical data in the human brain using /sup 11/C-Ro 15 - 1788 and positron emission tomography (PET).

  20. Dietary Virgin Olive Oil Reduces Blood Brain Barrier Permeability, Brain Edema, and Brain Injury in Rats Subjected to Ischemia-Reperfusion

    Directory of Open Access Journals (Sweden)

    Fatemeh Mohagheghi

    2010-01-01

    Full Text Available Recent studies suggest that dietary virgin olive oil (VOO reduces hypoxia-reoxygenation injury in rat brain slices. We sought to extend these observations in an in vivo study of rat cerebral ischemia-reperfusion injury. Four groups, each consisting of 18 Wistar rats, were studied. One group (control received saline, while three treatment groups received oral VOO (0.25, 0.5, and 0.75 mL/kg/day, respectively. After 30 days, blood lipid profiles were determined, before a 60-min period of middle cerebral artery occlusion (MCAO. After 24-h reperfusion, neurological deficit scores, infarct volume, brain edema, and blood brain barrier permeability were each assessed in subgroups of six animals drawn from each main group. VOO reduced the LDL/HDL ratio in doses of 0.25, 0.5, and 0.75 mL/kg/day in comparison to the control group (p < 0.05, and offered cerebroprotection from ischemia-reperfusion. For controls vs. doses of 0.25 vs. 0.5 vs. 0.75 mL/kg/day, attenuated corrected infarct volumes were 207.82 ± 34.29 vs. 206.41 ± 26.23 vs. 124.21 ± 14.73 vs. 108.46 ± 31.63 mm3; brain water content of the infarcted hemisphere was 82 ±± 0.25 vs. 81.5 ± 0.56 vs. 80.5 ± 0.22 vs. 80.5 ± 0.34%; and blood brain barrier permeability of the infarcted hemisphere was 11.31 ± 2.67 vs. 9.21 ± 2.28 vs. 5.83 ± 1.6 vs. 4.43 ± 0.93 µg/g tissue (p < 0.05 for measures in doses 0.5 and 0.75 mL/kg/day vs. controls. Oral administration of VOO reduces infarct volume, brain edema, blood brain barrier permeability, and improves neurologic deficit scores after transient MCAO in rats.

  1. Brain protective effect of dexmedetomidine on perioperative patients in temporal muscle sticking for moyamoya disease

    Directory of Open Access Journals (Sweden)

    Jun CHEN

    2014-06-01

    Full Text Available Objective To study the application of dexmedetomidine in patients undergoing temporal muscle sticking for moyamoya disease (MMD, and to discuss the possible mechanism of brain protection. Methods Sixty patients undergoing temporal muscle sticking operation were randomly divided into 2 groups: dexmedetomidine group (Group D, N = 30 and control group (Group S, N = 30, respectively receiving dexmedetomidine intravenous infusion (0.60 μ g/kg and the same dose of normal saline before anesthesia induction. In Group D, dexemdetomidine was administered continuously (intravenous pumping with the dose of 0.40 μg/(kg·h perioperatively, while the same dose of normal saline was administered in Group S. Heart rate (HR and mean arterial pressure (MAP were recorded at T0 (before administration, T1 (before tracheal intubation, T2 (1 min after intubation, T3 (at the moment of skin incision, T4 (before extubation and T5 (1 min after extubation respectively. Total amount of propofol, remifentanil and patients' recovery conditions after anesthesia were also recorded. Glutamine and malondialdehyde (MDA were measured and compared before and after operation. Results In group D, HR and MAP decreased significantly at T2-4 compared with T0 (P < 0.05, for all. Total amount of propofol, remifentanil in Group D was lower than that in Group S (P < 0.05, for all and the patients' recovery conditions in Group D after anesthesia was better than Group S (P = 0.000, for all, without occurence of shivering, cough and dysphoria (P < 0.05, for all. Glutamine and MDA increased after anesthesia compared with that before anesthesia in both 2 groups (P < 0.05, for all, however, it was higher in Group S than that in Group D (P < 0.05, for all. Conclusions Dexmedetomidine can provide stable hemodynamic condition during the anesthesia with patients undergoing temporal muscle sticking for moyamoya disease, and has a positive effect on improving both the outcome of the operation and

  2. Effect of methyl parathion on the muscle and brain acetylcholinesterase activity of matrinxã (Brycon cephalus

    Directory of Open Access Journals (Sweden)

    Almeida Luciana Cristina de

    2005-01-01

    Full Text Available Farming of the freshwater fish is emerging in Brazil and many species from the wild are promising. The teleost matrinxã (Brycon cephalus holds several characteristics such as fast growth rate, high commercial value and adaptability to artificial raring conditions, which make it a promising species for commerce. The use of pesticides in aquatic environment is frequent in Brazil, and methyl parathion is very common in aquaculture. We have determined the enzymatic activity of acetyl cholinesterase in white muscle and brain of matrinxã exposed to 2ppm of environmental methyl parathion for 24 hours. There was 64% and 69% of acetyl cholinesterase inhibition in muscle and brain respectively. These activities were not recovered after 8 days from exposure to this pesticide. It can be concluded that acetyl cholinesterase from those tissues was inhibited by small amounts of methyl parathion, and the main effect was observed in the brain.

  3. Nanoparticles and blood-brain barrier: the key to central nervous system diseases.

    Science.gov (United States)

    Domínguez, Alazne; Suárez-Merino, Blanca; Goñi-de-Cerio, Felipe

    2014-01-01

    Major central nervous system disorders represent a significant and worldwide public health problem. In fact, the therapeutic success of many pharmaceuticals developed to treat central nervous system diseases is still moderate, since the blood-brain barrier (BBB) limits the access of systemically administered compounds to the brain. Therefore, they require the application of a large total dose of a drug, and cause numerous toxic effects. The development of nanotechnological systems are useful tools to deliver therapeutics and/or diagnostic probes to the brain due to nanocarriers having the potential to improve the therapeutic effect of drugs and to reduce their side effects. This review provides a brief overview of the variety of carriers employed for central nervous system drug and diagnostic probes delivery. Further, this paper focuses on the novel nanocarriers developed to enhance brain delivery across the blood-brain barrier. Special attention is paid to liposomes, micelles, polymeric and lipid-based nanoparticles, dendrimers and carbon nanotubes. The recent developments in nanocarrier implementation through size/charge optimization and surface modifications (PEGylation, targeting delivery, and coating with surfactants) have been discussed. And a detailed description of the nanoscaled pharmaceutical delivery devices employed for the treatment of central nervous system disorders have also been defined. The aim of the review is to evaluate the nanotechnology-based drug delivery strategies to treat different central nervous system disorders.

  4. Unilateral Opening of Rat Blood-Brain Barrier Assisted by Diagnostic Ultrasound Targeted Microbubbles Destruction

    Directory of Open Access Journals (Sweden)

    Yali Xu

    2016-01-01

    Full Text Available Objective. Blood-brain barrier (BBB is a key obstacle that prevents the medication from blood to the brain. Microbubble-enhanced cavitation by focused ultrasound can open the BBB and proves to be valuable in the brain drug delivery. The study aimed to explore the feasibility, efficacy, and safety of unilateral opening of BBB using diagnostic ultrasound targeted microbubbles destruction in rats. Methods. A transtemporal bone irradiation of diagnostic ultrasound and intravenous injection of lipid-coated microbubbles were performed at unilateral hemisphere. Pathological changes were monitored. Evans Blue extravasation grades, extraction from brain tissue, and fluorescence optical density were quantified. Lanthanum nitrate was traced by transmission electron microscopy. Results. After diagnostic ultrasound mediated microbubbles destruction, Evans Blue extravasation and fluorescence integrated optical density were significantly higher in the irradiated hemisphere than the contralateral side (all p<0.01. Erythrocytes extravasations were demonstrated in the ultrasound-exposed hemisphere (4±1, grade 2 while being invisible in the control side. Lanthanum nitrate tracers leaked through interendothelial cleft and spread to the nerve fiber existed in the irradiation side. Conclusions. Transtemporal bone irradiation under DUS mediated microbubble destruction provides us with a more accessible, safer, and higher selective BBB opening approach in rats, which is advantageous in brain targeted drugs delivery.

  5. Transfer of opiorphin through a blood-brain barrier culture model.

    Science.gov (United States)

    Bocsik, Alexandra; Darula, Zsuzsanna; Tóth, Géza; Deli, Mária A; Wollemann, Mária

    2015-08-01

    Opioid peptides are potent analgesics with therapeutic potential in the treatment of acute and chronic pain. Their efficacy is limited by peptidases (enkephalinases). Opiorphin pentapeptide (QRFSR) is the first characterized human endogenous inhibitor of enkephalinases. The peptide is able to increase the binding and affinity of endogenous opiates to mu opioid receptors; thus, the mechanism of opiorphin may provide a new therapeutic approach in pain management. The analgesic effect of opiorphin was proven in several earlier published in vitro and in vivo studies. Our aim was to test the transfer of opiorphin through a blood-brain barrier model for the first time. The flux of opiorphin was tested on a blood-brain barrier culture model consisting of rat brain endothelial, glial and pericyte cells. Brain endothelial cells in this triple co-culture model form tight monolayers characterized by transendothelial electrical resistance measurement. Relative quantity of the peptide was estimated by mass spectrometry. The transfer of opiorphin through the blood-brain barrier model was estimated to be ∼3%, whereas the permeability coefficient was 0.53 ± 1.36 × 10(-6) cm/s (n = 4). We also observed rapid conversion of N-terminal glutamine into pyroglutamic acid during the transfer experiments. Our results indicate that opiorphin crosses cultured brain endothelial cells in the absence of serum factors in a significant amount. This is in agreement with previous in vivo data showing potentiation of enkephalin-mediated antinociception. We suggest that opiorphin may have a potential as a centrally acting novel drug to treat pain.

  6. [Disturbances of blood lipid content after acute disorders of brain blood flow].

    Science.gov (United States)

    Ivanova, N E; Lebedev, I A; Akinina, S A; Anishchenko, L I; Koltsov, V V; Beliavskiĭ, A R; Sokolova, A A; Iakovlev, S V

    2011-01-01

    The parameters of blood lipid spectrum have been analyzed in 421 patients who survived cerebral stroke and transitory ischemic attacks in 2004-2008. The study included people of Khanty-Mansiysk and Khanty-Mansi autonomous okrug and watchmen. The statistical analysis did not reveal differences between mean concentrations of total cholesterol, high and low density lipoproteins and triglycerides in the settled population and in watchmen. Mean values of all parameters, with the exception of high-density lipoprotein, were higher compared to normative values. The highest frequency of deviations was found for low-density lipoproteins (63.5% of cases). The highest concentrations of total cholesterol and low-density proteins were seen in patients after transitory ischemic attacks regardless of their sex. The comparison of blood lipid spectrum parameters in different age groups revealed significant differences only for total cholesterol.

  7. CT and MRI assessment and characterization using segmentation and 3D modeling techniques: applications to muscle, bone and brain

    Directory of Open Access Journals (Sweden)

    Paolo Gargiulo

    2014-03-01

    Full Text Available This paper reviews the novel use of CT and MRI data and image processing tools to segment and reconstruct tissue images in 3D to determine characteristics of muscle, bone and brain.This to study and simulate the structural changes occurring in healthy and pathological conditions as well as in response to clinical treatments. Here we report the application of this methodology to evaluate and quantify: 1. progression of atrophy in human muscle subsequent to permanent lower motor neuron (LMN denervation, 2. muscle recovery as induced by functional electrical stimulation (FES, 3. bone quality in patients undergoing total hip replacement and 4. to model the electrical activity of the brain. Study 1: CT data and segmentation techniques were used to quantify changes in muscle density and composition by associating the Hounsfield unit values of muscle, adipose and fibrous connective tissue with different colors. This method was employed to monitor patients who have permanent muscle LMN denervation in the lower extremities under two different conditions: permanent LMN denervated not electrically stimulated and stimulated. Study 2: CT data and segmentation techniques were employed, however, in this work we assessed bone and muscle conditions in the pre-operative CT scans of patients scheduled to undergo total hip replacement. In this work, the overall anatomical structure, the bone mineral density (BMD and compactness of quadriceps muscles and proximal femoral was computed to provide a more complete view for surgeons when deciding which implant technology to use. Further, a Finite element analysis provided a map of the strains around the proximal femur socket when solicited by typical stresses caused by an implant press fitting. Study 3 describes a method to model the electrical behavior of human brain using segmented MR images. The aim of the work is to use these models to predict the electrical activity of the human brain under normal and pathological

  8. Mechanisms of restriction of viral neuroinvasion at the blood-brain barrier.

    Science.gov (United States)

    Miner, Jonathan J; Diamond, Michael S

    2016-02-01

    The blood-brain barrier (BBB) consists of highly specialized cells including brain microvascular endothelial cells, astrocytes, microglia, pericytes, and neurons, which act in concert to restrict the entry of pathogens, immune cells, and soluble molecules into the central nervous system (CNS). If pathogens manage to cross the BBB and establish infection within the CNS, the BBB can open in a regulated manner to allow leukocyte transmigration into the CNS so that microbes, infected cells, and debris can be cleared. This review highlights how different inflammatory cytokines or signaling pathways disrupt or enhance BBB integrity in a way that regulates entry of neurotropic viruses into the CNS.

  9. Characterization of an in vitro Rhesus Macaque Blood-Brain Barrier

    OpenAIRE

    2002-01-01

    The blood-brain barrier has been modeled in vitro in a number of species, including rat, cow and human. Coculture of multiple cell types is required for the correct expression of tight junction proteins by microvascular brain endothelial cells (MBEC). Markers of inflammation, especially MHC-II, and cell adhesion molecules, such as VCAM-1, are not expressed on the luminal surface of the barrier under resting conditions. The rhesus macaque model has been used to study early events of HIV-neurop...

  10. Thigh muscle size and vascular function after blood flow-restricted elastic band training in older women

    Science.gov (United States)

    Yasuda, Tomohiro; Fukumura, Kazuya; Tomaru, Takanobu; Nakajima, Toshiaki

    2016-01-01

    We examined the effect of elastic band training with blood flow restriction (BFR) on thigh muscle size and vascular function in older women. Older women were divided into three groups: low-intensity elastic band BFR training (BFR-Tr, n = 10), middleto high-intensity elastic band training (MH-Tr, n = 10), and no training (Ctrl, n = 10) groups. BFR-Tr and MH-Tr groups performed squat and knee extension exercises using elastic band, 2 days/week for 12 weeks. During BFR-Tr exercise session, subjects wore pressure cuffs around the most proximal region of both thighs. The following measurements were taken before (pre) and 3-5 days after (post) the final training session: MRI-measured muscle cross-sectional area (CSA) at mid-thigh, maximum voluntary isometric contraction (MVIC) of knee extension, central systolic blood pressure (c-SBP), central-augmentation index (c-AIx), cardio-ankle vascular index testing (CAVI), ankle-brachial pressure index (ABI). Quadriceps muscle CSA (6.9%) and knee extension MVIC (13.7%) were increased (p muscle CSA as well as maximal muscle strength, but does not decrease vascular function in older women. PMID:27244884

  11. Chronic impairment of leg muscle blood flow following cardiac catheterization in childhood. [/sup 133/Xe clearance measurements

    Energy Technology Data Exchange (ETDEWEB)

    Skovranek, J.; Samanek, M.

    1979-01-01

    In 99 patients with congenital heart defects or chronic respiratory disease without clinical symptoms of disturbances in peripheral circulation, resting and maximal blood flow in the anterior tibial muscle of both extremities were investigated 2.7 yrs (average) after cardiac catheterization. The method used involved /sup 133/Xe clearance. Resting blood flow was normal and no difference could be demonstrated between the extremity originally used for catheterization and the contralateral control extremity. No disturbance in maximal blood flow could be proved in the extremity used for catheterization by the venous route only. Maximal blood flow was significantly lower in that extremity where the femoral artery had been catheterized or cannulated for pressure measurement and blood sampling. The disturbance in maximal flow was shown regardless of whether the arterial catheterization involved the Seldinger percutaneous technique, arteriotomy, or mere cannulation of the femoral artery. The values in the involved extremity did not differ significantly from the values in a healthy population.

  12. Expression of manganese superoxide dismutase in rat blood, heart and brain during induced systemic hypoxia

    Directory of Open Access Journals (Sweden)

    Septelia I. Wanandi

    2011-02-01

    Full Text Available Background: Hypoxia results in an increased generation of ROS. Until now, little is known about the role of MnSOD - a major endogenous antioxidant enzyme - on the cell adaptation response against hypoxia. The aim of this study was to  determine the MnSOD mRNA expression and levels of specific activity in blood, heart and brain of rats during induced systemic hypoxia.Methods: Twenty-five male Sprague Dawley rats were subjected to systemic hypoxia in an hypoxic chamber (at 8-10% O2 for 0, 1, 7, 14 and 21 days, respectively. The mRNA relative expression of MnSOD was analyzed using Real Time RT-PCR. MnSOD specific activity was determined using xanthine oxidase inhibition assay.Results: The MnSOD mRNA relative expression in rat blood and heart was decreased during early induced systemic hypoxia (day 1 and increased as hypoxia continued, whereas the mRNA expression in brain was increased since day 1 and reached its maximum level at day 7. The result of MnSOD specific activity during early systemic hypoxia was similar to the mRNA expression. Under very late hypoxic condition (day 21, MnSOD specific activity in blood, heart and brain was significantly decreased. We demonstrate a positive correlation between MnSOD mRNA expression and specific activity in these 3 tissues during day 0-14 of induced systemic hypoxia. Furthermore, mRNA expression and specific activity levels in heart strongly correlate with those in blood.Conclusion: The MnSOD expression at early and late phases of induced systemic hypoxia is distinctly regulated. The MnSOD expression in brain differs from that in blood and heart revealing that brain tissue can  possibly survive better from induced systemic hypoxia than heart and blood. The determination of MnSOD expression in blood can be used to describe its expression in heart under systemic hypoxic condition. (Med J Indones 2011; 20:27-33Keywords: MnSOD, mRNA expression, ROS, specific activity, systemic hypoxia

  13. Blood-brain barrier transport of non-viral gene and RNAi therapeutics.

    Science.gov (United States)

    Boado, Ruben J

    2007-09-01

    The development of gene- and RNA interference (RNAi)-based therapeutics represents a challenge for the drug delivery field. The global brain distribution of DNA genes, as well as the targeting of specific regions of the brain, is even more complicated because conventional delivery systems, i.e. viruses, have poor diffusion in brain when injected in situ and do not cross the blood-brain barrier (BBB), which is only permeable to lipophilic molecules of less than 400 Da. Recent advances in the "Trojan Horse Liposome" (THL) technology applied to the transvascular non-viral gene therapy of brain disorders presents a promising solution to the DNA/RNAi delivery obstacle. The THL is comprised of immunoliposomes carrying either a gene for protein replacement or small hairpin RNA (shRNA) expression plasmids for RNAi effect, respectively. The THL is engineered with known lipids containing polyethyleneglycol (PEG), which stabilizes its structure in vivo in circulation. The tissue target specificity of THL is given by conjugation of approximately 1% of the PEG residues to peptidomimetic monoclonal antibodies (MAb) that bind to specific endogenous receptors (i.e. insulin and transferrin receptors) located on both the BBB and the brain cellular membranes, respectively. These MAbs mediate (a) receptor-mediated transcytosis of the THL complex through the BBB, (b) endocytosis into brain cells and (c) transport to the brain cell nuclear compartment. The present review presents an overview of the THL technology and its current application to gene therapy and RNAi, including experimental models of Parkinson's disease and brain tumors.

  14. Effects of detraining after blood flow-restricted low-intensity concentric or eccentric training on muscle size and strength.

    Science.gov (United States)

    Yasuda, Tomohiro; Loenneke, Jeremy P; Thiebaud, Robert S; Abe, Takashi

    2015-01-01

    We investigated the effects of 6 weeks of detraining on muscle size and strength in young men who had previously participated in 6 weeks (3 days/week) of 30 % of concentric one-repetition maximal (1-RM) dumbbell curl training [one arm: concentric blood flow restricted (BFR) exercise (CON-BFR); the other arm: eccentric BFR exercise (ECC-BFR)]. MRI-measured muscle cross-sectional area (CSA) at 10 cm above the elbow joint increased from pre to post (p hypertrophy.

  15. Mitochondrial energetic metabolism perturbations in skeletal muscles and brain of zebrafish (Danio rerio) exposed to low concentrations of waterborne uranium

    Energy Technology Data Exchange (ETDEWEB)

    Lerebours, Adelaide; Adam-Guillermin, Christelle [Laboratoire de Radioecologie et d' Ecotoxicologie, Institut de Radioprotection et de Surete Nucleaire, Bat 186, BP 3, 13115 Saint-Paul-Lez-Durance Cedex (France); Brethes, Daniel [CNRS, UMR 5095, Institut de Biochimie et Genetique Cellulaires, Universite Victor Segalen-Bordeaux 2 (France); Frelon, Sandrine; Floriani, Magali; Camilleri, Virginie; Garnier-Laplace, Jacqueline [Laboratoire de Radioecologie et d' Ecotoxicologie, Institut de Radioprotection et de Surete Nucleaire, Bat 186, BP 3, 13115 Saint-Paul-Lez-Durance Cedex (France); Bourdineaud, Jean-Paul, E-mail: jp.bourdineaud@epoc.u-bordeaux1.fr [CNRS, UMR 5095, Institut de Biochimie et Genetique Cellulaires, Universite Victor Segalen-Bordeaux 2 (France)

    2010-10-01

    Anthropogenic release of uranium (U), originating from the nuclear fuel cycle or military activities, may considerably increase U concentrations in terrestrial and aquatic ecosystems above the naturally occurring background levels found throughout the environment. With a projected increase in the world-wide use of nuclear power, it is important to improve our understanding of the possible effects of this metal on the aquatic fauna at concentrations commensurate with the provisional drinking water guideline value of the World Health Organization (15 {mu}g U/L). The present study has examined the mitochondrial function in brain and skeletal muscles of the zebrafish, Danio rerio, exposed to 30 and 100 {mu}g/L of waterborne U for 10 and 28 days. At the lower concentration, the basal mitochondrial respiration rate was increased in brain at day 10 and in muscles at day 28. This is due to an increase of the inner mitochondrial membrane permeability, resulting in a decrease of the respiratory control ratio. In addition, levels of cytochrome c oxidase subunit IV (COX-IV) increased in brain at day 10, and those of COX-I increased in muscles at day 28. Histological analyses performed by transmission electron microscopy revealed an alteration of myofibrils and a dilatation of endomysium in muscle cells. These effects were largest at the lowest concentration, following 28 days of exposure.

  16. Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects

    DEFF Research Database (Denmark)

    Dam, Gitte; Keiding, Susanne; Munk, Ole Lajord

    2011-01-01

    Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle...... the metabolism of blood-supplied ammonia and the A-V measurements were used to measure the total ammonia metabolism across the thigh muscle. After intake of BCAA, blood ammonia increased more than 30% in both groups of subjects (both P ....05). BCAA intake led to a massive glutamine release from the muscle (cirrhotic patients, P BCAA enhanced the intrinsic muscle metabolism of ammonia but not the metabolism of blood-supplied ammonia in both the patients with cirrhosis and in the healthy...

  17. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors

    DEFF Research Database (Denmark)

    Larsson, H B; Stubgaard, M; Frederiksen, Jette Lautrup Battistini;

    1990-01-01

    In this study quantitation of the degree of deficiency of the blood-brain barrier (BBB) in patients with multiple sclerosis or brain tumors, by using MRI, is shown to be possible. As a measure of permeability of the BBB to Gadolinium-DTPA (Gd-DTPA) the flux per unit of distribution volume per unit...

  18. Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging : A possible role in progressive neurodegeneration

    NARCIS (Netherlands)

    Bartels, Anna L.; Kortekaas, Rudie; Bart, Joost; Willemsen, Antoon T. M.; de Klerk, Onno L.; de Vries, Jeroen J.; van Oostrom, Joost C. H.; Leenders, Klaus L.

    2009-01-01

    Cerebrovascular P-glycoprotein (P-gp) acts at the blood-brain barrier (BBB) as an active cell membrane efflux pump for several endogenous and exogenous compounds. Age-associated decline in P-gp function could facilitate the accumulation of toxic substances in the brain, thus increasing the risk of n

  19. Effects of short-term detraining following blood flow restricted low-intensity training on muscle size and strength.

    Science.gov (United States)

    Yasuda, Tomohiro; Loenneke, Jeremy P; Ogasawara, Riki; Abe, Takashi

    2015-01-01

    We investigated the effects of 3 weeks of detraining on muscle cross-sectional area (CSA) and one-repetition maximum strength (1-RM) in young men who had previously participated in 6 weeks (3 days week(-1) ) of bench press training [blood flow restricted low-intensity (LI-BFR; n = 10, 20% 1-RM) or high-intensity (HI; n = 7, 75% 1-RM)]. Bench press 1-RM and muscle CSA of triceps brachii (TB) and pectoralis major (PM) were evaluated before (pre) and after training period (post) as well as after detraining period (detraining). Bench press 1-RM was higher at both post and detraining than at pre for LI-BFR (Pmuscle CSA were higher at both post and detraining than at pre for the HI group (Pmuscle CSA) was higher at both post and detraining than at pre for the HI group (Pmuscle strength following 6 weeks of training with LI-BFR as well as HI was well preserved at 3 weeks of detraining. HI-induced muscle strength appears to be dependent upon both neural adaptations and muscle hypertrophy with training and detraining. On the other hand, LI-BFR-induced muscle strength appears to be related primarily to muscle hypertrophy with training and to neural adaptations with detraining.

  20. Estrogen provides neuroprotection against brain edema and blood brain barrier disruption through both estrogen receptors α and β following traumatic brain injury

    Directory of Open Access Journals (Sweden)

    Vida Naderi

    2015-02-01

    Full Text Available Objective(s:Estrogen (E2 has neuroprotective effects on blood-brain-barrier (BBB after traumatic brain injury (TBI. In order to investigate the roles of estrogen receptors (ERs in these effects, ER-α antagonist (MPP and, ER-β antagonist (PHTPP, or non-selective estrogen receptors antagonist (ICI 182780 were administered. Materials and Methods: Ovariectomized rats were divided into 10 groups, as follows: Sham, TBI, E2, oil, MPP+E2, PHTPP+E2, MPP+PHTPP+E2, ICI+E2, MPP, and DMSO. E2 (33.3 µg/Kg or oil were administered 30 min after TBI. 1 dose (150 µg/Kg of each of MPP, PHTPP, and (4 mg/kg ICI182780 was injected two times, 24 hr apart, before TBI and estrogen treatment. BBB disruption (Evans blue content and brain edema (brain water content evaluated 5 hr and 24 hr after the TBI were evaluated, respectively. Results: The results showed that E2 reduced brain edema after TBI compared to vehicle (P

  1. Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs.

    Science.gov (United States)

    Ufnal, Marcin; Skrzypecki, Janusz

    2014-04-01

    Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure.

  2. CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier

    Science.gov (United States)

    Haskó, János; Fazakas, Csilla; Molnár, Judit; Nyúl-Tóth, Ádám; Herman, Hildegard; Hermenean, Anca; Wilhelm, Imola; Persidsky, Yuri; Krizbai, István A.

    2014-01-01

    During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2); therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A), GPR18 (transcriptional variant 1) and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A), GPR18 (transcriptional variants 1 and 2), GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma. PMID:24815068

  3. CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    János Haskó

    2014-05-01

    Full Text Available During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB. The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2; therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A, GPR18 (transcriptional variant 1 and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A, GPR18 (transcriptional variants 1 and 2, GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma.

  4. Are blood flow and lipolysis in subcutaneous adipose tissue influenced by contractions in adjacent muscles in humans?

    DEFF Research Database (Denmark)

    Stallknecht, Bente; Dela, Flemming; Helge, Jørn Wulff

    2006-01-01

    Aerobic exercise increases whole body adipose tissue lipolysis, but is lipolysis higher in subcutaneous adipose tissue (SCAT) adjacent to contracting muscles than in SCAT adjacent to resting muscles? Ten healthy, overnight-fasted males performed one-legged knee extension exercise at 25% of maximal...... workload (W(max)) for 30 min followed by exercise at 55% W(max) for 120 min with the other leg and finally exercised at 85% W(max) for 30 min with the first leg. Subjects rested for 30 min between exercise periods. Femoral SCAT blood flow was estimated from washout of (133)Xe, and lipolysis was calculated...... from femoral SCAT interstitial and arterial glycerol concentrations and blood flow. In general, blood flow and lipolysis were higher in femoral SCAT adjacent to contracting than adjacent to resting muscle (time 15-30 min; blood flow: 25% W(max) 6.6 +/- 1.0 vs. 3.9 +/- 0.8 ml x 100 g(-1) x min(-1), P...

  5. Permeability of the blood-brain barrier predicts conversion from optic neuritis to multiple sclerosis

    DEFF Research Database (Denmark)

    Cramer, Stig P; Modvig, Signe; Simonsen, Helle Juhl

    2015-01-01

    Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities in the per......Optic neuritis is an acute inflammatory condition that is highly associated with multiple sclerosis. Currently, the best predictor of future development of multiple sclerosis is the number of T2 lesions visualized by magnetic resonance imaging. Previous research has found abnormalities...... with cerebrospinal fluid markers of inflammation, cellular trafficking and blood-brain barrier breakdown. To this end, we applied dynamic contrast-enhanced magnetic resonance imaging at 3 T to measure blood-brain barrier permeability in 39 patients with monosymptomatic optic neuritis, all referred for imaging...

  6. Comparison of blood-brain barrier disruption by intracarotid iopamidol and methylglucamine iothalamate.

    Science.gov (United States)

    Sage, M R; Wilcox, J; Evill, C A; Benness, G T

    1983-01-01

    Using a canine model, the effect of intracarotid injections of the ionic contrast medium methylglucamine iothalamate was compared with that of the nonionic contrast medium iopamidol of similar iodine concentration (280 mg 1/ml). The degree and distribution of blood-brain barrier disruption was assessed using Evans blue stain as a visual marker and by contrast enhancement measured by a computed tomographic (CT) scanner. In all studies with methylglucamine iothalamate, Evans blue staining was demonstrated, and CT enhancement demonstrated a significant mean difference (p less than 0.01) between the control and injected hemispheres. The absence of blood-brain barrier disruption with iopamidol is probably related to its lower osmolality (570 mosmol/kg) compared with methylglucamine iothalamate (1,424 mosmol/kg) and the absence of any cation.

  7. Changes in blood-brain barrier function modify the neuroendocrine response to circulating substances.

    Science.gov (United States)

    Jezová, D; Johansson, B B; Oprsalová, Z; Vigas, M

    1989-04-01

    It is known that various experimental, pathological and even physiological situations may be accompanied by transient increases in blood-brain barrier (BBB) permeability. The hypothesis that under such conditions the blood-borne substances can reach the active sites in the brain in concentrations high enough to influence central control of hormone release was verified in these studies. A suitable experimental model of BBB opening by protamine sulfate administration in conscious rats was introduced. Using this model it was shown that the dopaminergic blocker domperidone inhibited apomorphine-induced ACTH release if permeability of the BBB was increased, but not under normal conditions. It is suggested that the changes in BBB function can modify the neuroendocrine response also to other circulating substances and this may be an important, until now unconsidered phenomenon in neuroendocrine research.

  8. Brain glucagon-like peptide–1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage

    Science.gov (United States)

    Knauf, Claude; Cani, Patrice D.; Perrin, Christophe; Iglesias, Miguel A.; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J.; Kahn, C. Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M.; Postic, Catherine; Burcelin, Rémy

    2005-01-01

    Intestinal glucagon-like peptide–1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9–39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state. PMID:16322793

  9. Brain glucagon-like peptide-1 increases insulin secretion and muscle insulin resistance to favor hepatic glycogen storage.

    Science.gov (United States)

    Knauf, Claude; Cani, Patrice D; Perrin, Christophe; Iglesias, Miguel A; Maury, Jean François; Bernard, Elodie; Benhamed, Fadilha; Grémeaux, Thierry; Drucker, Daniel J; Kahn, C Ronald; Girard, Jean; Tanti, Jean François; Delzenne, Nathalie M; Postic, Catherine; Burcelin, Rémy

    2005-12-01

    Intestinal glucagon-like peptide-1 (GLP-1) is a hormone released into the hepatoportal circulation that stimulates pancreatic insulin secretion. GLP-1 also acts as a neuropeptide to control food intake and cardiovascular functions, but its neural role in glucose homeostasis is unknown. We show that brain GLP-1 controlled whole-body glucose fate during hyperglycemic conditions. In mice undergoing a hyperglycemic hyperinsulinemic clamp, icv administration of the specific GLP-1 receptor antagonist exendin 9-39 (Ex9) increased muscle glucose utilization and glycogen content. This effect did not require muscle insulin action, as it also occurred in muscle insulin receptor KO mice. Conversely, icv infusion of the GLP-1 receptor agonist exendin 4 (Ex4) reduced insulin-stimulated muscle glucose utilization. In hyperglycemia achieved by i.v. infusion of glucose, icv Ex4, but not Ex9, caused a 4-fold increase in insulin secretion and enhanced liver glycogen storage. However, when glucose was infused intragastrically, icv Ex9 infusion lowered insulin secretion and hepatic glycogen levels, whereas no effects of icv Ex4 were observed. In diabetic mice fed a high-fat diet, a 1-month chronic i.p. Ex9 treatment improved glucose tolerance and fasting glycemia. Our data show that during hyperglycemia, brain GLP-1 inhibited muscle glucose utilization and increased insulin secretion to favor hepatic glycogen stores, preparing efficiently for the next fasting state.

  10. Organochlorine contaminants in the muscle, liver and brain of seabirds (Larus) from the coastal area of the Southern Baltic.

    Science.gov (United States)

    Falkowska, Lucyna; Reindl, Andrzej R; Grajewska, Agnieszka; Lewandowska, Anita U

    2016-11-01

    The presence of persistent organic pollutants in the environment manifests itself most strongly in the marine trophic chain, where the highest link is comprised of seabirds. At the same time, seabirds are excellent indicators of contamination in their habitat. The present study concentrates on toxic substances: polychlorinated dibenzo-p-dioxin (PCDDs), polychlorinated dibenzofurans (PCDFs) and chlorinated organic pesticides (OCPs) accumulated in the livers, pectoral muscles and brains of dead gulls collected along the Polish coast of the Baltic Sea in the years 2010-12. The highest toxic equivalence was determined in the livers of Larus argentatus (TEQ(birds TEF)-28.3pgg(-1) ww) and Larus marinus (TEQ(birds TEF)-29.9pgg(-1) ww.). However, the toxic equivalence of muscles was lower and amounted to 3.9pgg(-1) ww. and 7.8pgg(-1) ww. respectively for the two species. The lowest toxic equivalence was found in the brains of birds, where only one, the most toxic, 2,3,7,8 TCDD congener was found (TEQ(birds TEF) 0.87pgg(-1) ww). The highest concentration of chloroorganic pesticides was determined in the brains of the birds (total OCP 167.8pgg(-1) ww.), lower concentrations were found in the livers (total OCP 92.1pgg(-1) ww.) and muscles (total OCP 43.1pgg(-1) ww.). With regard to pesticides, the highest proportion in the total OCP content was constituted by DDT and its isomers (liver 81%, muscles 77% and brain 55%). High concentrations of the studied pollutants in the livers of gulls found dead on the coast of the Southern Baltic could have been effected by levels of contamination in the birds' last meals, which resulted in a seven-fold increase of the liver's toxic equivalence and a two-fold increase in OCP concentration in relation to muscles.

  11. Changes in the permeability of blood brain barrier and endothelial cell damage after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Ke Liu; Jiansheng Li

    2006-01-01

    OBJECTIVE: To investigate the effect of endothelial cells on the permeability of blood brain barrier (BBB) after brain injury and its effect mechanism.DATA SOURCES: We searched for the articles of permeability of BBB and endothelial cell injury after brain ischemia, which were published between January 1982 and December 2005, with the key words of "cerebral ischemia damage,blood brain barrier ( BBB),permeability,effect of endothelial cell (EC) and its variation mechanism"in English.STUDY SELECTION: The materials were primarily selected. The articles related to the changes in the permeability of BBB and the effect of endothelial cells as well as the change mechanism after cerebral ischemia damage were chosen. Repetitive studies or review articles were excluded.DATA EXTRACTION: Totally 55 related articles were collected, and 35 were excluded due to repetitive or review articles, finally 20 articles were involved.DATA SYNTHESIS: The content or viewpoints of involved literatures were analyzed. Cerebral ischemia had damage for endothelial cells, such as the inflow of a lot of Ca2+, the production of nitrogen monoxide and oxygen free radical, and aggravated destruction of BBB. After acceptors of inflammatory mediators on cerebrovascular endothelial cell membrane, such as histamine, bradykinin , 5-hydroxytryptamine and so on are activated, endothelial cells shrink and the permeability of BBB increases. Its mechanism involves in the inflow of extracellular Ca2+and the release of intracellular Ca2+ in the cells. Glycocalyx molecule on the surface of endothelial cell, having structural polytropy, is the determinative factor of the permeability of BBB. VEGF, intensively increasing the vasopermeability and mainly effecting on postcapillary vein and veinlet, is the strongest known blood vessel permeation reagent. Its chronic overexpression in the brain can lead the destruction of BBB.CONCLUSION: The injury of endothelial cell participants in the pathological mechanism of BBB

  12. MAPK and pro-inflammatory mediators in the walls of brain blood vessels following cerebral ischemia

    OpenAIRE

    Maddahi, Aida

    2012-01-01

    INTRODUCTION Stroke is a serious neurological disease which may lead to death and severe disability [1, 2]. There are two major types of stroke: ischemic and hemorrhagic stroke. Both are associated with disruption of blood flow to a part of the brain with rapid depletion of cellular energy and oxygen, resulting in ionic disturbances and eventually neuronal cell death [3]. The pathologic process that develops after stroke is divided into acute (within hours), sub-acute (hours to days), ...

  13. Rheoencephalography (REG) as a Non-Invasive Monitoring Alternative for the Assessment of Brain Blood Flow

    Science.gov (United States)

    2004-09-01

    bioimpedance (rheoencephalography - REG) measurement as a non-invasive, continuous method for assessing the status of cerebral blood flow (CBF) in combat...Dunster KR, Colditz PB, Ward LC. Noninvasive measurement of cerebral bioimpedance for detection of cerebral edema in the neonatal piglet. Brain Res...REG measurements and DC impedance (Ro) were recorded simultaneously on a portable IBM compatible computer using CODAS (DATAQ, Inc., Akron, OH) data

  14. A fragment-based approach for the in silico prediction of blood-brain barrier permeation

    OpenAIRE

    Moda, Tiago L.; Carrara, Alexandre E.; Andricopulo, Adriano Defini

    2012-01-01

    Blood-brain barrier (BBB) permeation is an essential property for drugs that act in the central nervous system (CNS) for the treatment of human diseases, such as epilepsy, depression, Alzheimer's disease, Parkinson disease, schizophrenia, among others. In the present work, quantitative structure-property relationship (QSPR) studies were conducted for the development and validation of in silico models for the prediction of BBB permeation. The data set used has substantial chemical diversity an...

  15. Comparison between PVHIS on the MRI and the permeability of brain blood vessels in elderly patients

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, Katsuhiko; Tanaka, Yuriko; Kubo, Hideki; Takagi, Yasushi; Tachikawa, Shinzo (Omotemachi Hospital, Tachikawa General Hospital, Tokyo (Japan)); Katsunuma, Hideyo

    1989-11-01

    The degree of PVHIS (periventricular high intensity signal) on the MRI was composed with the permeability of brain blood vessels using the cerebrospinal fluid (CSF)/serum ratio for albumin, and the CSF/serum ratio for IgG in elderly patients. The 47 elderly patients (mean age=79.9) were divided into three groups: (1) Mild group (20 cases, M:6, F:14, mean age=75.8), (2) Moderate group (18 cases, M:7, F:11, mean age=82.6), (3) Severe group (9 cases, M:2, F:7, mean age=82.9), in accordance with the degree of PVHIS on the MRI. The MRI was operated at a field strength of 0.22 tesla. The pulse sequence (used on all patients) had a repetition times (TR) of 2,000 msec and a time to echo (TE) of 40 msec. The levels of albumin and IgG in the serum and CSF were measured. The CSF/serum ratio for albumin was used of analyze the permeability of the brain blood vessels in each group. There was no significant difference in the level of the serum albumin, the CSF albumin, the serum IgG, the CSF IgG and the CSF/serum ratio for IgG among the three groups. The same was found to be true for the IgG index which indicates the synthesis of immunoglobulin in the central nervous system. However, there was a statistically significant difference (p<0.05) in the CSF/serum ratio for albumin between groups (1) and (3). The increased CSF/serum ratio for albumin in the severe group indicated there were confluent lesions involving the entire extent of the periventriular white matter on the MRI. This suggested an increased permeability of brain blood vessels which revealed the dysfunction of the blood brain barrier due to affected cerebral endothelial cells in capillaries. (author).

  16. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain

    OpenAIRE

    2016-01-01

    The brain has high metabolic and energy needs and requires continuous cerebral blood flow (CBF), which is facilitated by a tight coupling between neuronal activity, CBF, and metabolism. Upon neuronal activation, there is an increase in energy demand, which is then met by a hemodynamic response that increases CBF. Such regional CBF increase in response to neuronal activation is observed using neuroimaging techniques such as functional magnetic resonance imaging and positron emission tomography...

  17. Muscle Deoxygenation Causes Muscle Fatigue

    Science.gov (United States)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D.

    1999-01-01

    Muscle fatigue is a common musculoskeletal disorder in the work place, and may be a harbinger for more disabling cumulative trauma disorders. Although the cause of fatigue is multifactorial, reduced blood flow and muscle oxygenation may be the primary factor in causing muscle fatigue during low intensity muscle exertion. Muscle fatigue is defined as a reduction in muscle force production, and also occurs among astronauts who are subjected to postural constraints while performing lengthy, repetitive tasks. The objectives of this research are to: 1) develop an objective tool to study the role of decreased muscle oxygenation on muscle force production, and 2) to evaluate muscle fatigue during prolonged glovebox work.

  18. Targeting nanoparticles across the blood-brain barrier with monoclonal antibodies.

    Science.gov (United States)

    Loureiro, Joana A; Gomes, Bárbara; Coelho, Manuel A N; do Carmo Pereira, Maria; Rocha, Sandra

    2014-04-01

    Development of therapeutics for brain disorders is one of the more difficult challenges to be overcome by the scientific community due to the inability of most molecules to cross the blood-brain barrier (BBB). Antibody-conjugated nanoparticles are drug carriers that can be used to target encapsulated drugs to the brain endothelial cells and have proven to be very promising. They significantly improve the accumulation of the drug in pathological sites and decrease the undesirable side effect of drugs in healthy tissues. We review the systems that have demonstrated promising results in crossing the BBB through receptor-mediated endocytic mechanisms for the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

  19. Novel insights in the dysfunction of human blood-brain barrier after glycation.

    Science.gov (United States)

    Hussain, Maryam; Bork, Kaya; Gnanapragassam, Vinayaga S; Bennmann, Dorit; Jacobs, Kathleen; Navarette-Santos, Alexander; Hofmann, Britt; Simm, Andreas; Danker, Kerstin; Horstkorte, Rüdiger

    2016-04-01

    The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE=glycation) interfere with the BBB integrity and function. Here, we present data that carbonyl stress induced by methylglyoxal leads to glycation of endothelial cells and the basement membrane, which interferes with the barrier-function and with the expression of RAGE, occludin and ZO-1. Furthermore, methylglyoxal induced carbonyl stress promotes the expression of the pro-inflammatory interleukins IL-6 and IL-8. In summary, this study provides new insights into the relationship between AGE formation by carbonyl stress and brain microvascular endothelial barrier dysfunction.

  20. Galectin-1 suppresses methamphetamine induced neuroinflammation in human brain microvascular endothelial cells: Neuroprotective role in maintaining blood brain barrier integrity.

    Science.gov (United States)

    Parikh, Neil U; Aalinkeel, R; Reynolds, J L; Nair, B B; Sykes, D E; Mammen, M J; Schwartz, S A; Mahajan, S D

    2015-10-22

    Methamphetamine (Meth) abuse can lead to the breakdown of the blood-brain barrier (BBB) integrity leading to compromised CNS function. The role of Galectins in the angiogenesis process in tumor-associated endothelial cells (EC) is well established; however no data are available on the expression of Galectins in normal human brain microvascular endothelial cells and their potential role in maintaining BBB integrity. We evaluated the basal gene/protein expression levels of Galectin-1, -3 and -9 in normal primary human brain microvascular endothelial cells (BMVEC) that constitute the BBB and examined whether Meth altered Galectin expression in these cells, and if Galectin-1 treatment impacted the integrity of an in-vitro BBB. Our results showed that BMVEC expressed significantly higher levels of Galectin-1 as compared to Galectin-3 and -9. Meth treatment increased Galectin-1 expression in BMVEC. Meth induced decrease in TJ proteins ZO-1, Claudin-3 and adhesion molecule ICAM-1 was reversed by Galectin-1. Our data suggests that Galectin-1 is involved in BBB remodeling and can increase levels of TJ proteins ZO-1 and Claudin-3 and adhesion molecule ICAM-1 which helps maintain BBB tightness thus playing a neuroprotective role. Galectin-1 is thus an important regulator of immune balance from neurodegeneration to neuroprotection, which makes it an important therapeutic agent/target in the treatment of drug addiction and other neurological conditions.

  1. From blood to brain: amoeboid microglial cell, a nascent macrophage and its functions in developing brain

    Institute of Scientific and Technical Information of China (English)

    Charanjit KAUR; S Thameem DHEEN; Eng-ang LING

    2007-01-01

    Amoeboid microglial cells (AMC) in the developing brain are active macrophages.The macrophagic nature of these cells has been demonstrated by many methods,such as the localization of various hydrolytic enzymes and the presence of comple-ment type 3 surface receptors in them. More importantly is the direct visualization of these cells engaged in the phagocytosis of degenerating cells at the ultrastruc-tural level. Further evidence of them being active macrophages is the avid inter-nalization of tracers administered by the intravenous or intraperitoneal routes in developing rats. The potential involvement of AMC in immune functions is sup-ported by the induced expression of major histocompatibility complex class Ⅰ and Ⅱ antigens on them when challenged by lipopolysaccharide or interferon-γ. Im-munosuppressive drugs, such as glucocorticoids and immune function-enhanc-ing drugs like melatonin, affect the expression of surface receptors and antigens and the release of cytokines by AMC. Recent studies in our laboratory have shown the expression of insulin-like growth factors, endothelins, 21,31-cyclic nucle-otide 31-phosphodiesterase, and N-methyl-D-asparate receptors. This along with the release of chemokines, such as stromal derived factor-la and monocyte chemoattractant protein-1, suggests multiple functional roles of AMC in early brain development.

  2. Brain-derived neurotrophic factor enhances cholinergic contraction of longitudinal muscle of rabbit intestine via activation of phospholipase C.

    Science.gov (United States)

    Al-Qudah, M; Anderson, C D; Mahavadi, S; Bradley, Z L; Akbarali, H I; Murthy, K S; Grider, J R

    2014-02-15

    Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of proteins best known for its role in neuronal survival, differentiation, migration, and synaptic plasticity in central and peripheral neurons. BDNF is also widely expressed in nonneuronal tissues including the gastrointestinal tract. The role of BDNF in intestinal smooth muscle contractility is not well defined. The aim of this study was to identify the role of BDNF in carbachol (CCh)- and substance P (SP)-induced contraction of intestinal longitudinal smooth muscle. BDNF, selective tropomyosin-related kinase B (TrkB) receptor agonists, and pharmacological inhibitors of signaling pathways were examined for their effects on contraction of rabbit intestinal longitudinal muscle strips induced by CCh and SP. BDNF activation of intracellular signaling pathways was examined by Western blot in homogenates of muscle strips and isolated muscle cells. One-hour preincubation with BDNF enhanced intestinal muscle contraction induced by CCh but not by SP. The selective synthetic TrkB agonists LM 22A4 and 7,8-dihydroxyflavone produced similar effects to BDNF. The Trk antagonist K-252a, a TrkB antibody but not p75NTR antibody, blocked the effect of BDNF. The enhancement of CCh-induced contraction by BDNF was blocked by the phospholipase C (PLC) antagonist U73122, but not by ERK1/2 or Akt antagonists. Direct measurement in muscle strips and isolated muscle cells showed that BDNF caused phosphorylation of TrkB receptors and PLC-γ, but not ERK1/2 or Akt. We conclude that exogenous BDNF augments the CCh-induced contraction of longitudinal muscle from rabbit intestine by activating TrkB receptors and subsequent PLC activation.

  3. Endothelial cells of the blood-brain barrier: a target for glucocorticoids and estrogens?

    Science.gov (United States)

    Dietrich, Jean-Bernard

    2004-01-01

    Adhesion molecules are involved in the leukocyte recruitment of leukocytes at the blood-brain barrier. For this reason, it is important to understand how the regulation of their gene expression controls lymphocyte adhesion to endothelial cells in microvessels. Indeed, due to their specificity and diversity, adhesion molecules involved in extravasation play an essential role in the recruitment of activated leukocytes and activation of inflammation. Multiple sclerosis results from a chronic inflammation of the CNS which is mediated by infiltration of inflammatory cells from the immune system. Administration of glucocorticoids is a routine method to control multiple sclerosis since naturally derived or synthetic glucocorticoids are potent immunosuppressive and anti-inflammatory agents. Glucocorticoids also have beneficial effects in stabilizing the blood-brain barrier, as steroid hormones regulate the expression of adhesion molecule genes in endothelial cells. Other hormones such as estrogens modulate many endothelial cell biological activities, among them adhesion to leukocytes. They regulate expression of adhesion molecules genes on endothelial cells and are useful for the treatment of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The effects of glucocorticoids and estrogens on the expression of adhesion molecules on endothelial cells, including microvascular endothelial cells of the blood-brain barrier, are reviewed in this paper, as well as the involvement of these hormones in the therapy of experimental autoimmune encephalomyelitis and multiple sclerosis.

  4. Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier.

    Science.gov (United States)

    Pardridge, William M

    2010-04-01

    Nonviral plasmid DNA is delivered to the brain via a transvascular route across the blood-brain barrier (BBB) following intravenous administration of DNA encapsulated within Trojan horse liposomes (THLs), also called PEGylated immunoliposomes (PILs). The liposome surface is covered with several thousand strands of polymer (e.g., polyethylene glycol [PEG]), and the tips of 1%-2% of the polymer strands are conjugated with a targeting monoclonal antibody that acts as a molecular Trojan horse (MTH). The MTH binds to a receptor (e.g., for transferrin or insulin) on the BBB and brain cell membrane, triggering receptor-mediated transcytosis of the THL across the BBB in vivo, and receptor-mediated endocytosis into brain cells beyond the BBB. The persistence of transgene expression in the brain is inversely related to the rate of degradation of the episomal plasmid DNA. THL technology enables an exogenous gene to be widely expressed in the majority of cells in adult brain (or other organs) within 1 d of a single intravenous administration. Applications of the THLs include tissue-specific gene expression with tissue-specific promoters, complete normalization of striatal tyrosine hydroxylase in experimental Parkinson's disease following intravenous tyrosine hydroxylase gene therapy, a 100% increase in survival time of mice with brain tumors following weekly intravenous antisense gene therapy using THLs, and a 90% increase in survival time with weekly intravenous RNA interference (RNAi) gene therapy in mice with intracranial brain tumors. This protocol describes the preparation of THLs for use in gene transfer in vitro or in vivo.

  5. Effects of insulin on hexose transport across blood-brain barrier in normoglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Namba, H.; Lucignani, G.; Nehlig, A.; Patlak, C.; Pettigrew, K.; Kennedy, C.; Sokoloff, L.

    1987-03-01

    The effects of insulin on 3-O-(/sup 14/C) methylglucose transport across the blood-brain barrier (BBB) were studied in conscious rats under steady-state normoglycemic conditions. The (/sup 14/C)methylglucose was infused intravenously at a constant rate, and animals were killed at various times between 5 and 30 min after the initiation of the infusion. The time course of the arterial plasma concentration of (/sup 14/C)methylglucose was determined in timed arterial blood samples taken during the infusion. Local cerebral tissue concentrations of (/sup 14/C)methylglucose at the time of killing were determined by quantitative autoradiography of brain sections. The rate constants for inward and outward transport of (/sup 14/C)methylglucose across the BBB, K/sub 1/, and k/sub 2/, respectively, were estimated by a least-squares, best-fit of a kinetic equation to the measured time courses of plasma and tissue concentrations. The equilibrium distribution ration, K/sub 1//k/sub 2/, for (/sup 14/C)methylglucose in brain increased by approx. 10-11% in the hyperinsulinemic animals. Because 3-O-(/sup 14/C)methylglucose shares the same carrier that transports glucose and other hexoses across the BBB, these results suggest that hyperinsulinemia decreases the rate constants for transport but increases the distribution space for hexoses in brain. These effects are, however, quite small and are probably minor or negligible when compared with the major effects of insulin in other tissues.

  6. A stable and reproducible human blood-brain barrier model derived from hematopoietic stem cells.

    Directory of Open Access Journals (Sweden)

    Romeo Cecchelli

    Full Text Available The human blood brain barrier (BBB is a selective barrier formed by human brain endothelial cells (hBECs, which is important to ensure adequate neuronal function and protect the central nervous system (CNS from disease. The development of human in vitro BBB models is thus of utmost importance for drug discovery programs related to CNS diseases. Here, we describe a method to generate a human BBB model using cord blood-derived hematopoietic stem cells. The cells were initially differentiated into ECs followed by the induction of BBB properties by co-culture with pericytes. The brain-like endothelial cells (BLECs express tight junctions and transporters typically observed in brain endothelium and maintain expression of most in vivo BBB properties for at least 20 days. The model is very reproducible since it can be generated from stem cells isolated from different donors and in different laboratories, and could be used to predict CNS distribution of compounds in human. Finally, we provide evidence that Wnt/β-catenin signaling pathway mediates in part the BBB inductive properties of pericytes.

  7. Effects of blood flow restricted low-intensity concentric or eccentric training on muscle size and strength.

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    Yasuda, Tomohiro; Loenneke, Jeremy P; Thiebaud, Robert S; Abe, Takashi

    2012-01-01

    We investigated the acute and chronic effects of low-intensity concentric or eccentric resistance training with blood flow restriction (BFR) on muscle size and strength. Ten young men performed 30% of concentric one repetition maximal dumbbell curl exercise (four sets, total 75 reps) 3 days/week for 6 weeks. One arm was randomly chosen for concentric BFR (CON-BFR) exercise only and the other arm performed eccentric BFR (ECC-BFR) exercise only at the same exercise load. During the exercise session, iEMG for biceps brachii muscles increased progressively during CON-BFR, which was greater (pexercise, muscle thickness (MTH) of the elbow flexors acutely increased (phypertrophy with BFR resistance training.

  8. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

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    Hunter Kerry

    2012-03-01

    Full Text Available Abstract Background Type 2 diabetes is a risk factor for Alzheimer's disease (AD, most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza and exenatide (Byetta are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R. Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized. Results In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza and lixisenatide (Lyxumia. We measured the kinetics of crossing the blood brain barrier (BBB, activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip. when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective. Conclusions Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of

  9. The protective effect of HET0016 on brain edema and blood-brain barrier dysfunction after cerebral ischemia/reperfusion.

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    Liu, Yu; Wang, Di; Wang, Huan; Qu, Youyang; Xiao, Xingjun; Zhu, Yulan

    2014-01-28

    N-hydroxy-N-(4-butyl-2-methylphenyl) formamidine (HET0016) is a specific 20-hydroxyeicosatetraenoic acid (20-HETE) inhibitor which was first synthesized in 2001. It has been demonstrated that HET0016 reduces cerebral infarction volume in rat middle cerebral artery occlusion (MCAO) models. However, little is known about the role of HET0016 in the blood-brain barrier (BBB) dysfunction after cerebral ischemia/reperfusion (I/R) injury. The present study was designed to examine the effect of HET0016 in a MCAO and reperfusion rat model to determine whether it protects against brain edema and BBB disruption. Rats were subjected to 90 min MCAO, followed by 4, 24, 48, and 72 h reperfusion. Brain edema was measured according to the wet and dry weight method. BBB permeability based on the extravasation of Evans blue and sodium fluorescein was detected. BBB ultrastructure alterations were presented through transmission electron microscope. Superoxide production in ischemic tissue was also measured by dihydroethidium fluorescent probe. Western blot was used to analyze the expression of Claudin-5, ZO-1, MMP-9, and JNK pathway. At 24h after reperfusion, HET0016 reduced brain edema and BBB leakage. Ultrastructural damage of BBB and the increase of superoxide production were attenuated by HET0016 treatment. Western blot showed that HET0016 suppressed the activation of MMP-9 and JNK pathway but restored the expression of Claudin-5 and ZO-1. In conclusion, these results suggest that HET0016 protects BBB dysfunction after I/R by regulating the expression of MMP-9 and tight junction proteins. Furthermore, inhibition of oxidative stress and JNK pathway may be involved in this protecting effect.

  10. Endocan immunoreactivity in the mouse brain: method for identifying nonfunctional blood vessels

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    Frahm, Krystle A.; Nash, Connor P.; Tobet, Stuart A.

    2013-01-01

    Endocan is a secreted proteoglycan that has been shown to indicate angiogenic activity: remodeling in several tumor types in humans and mice. Serum endocan levels also indicate prognosis and has been proposed as a biomarker for certain cancers. Recently, monoclonal antibodies directed against mouse endocan have been developed allowing for further characterization of endocan function and potentially as a marker for angiogenesis through immunoreactivity in endothelial tip cells. The results of the current study show that endocan immunoreactivity in the mouse brain is present in blood vascular networks including but not limited to the cortex, hippocampus and paraventricular nucleus of the hypothalamus in C57BL/6J and FVB/N mice. Endocan immunoreactivity did not vary during postnatal development or by sex. Interestingly, after vascular perfusion with fluorescein isothiocyanate (FITC), endothelial cells positive for FITC were immunonegative for endocan suggesting FITC interference with the immunohistochemistry. A small number of FITC-negative blood vessels were endocan immunoreactive suggesting the identification of new blood vessels that are not yet functional. The current study shows that endocan is normally present in the mouse brain and prior vascular perfusion with FITC may provide a useful tool for identify newly forming blood vessels. PMID:24055127

  11. Cerebral blood flow modulation insufficiency in brain networks in multiple sclerosis: A hypercapnia MRI study.

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    Marshall, Olga; Chawla, Sanjeev; Lu, Hanzhang; Pape, Louise; Ge, Yulin

    2016-12-01

    Cerebrovascular reactivity measures vascular regulation of cerebral blood flow and is responsible for maintaining healthy neurovascular coupling. Multiple sclerosis exhibits progressive neurodegeneration and global cerebrovascular reactivity deficits. This study investigates varied degrees of cerebrovascular reactivity impairment in different brain networks, which may be an underlying cause for functional changes in the brain, affecting long-distance projection integrity and cognitive function; 28 multiple sclerosis and 28 control subjects underwent pseudocontinuous arterial spin labeling perfusion MRI to measure cerebral blood flow under normocapnia (room air) and hypercapnia (5% carbon dioxide gas mixture) breathing. Cerebrovascular reactivity, measured as normocapnic to hypercapnic cerebral blood flow percent increase normalized by end-tidal carbon dioxide change, was determined from seven functional networks (default mode, frontoparietal, somatomotor, visual, limbic, dorsal, and ventral attention networks). Group analysis showed significantly decreased cerebrovascular reactivity in patients compared to controls within the default mode, frontoparietal, somatomotor, and ventral attention networks after multiple comparison correction. Regression analysis showed a significant correlation of cerebrovascular reactivity with lesion load in the default mode and ventral attention networks and with gray matter atrophy in the default mode network. Functional networks in multiple sclerosis patients exhibit varied amounts of cerebrovascular reactivity deficits. Such blood flow regulation abnormalities may contribute to functional communication disruption in multiple sclerosis.

  12. Blood-brain barrier P-glycoprotein function in Alzheimer's disease.

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    van Assema, Daniëlle M E; Lubberink, Mark; Bauer, Martin; van der Flier, Wiesje M; Schuit, Robert C; Windhorst, Albert D; Comans, Emile F I; Hoetjes, Nikie J; Tolboom, Nelleke; Langer, Oliver; Müller, Markus; Scheltens, Philip; Lammertsma, Adriaan A; van Berckel, Bart N M

    2012-01-01

    A major pathological hallmark of Alzheimer's disease is accumulation of amyloid-β in senile plaques in the brain. Evidence is accumulating that decreased clearance of amyloid-β from the brain may lead to these elevated amyloid-β levels. One of the clearance pathways of amyloid-β is transport across the blood-brain barrier via efflux transporters. P-glycoprotein, an efflux pump highly expressed at the endothelial cells of the blood-brain barrier, has been shown to transport amyloid-β. P-glycoprotein function can be assessed in vivo using (R)-[(11)C]verapamil and positron emission tomography. The aim of this study was to assess blood-brain barrier P-glycoprotein function in patients with Alzheimer's disease compared with age-matched healthy controls using (R)-[(11)C]verapamil and positron emission tomography. In 13 patients with Alzheimer's disease (age 65 ± 7 years, Mini-Mental State Examination 23 ± 3), global (R)-[(11)C]verapamil binding potential values were increased significantly (P = 0.001) compared with 14 healthy controls (aged 62 ± 4 years, Mini-Mental State Examination 30 ± 1). Global (R)-[(11)C]verapamil binding potential values were 2.18 ± 0.25 for patients with Alzheimer's disease and 1.77 ± 0.41 for healthy controls. In patients with Alzheimer's disease, higher (R)-[(11)C]verapamil binding potential values were found for frontal, parietal, temporal and occipital cortices, and posterior and anterior cingulate. No significant differences between groups were found for medial temporal lobe and cerebellum. These data show altered kinetics of (R)-[(11)C]verapamil in Alzheimer's disease, similar to alterations seen in studies where P-glycoprotein is blocked by a pharmacological agent. As such, these data indicate that P-glycoprotein function is decreased in patients with Alzheimer's disease. This is the first direct evidence that the P-glycoprotein transporter at the blood-brain barrier is compromised in sporadic

  13. Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption.

    Science.gov (United States)

    Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi; McDannold, Nathan J

    2016-09-28

    HER2-targeting antibodies (i.e. trastuzumab and pertuzumab) prolong survival in HER2-positive breast cancer patients with extracranial metastases. However, the response of brain metastases to these drugs is poor, and it is hypothesized that the blood-brain barrier (BBB) limits drug delivery to the brain. We investigated whether we could improve the response by temporary disruption of the BBB using focused ultrasound in combination with microbubbles. To study this, we inoculated 30 nude rats with HER2-positive cells derived from a brain metastasis of a breast cancer patient (MDA-MB-361). The animals were divided into three groups: a control-group that received no treatment; an antibody-only group that received six weekly treatments of trastuzumab and pertuzumab; and an ultrasound+antibody group that received trastuzumab and pertuzumab in combination with six weekly sessions of BBB disruption using focused ultrasound. In two animals, the leakiness of the tumors before disruption was evaluated using contrast-enhanced T1-weighted magnetic resonance imaging and found that the tumors were not leaky. The same technique was used to evaluate the effectiveness of BBB disruption, which was successful in all sessions. The tumor in the control animals grew exponentially with a growth constant of 0.042±0.011mm(3)/day. None of the antibody-only animals responded to the treatment and the growth constant was 0.033±0.009mm(3)/day during the treatment period. Four of the ten animals in the ultrasound+antibody-group showed a response to the treatment with an average growth constant of 0.010±0.007mm(3)/day, compared to a growth constant 0.043±0.013mm(3)/day for the six non-responders. After the treatment period, the tumors in all groups grew at similar rates. As the tumors were not leaky before BBB disruption and there were no responders in the antibody-only group, these results show that at least in some cases disruption of the BBB is necessary for a response to the antibodies in

  14. Effect of Xingnaojing injection on cerebral edema and blood-brain barrier in rats following traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    XU Miao; SU Wei; XU Qiu-ping; HUANG Wei-dong

    2010-01-01

    Objective:To explore the effects of Xingnaojing injection on cerebral edema and blood-brain barrier (BBB) in rats following traumatic brain injury (TBI).Methods: A total of 108 adult male Sprague-Dawley rats were used as subjects and randomly assigned to three groups:sham-operation,TBI and Xingnaojing injection was set up by the improved device of Feeney's weightcontent and BBB permeability expressed as Evans blue content were measured at 1, 3, 5 and 7 days after surgery.Results: In sham-operation group, brain water content and Evans blue content in brain tissue were 78.97%±1.22%and 5.13μg±0.71μg. Following TBI, water content in brain tissue was increased significantly at 1, 3, 5 and 7 days (83.49%±0.54%, 82.74%±0.72%, 80.22%±0.68%, 79.21%±0.60%), being significantly higher than that in sham operation group (P<0.05). Evans blue content was increased in TBI group (16.54 μg±0.60 μg, 14.92μg±0.71μg, 12.44 μg ±0.92μg, 10.14μg±0.52 μg) as compared with sham-operation group(P<0.05). After treatment with Xingnaojing injection, brain water content decreased as compared with TBI group (81.91%±1.04%, 80.38%±0.72%, 79.54%±0.58%,78.60%±0.77%, P<0.05). Xingnaojing injection also reduced the leakage of BBB as compared with TBI group (15.11 μg± 0.63 μg, 13.62 μg±0.85μg, 10.06 μg±0.67 μg, 9.54 μg±0.41 μg,P<0.05).Conclusion: Xingnaojing injection could alleviate cerebral edema following TBI via reducing permeability ofBBB.

  15. Carbenoxolone does not cross the blood brain barrier: an HPLC study

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    Burnham William M

    2006-01-01

    Full Text Available Abstract Background Carbenoxolone (CBX is a widely used gap junctional blocker. Considering several reports indicating that transient gap junctional blockade could be a favourable intervention following injuries to central nervous tissue, and some current enthusiasm in studies using systemic injections of CBX, it is imperative to consider the penetration of CBX into central nervous tissue after systemic administrations. So far, only very indirect evidence suggests that CBX penetrates into the central nervous system after systemic administrations. We thus determined the amounts of CBX present in the blood and the cerebrospinal fluid of rats after intraperitoneal administration, using high performance liquid chromatography Results CBX was found in the blood of the animals, up to 90 minutes post-injection. However, the cerebrospinal fluid concentration of CBX was negligible. Conclusion Thus, we conclude that, most likely, CBX does not penetrate the blood brain barrier and therefore recommend careful consideration in the manner of administration, when a central effect is desired.

  16. Mortality and blood pressure in emergency patients with traumatic brain injury: a retrospective cohort study

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    Pizza-Restrepo, María Juliana

    2016-10-01

    Full Text Available Introduction: Blood pressure is of special relevance in patients with traumatic brain injury (TBI at admission to emergency services, since it is the basis of cerebral perfusion pressure. The purpose of this research was to estimate the association between blood pressure values measured on admission and hospital mortality in patients with TBI. Methods: Retrospective cohort study in patients older than 18 years admitted with TBI to Hospital Pablo Tobón Uribe, in Medellín (Colombia between January 2012 and January 2014. A multivariate logistic regression model was performed to estimate the independent effect of blood pressure values on mortality. Results: 582 patients with a median age of 36 years (IQR = 25-59 77.1 % of them males (n = 449 were evaluated. Mortality according to categories of systolic blood pressure at admission (150 mmHg was as follows: 34.6 % (18/52, 13.3 % (56/421 and 29.4 % (32/109, respectively. Univariate analysis showed that blood pressure less than 100 or greater than 150 mm Hg were associated with hospital mortality, but that association lost magnitude and statistical significance (OR = 1.81; 95 % CI = 0.94-3.48 and OR = 1.91; 95 % CI = 0.86-4.54, respectively after adjustment by Glasgow coma scale, oxygen saturation and cerebral edema. Conclusions: We did not demonstrate a statistically significant association between blood pressure values at admission to the emergency service and mortality in patients with TBI.

  17. Measurement of cerebral blood flow rate and its relationship with brain function using optical coherence tomography

    Science.gov (United States)

    Liu, Jian; Wang, Yi; Zhao, Yuqian; Dou, Shidan; Ma, Yushu; Ma, Zhenhe

    2016-03-01

    Activity of brain neurons will lead to changes in local blood flow rate (BFR). Thus, it is important to measure the local BFR of cerebral cortex on research of neuron activity in vivo, such as rehabilitation evaluation after stroke, etc. Currently, laser Doppler flowmetry is commonly used for blood flow measurement, however, relatively low resolution limits its application. Optical coherence tomography (OCT) is a powerful noninvasive 3D imaging modality with high temporal and spatial resolutions. Furthermore, OCT can provide flow distribution image by calculating Doppler frequency shift which makes it possible for blood flow rate measurement. In this paper, we applied OCT to measure the blood flow rate of the primary motor cortex in rats. The animal was immobilized and anesthetized with isoflurane, an incision was made along the sagittal suture, and bone was exposed. A skull window was opened on the primary motor cortex. Then, blood flow rate changes in the primary motor cortex were monitored by our homemade spectral domain OCT with a stimulation of the passive movement of the front legs. Finally, we established the relationship between blood flow rate and the test design. The aim is to demonstrate the potential of OCT in the evaluation of cerebral cortex function.

  18. The Role of Lumbar Sympathetic Nerves in Regulation of Blood Flow to Skeletal Muscle during Anaphylactic Hypotension in Anesthetized Rats.

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    Jie Song

    Full Text Available During hypovolemic shock, skeletal muscle blood flow could be redistributed to vital organs via vasoconstriction in part evoked by activation of the innervating sympathetic nerve activity. However, it is not well known whether this mechanism operates during anaphylactic shock. We determined the femoral artery blood flow (FBF and lumbar sympathetic nerve activity (LSNA mainly regulating the hindquater muscle blood flow during anaphylactic hypotension in anesthetized rats. Anesthetized Sprague-Dawley rats were randomly allocated to the following groups (n = 7/group: (1 non-sensitized, (2 anaphylaxis, (3 anaphylaxis-lumbar sympathectomy (LS and (4 anaphylaxis-sinoaortic denervation (SAD groups. Anaphylaxis was induced by an intravenous injection of the ovalbumin antigen to the sensitized rats. The systemic arterial pressure (SAP, heart rate (HR, central venous pressure (CVP, FBF and LSNA were continuously measured. In the anaphylaxis group, LSNA and HR increased, while SAP and FBF decreased after antigen injection. In the anaphylaxis-SAD group, LSNA did not significantly change during the early phase, but the responses of SAP and FBF were similar to those in the anaphylaxis group. In the anaphylaxis-LS group, both FBF and SAP decreased similarly to the anaphylaxis group during anaphylactic hypotension. These results indicated that LSNA increased via baroreceptor reflex, but this sympathoexcitation or LS did not affect antigen-induced decreases in FBF or SAP. Lumbar sympathetic nerves are not involved in regulation of the blood flow to the hindlimb or systemic blood pressure during anaphylactic hypotension in anesthetized rats.

  19. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

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    Shize Jiang

    Full Text Available The blood-brain barrier (BBB impedes entry of many drugs into the brain, limiting clinical efficacy. A safe and efficient method for reversibly increasing BBB permeability would greatly facilitate central nervous system (CNS drug delivery and expand the range of possible therapeutics to include water soluble compounds, proteins, nucleotides, and other large molecules. We examined the effect of vascular endothelial growth factor (VEGF on BBB permeability in Kunming (KM mice. Human VEGF165 was administered to treatment groups at two concentrations (1.6 or 3.0 µg/mouse, while controls received equal-volume saline. Changes in BBB permeability were measured by parenchymal accumulation of the contrast agent Gd-DTPA as assessed by 7 T magnetic resonance imaging (MRI. Mice were then injected with Evans blue, sacrificed 0.5 h later, and perfused transcardially. Brains were removed, fixed, and sectioned for histological study. Both VEGF groups exhibited a significantly greater signal intensity from the cerebral cortex and basal ganglia than controls (P<0.001. Evans blue fluorescence intensity was higher in the parenchyma and lower in the cerebrovasculature of VEGF-treated animals compared to controls. No significant brain edema was observed by diffusion weighted MRI (DWI or histological staining. Exogenous application of VEGF can increase the permeability of the BBB without causing brain edema. Pretreatment with VEGF may be a feasible method to facilitate drug delivery into the CNS.

  20. Dimethyl fumarate attenuates cerebral edema formation by protecting the blood-brain barrier integrity.

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    Kunze, Reiner; Urrutia, Andrés; Hoffmann, Angelika; Liu, Hui; Helluy, Xavier; Pham, Mirko; Reischl, Stefan; Korff, Thomas; Marti, Hugo H

    2015-04-01

    Brain edema is a hallmark of various neuropathologies, but the underlying mechanisms are poorly understood. We aim to characterize how tissue hypoxia, together with oxidative stress and inflammation, leads to capillary dysfunction and breakdown of the blood-brain barrier (BBB). In a mouse stroke model we show that systemic treatment with dimethyl fumarate (DMF), an antioxidant drug clinically used for psoriasis and multiple sclerosis, significantly prevented edema formation in vivo. Indeed, DMF stabilized the BBB by preventing disruption of interendothelial tight junctions and gap formation, and decreased matrix metalloproteinase activity in brain tissue. In vitro, DMF directly sustained endothelial tight junctions, inhibited inflammatory cytokine expression, and attenuated leukocyte transmigration. We also demonstrate that these effects are mediated via activation of the redox sensitive transcription factor NF-E2 related factor 2 (Nrf2). DMF activated the Nrf2 pathway as shown by up-regulation of several Nrf2 target genes in the brain in vivo, as well as in cerebral endothelial cells and astrocytes in vitro, where DMF also increased protein abundance of nuclear Nrf2. Finally, Nrf2 knockdown in endothelial cells aggravated subcellular delocalization of tight junction proteins during ischemic conditions, and attenuated the protective effect exerted by DMF. Overall, our data suggest that DMF protects from cerebral edema formation during ischemic stroke by targeting interendothelial junctions in an Nrf2-dependent manner, and provide the basis for a completely new approach to treat brain edema.

  1. Trojan Horse Transit Contributes to Blood-Brain Barrier Crossing of a Eukaryotic Pathogen

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    Santiago-Tirado, Felipe H.; Onken, Michael D.; Cooper, John A.; Klein, Robyn S.

    2017-01-01

    ABSTRACT The blood-brain barrier (BBB) protects the central nervous system (CNS) by restricting the passage of molecules and microorganisms. Despite this barrier, however, the fungal pathogen Cryptococcus neoformans invades the brain, causing a meningoencephalitis that is estimated to kill over 600,000 people annually. Cryptococcal infection begins in the lung, and experimental evidence suggests that host phagocytes play a role in subsequent dissemination, although this role remains ill defined. Additionally, the disparate experimental approaches that have been used to probe various potential routes of BBB transit make it impossible to assess their relative contributions, confounding any integrated understanding of cryptococcal brain entry. Here we used an in vitro model BBB to show that a “Trojan horse” mechanism contributes significantly to fungal barrier crossing and that host factors regulate this process independently of free fungal transit. We also, for the first time, directly imaged C. neoformans-containing phagocytes crossing the BBB, showing that they do so via transendothelial pores. Finally, we found that Trojan horse crossing enables CNS entry of fungal mutants that cannot otherwise traverse the BBB, and we demonstrate additional intercellular interactions that may contribute to brain entry. Our work elucidates the mechanism of cryptococcal brain invasion and offers approaches to study other neuropathogens. PMID:28143979

  2. Blood-Brain Barrier Alterations Provide Evidence of Subacute Diaschisis in an Ischemic Stroke Rat Model

    Science.gov (United States)

    Garbuzova-Davis, Svitlana; Rodrigues, Maria C. O.; Hernandez-Ontiveros, Diana G.; Tajiri, Naoki; Frisina-Deyo, Aric; Boffeli, Sean M.; Abraham, Jerry V.; Pabon, Mibel; Wagner, Andrew; Ishikawa, Hiroto; Shinozuka, Kazutaka; Haller, Edward; Sanberg, Paul R.; Kaneko, Yuji; Borlongan, Cesario V.

    2013-01-01

    Background Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB) competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. Methodology/Principal Findings In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO), significant BBB alterations characterized by large Evans Blue (EB) parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. Conclusions/Significance These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke. PMID:23675488

  3. Blood-brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model.

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    Svitlana Garbuzova-Davis

    Full Text Available BACKGROUND: Comprehensive stroke studies reveal diaschisis, a loss of function due to pathological deficits in brain areas remote from initial ischemic lesion. However, blood-brain barrier (BBB competence in subacute diaschisis is uncertain. The present study investigated subacute diaschisis in a focal ischemic stroke rat model. Specific focuses were BBB integrity and related pathogenic processes in contralateral brain areas. METHODOLOGY/PRINCIPAL FINDINGS: In ipsilateral hemisphere 7 days after transient middle cerebral artery occlusion (tMCAO, significant BBB alterations characterized by large Evans Blue (EB parenchymal extravasation, autophagosome accumulation, increased reactive astrocytes and activated microglia, demyelinization, and neuronal damage were detected in the striatum, motor and somatosensory cortices. Vascular damage identified by ultrastuctural and immunohistochemical analyses also occurred in the contralateral hemisphere. In contralateral striatum and motor cortex, major ultrastructural BBB changes included: swollen and vacuolated endothelial cells containing numerous autophagosomes, pericyte degeneration, and perivascular edema. Additionally, prominent EB extravasation, increased endothelial autophagosome formation, rampant astrogliosis, activated microglia, widespread neuronal pyknosis and decreased myelin were observed in contralateral striatum, and motor and somatosensory cortices. CONCLUSIONS/SIGNIFICANCE: These results demonstrate focal ischemic stroke-induced pathological disturbances in ipsilateral, as well as in contralateral brain areas, which were shown to be closely associated with BBB breakdown in remote brain microvessels and endothelial autophagosome accumulation. This microvascular damage in subacute phase likely revealed ischemic diaschisis and should be considered in development of treatment strategies for stroke.

  4. Characterization of the L-glutamate clearance pathways across the blood-brain barrier and the effect of astrocytes in an in vitro blood-brain barrier model

    DEFF Research Database (Denmark)

    Helms, Hans CC; Aldana, Blanca I; Groth, Simon;

    2017-01-01

    The aim was to characterize the clearance pathways for L-glutamate from the brain interstitial fluid across the blood-brain barrier using a primary in vitro bovine endothelial/rat astrocyte co-culture. Transporter profiling was performed using uptake studies of radiolabeled L-glutamate with co...

  5. Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo.

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    Sofie Stalmans

    Full Text Available Cell-penetrating peptides (CPPs are a group of peptides, which have the ability to cross cell membrane bilayers. CPPs themselves can exert biological activity and can be formed endogenously. Fragmentary studies demonstrate their ability to enhance transport of different cargoes across the blood-brain barrier (BBB. However, comparative, quantitative data on the BBB permeability of different CPPs are currently lacking. Therefore, the in vivo BBB transport characteristics of five chemically diverse CPPs, i.e. pVEC, SynB3, Tat 47-57, transportan 10 (TP10 and TP10-2, were determined. The results of the multiple time regression (MTR analysis revealed that CPPs show divergent BBB influx properties: Tat 47-57, SynB3, and especially pVEC showed very high unidirectional influx rates of 4.73 μl/(g × min, 5.63 μl/(g × min and 6.02 μl/(g × min, respectively, while the transportan analogs showed a negligible to low brain influx. Using capillary depletion, it was found that 80% of the influxed peptides effectively reached the brain parenchyma. Except for pVEC, all peptides showed a significant efflux out of the brain. Co-injection of pVEC with radioiodinated bovine serum albumin (BSA did not enhance the brain influx of radiodionated BSA, indicating that pVEC does not itself significantly alter the BBB properties. A saturable mechanism could not be demonstrated by co-injecting an excess dose of non-radiolabeled CPP. No significant regional differences in brain influx were observed, with the exception for pVEC, for which the regional variations were only marginal. The observed BBB influx transport properties cannot be correlated with their cell-penetrating ability, and therefore, good CPP properties do not imply efficient brain influx.

  6. Surfactants, not size or zeta-potential influence blood-brain barrier passage of polymeric nanoparticles.

    Science.gov (United States)

    Voigt, Nadine; Henrich-Noack, Petra; Kockentiedt, Sarah; Hintz, Werner; Tomas, Jürgen; Sabel, Bernhard A

    2014-05-01

    Nanoparticles (NP) can deliver drugs across the blood-brain barrier (BBB), but little is known which of the factors surfactant, size and zeta-potential are essential for allowing BBB passage. To this end we designed purpose-built fluorescent polybutylcyanoacrylate (PBCA) NP and imaged the NP's passage over the blood-retina barrier - which is a model of the BBB - in live animals. Rats received intravenous injections of fluorescent PBCA-NP fabricated by mini-emulsion polymerisation to obtain various NP's compositions that varied in surfactants (non-ionic, anionic, cationic), size (67-464nm) and zeta-potential. Real-time imaging of retinal blood vessels and retinal tissue was carried out with in vivo confocal neuroimaging (ICON) before, during and after NP's injection. Successful BBB passage with subsequent cellular labelling was achieved if NP were fabricated with non-ionic surfactants or cationic stabilizers but not when anionic compounds were added. NP's size and charge had no influence on BBB passage and cell labelling. This transport was not caused by an unspecific opening of the BBB because control experiments with injections of unlabelled NP and fluorescent dye (to test a "door-opener" effect) did not lead to parenchymal labelling. Thus, neither NP's size nor chemo-electric charge, but particle surface is the key factor determining BBB passage. This result has important implications for NP engineering in medicine: depending on the surfactant, NP can serve one of two opposite functions: while non-ionic tensides enhance brain up-take, addition of anionic tensides prevents it. NP can now be designed to specifically enhance drug delivery to the brain or, alternatively, to prevent brain penetration so to reduce unwanted psychoactive effects of drugs or prevent environmental nanoparticles from entering tissue of the central nervous system.

  7. Recruitment of neutrophils across the blood-brain barrier: the role of posttraumatic hepatic ischemia

    Directory of Open Access Journals (Sweden)

    Mantovani Mario

    2003-01-01

    Full Text Available PURPOSE: To study the effects of total hepatic ischemia, and reperfusion on the accumulation of neutrophils in the brain of rats submitted to normovolemic conditions as well as to controlled hemorrhagic shock state. METHODS: Thirty two adult male Wistar rats, were divided into four groups: the Control group, was submitted to the standard procedures for a period of 60 min of observation; Shock group, was submitted to controlled hemorrhagic shock (mean arterial blood pressure=40mmHg, 20min followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1 and reperfusion for 60min; Pringle group, was submitted to total hepatic ischemia for 15min and reperfusion for 60min. The total group was submitted to controlled hemorrhagic shock for 20min followed by volemic resuscitation (lactated Ringer's solution + blood, 3:1, total hepatic ischemia for 15min and reperfusion for 60min. Measurements of serum lactate and base excess were used to characterize the hemorrhagic shock state with low tissue perfusion. The counting of neutrophils on the brain was performed after the euthanasia of animals. RESULTS: The values for the counting of neutrophils on the brain indicate that did not occur difference among studied groups (p=0.196 (Control 0.12± 0.11, Shock 0.12± 0.13, Pringle 0.02± 0.04, Total 0.14± 0.16. CONCLUSION: Hemorrhagic shock associated to total hepatic ischemia for 15 minutes, followed by 60 minutes of reperfusion, did not causes significant neutrophils accumulation in the brain of rats.

  8. [Electrolyte makeup of the blood plasma and skeletal muscles of rats after a flight on the Kosmos-690 biosatellite].

    Science.gov (United States)

    Nesterov, V P; Tigranian, R A

    1979-01-01

    Measurements of Na+, K+, Mg2+ and Ca2+ concentrations in the functionally different muscles (soleus, plantaris, diaphragm muscles) and plasma of the rats flown for 20.5 days aboard the biosatellite Cosmos-690 did not show any significant changes as compared with the controls. At the same time a decrease of the K+/Na+ ratio and a similar shift of Mg2+ and Ca2+ concentrations in plasma of irradiated rats as compared with these of non-irradiated animals demonstrated that the combined effects of space flight factors and gamma-irradiation influenced the system of ionic homeostasis in the blood. In the animals sacrificed on the R + 1 day the K+/Na+ ratio in the soleus muscle changed in favor of Na+ and in the plantaris muscle in favor of K+, and remained essentially unchanged in the diaphragm. The comparison of the flight experiments with the ground-based controls showed that ion changes in muscles occurred due to ionizing radiation rather than due to weightlessness.

  9. Associations between Muscle Strength Asymmetry and Impairments in Gait and Posture in Young Brain-Injured Patients.

    Science.gov (United States)

    Drijkoningen, David; Caeyenberghs, Karen; Vander Linden, Catharine; Van Herpe, Katrin; Duysens, Jacques; Swinnen, Stephan P

    2015-09-01

    Traumatic brain injury (TBI) can lead to deficits in gait and posture, which are often asymmetric. A possible factor mediating these deficits may be asymmetry in strength of the leg muscles. However, muscle strength in the lower extremities has rarely been investigated in (young) TBI patients. Here, we investigated associations between lower-extremity muscle weakness, strength asymmetry, and impairments in gait and posture in young TBI patients. A group of young patients with moderate-to-severe TBI (n=19; age, 14 years 11 months ±2 years) and a group of typically developing subjects (n=31; age, 14 years 1 month±3 years) participated in this study. A force platform was used to measure postural sway to quantify balance control during normal standing and during conditions of compromised visual and/or somatosensory feedback. Spatiotemporal gait parameters were assessed during comfortable and fast-speed walking, using an electronic walkway. Muscle strength in four lower-extremity muscle groups was measured bilaterally using a handheld dynamometer. Findings revealed that TBI patients had poorer postural balance scores across all sensory conditions, as compared to typically developing subjects. During comfortable and fast gait, TBI patients demonstrated a lower gait velocity, longer double-support phase, and increased step-length asymmetry. Further, TBI patients had a reduced strength of leg muscles and an increased strength asymmetry. Correlation analyses revealed that asymmetry in muscle strength was predictive of a poorer balance control and a more variable and asymmetric gait. To the best of our knowledge, this is the first study to measure strength asymmetry in leg muscles of a sample of TBI patients and illustrate the importance of muscular asymmetry as a potential marker and possible risk factor of impairments in control of posture and gait.

  10. Muscle biopsy

    Science.gov (United States)

    ... Inflammatory diseases of muscle (such as polymyositis or dermatomyositis ) Diseases of the connective tissue and blood vessels ( ... disease that involves inflammation and a skin rash ( dermatomyositis ) Inherited muscle disorder ( Duchenne muscular dystrophy ) Inflammation of ...

  11. Blood-brain barrier permeability during dopamine-induced hypertension in fetal sheep.

    Science.gov (United States)

    Harris, A P; Robinson, R; Koehler, R C; Traystman, R J; Gleason, C A

    2001-07-01

    Dopamine is often used as a pressor agent in sick newborn infants, but an increase in arterial blood pressure could disrupt the blood-brain barrier (BBB), especially in the preterm newborn. Using time-dated pregnant sheep, we tested the hypothesis that dopamine-induced hypertension increases fetal BBB permeability and cerebral water content. Barrier permeability was assessed in nine brain regions, including cerebral cortex, caudate, thalamus, brain stem, cerebellum, and spinal cord, by intravenous injection of the small tracer molecule [(14)C]aminoisobutyric acid at 10 min after the start of dopamine or saline infusion. We studied 23 chronically catheterized fetal sheep at 0.6 (93 days, n = 10) and 0.9 (132 days, n = 13) gestation. Intravenous infusion of dopamine increased mean arterial pressure from 38 +/- 3 to 53 +/- 5 mmHg in 93-day fetuses and from 55 +/- 5 to 77 +/- 8 mmHg in 132-day fetuses without a decrease in arterial O(2) content. These 40% increases in arterial pressure are close to the maximum hypertension reported for physiological stresses at these ages in fetal sheep. No significant increases in the brain transfer coefficient of aminoisobutyric acid were detected in any brain region in dopamine-treated fetuses compared with saline controls at 0.6 or 0.9 gestation. There was also no significant increase in cortical water content with dopamine infusion at either age. We conclude that a 40% increase in mean arterial pressure during dopamine infusion in normoxic fetal sheep does not produce substantial BBB disruption or cerebral edema even as early as 0.6 gestation.

  12. Melatonin reduces traumatic brain injur y-induced oxidative stress in the cerebral cortex and blood of rats

    Institute of Scientific and Technical Information of China (English)

    Nilgnenol; Mustafa Nazrolu

    2014-01-01

    Free radicals induced by traumatic brain injury have deleterious effects on the function and antioxidant vitamin levels of several organ systems including the brain. Melatonin possesses antioxidant effect on the brain by maintaining antioxidant enzyme and vitamin levels. We in-vestigated the effects of melatonin on antioxidant ability in the cerebral cortex and blood of traumatic brain injury rats. Results showed that the cerebral cortex β-carotene, vitamin C, vita-min E, reduced glutathione, and erythrocyte reduced glutathione levels, and plasma vitamin C level were decreased by traumatic brain injury whereas they were increased following melatonin treatment. In conclusion, melatonin seems to have protective effects on traumatic brain inju-ry-induced cerebral cortex and blood toxicity by inhibiting free radical formation and supporting antioxidant vitamin redox system.

  13. Relative value of diverse brain MRI and blood-based biomarkers for predicting cognitive decline in the elderly

    Science.gov (United States)

    Madsen, Sarah K.; Ver Steeg, Greg; Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Nir, Talia M.; Hua, Xue; Gutman, Boris A.; Galstyan, Aram; Thompson, Paul M.

    2016-03-01

    Cognitive decline accompanies many debilitating illnesses, including Alzheimer's disease (AD). In old age, brain tissue loss also occurs along with cognitive decline. Although blood tests are easier to perform than brain MRI, few studies compare brain scans to standard blood tests to see which kinds of information best predict future decline. In 504 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we first used linear regression to assess the relative value of different types of data to predict cognitive decline, including 196 blood panel biomarkers, 249 MRI biomarkers obtained from the FreeSurfer software, demographics, and the AD-risk gene APOE. A subset of MRI biomarkers was the strongest predictor. There was no specific blood marker that increased predictive accuracy on its own, we found that a novel unsupervised learning method, CorEx, captured weak correlations among blood markers, and the resulting clusters offered unique predictive power.

  14. DNA and RNA analysis of blood and muscle from bodies with variable postmortem intervals

    DEFF Research Database (Denmark)

    Hansen, Jakob; Lesnikova, Iana; Funder, Anette Mariane Daa;

    2014-01-01

    % of the formalin fixed and paraffin embedded (FFPE) muscle specimens. A quality assessment of muscle-derived DNA showed increased fragmentation with advancing body decomposition and generally more fragmentation in DNA from FFPE tissue than in DNA from frozen tissue. It was possible to amplify 1,000 basepair (bp......) DNA fragments from all samples with postmortem intervals below 3 days whereas 400-600 bp long fragments typically could be amplified from the most decomposed muscle specimens. RNA was less stable than DNA in postmortem muscle tissue, yet selected mRNA molecules could be detected by reverse...

  15. Transport characteristics of guanidino compounds at the blood-brain barrier and blood-cerebrospinal fluid barrier: relevance to neural disorders

    Directory of Open Access Journals (Sweden)

    Tachikawa Masanori

    2011-02-01

    Full Text Available Abstract Guanidino compounds (GCs, such as creatine, phosphocreatine, guanidinoacetic acid, creatinine, methylguanidine, guanidinosuccinic acid, γ-guanidinobutyric acid, β-guanidinopropionic acid, guanidinoethane sulfonic acid and α-guanidinoglutaric acid, are present in the mammalian brain. Although creatine and phosphocreatine play important roles in energy homeostasis in the brain, accumulation of GCs may induce epileptic discharges and convulsions. This review focuses on how physiologically important and/or neurotoxic GCs are distributed in the brain under physiological and pathological conditions. Transporters for GCs at the blood-brain barrier (BBB and the blood-cerebrospinal fluid (CSF barrier (BCSFB have emerged as substantial contributors to GCs distribution in the brain. Creatine transporter (CRT/solute carrier (SLC 6A8 expressed at the BBB regulates creatine concentration in the brain, and represents a major pathway for supply of creatine from the circulating blood to the brain. CRT may be a key factor facilitating blood-to-brain guanidinoacetate transport in patients deficient in S-adenosylmethionine:guanidinoacetate N-methyltransferase, the creatine biosynthetic enzyme, resulting in cerebral accumulation of guanidinoacetate. CRT, taurine transporter (TauT/SLC6A6 and organic cation transporter (OCT3/SLC22A3 expressed at the BCSFB are involved in guanidinoacetic acid or creatinine efflux transport from CSF. Interestingly, BBB efflux transport of GCs, including guanidinoacetate and creatinine, is negligible, though the BBB has a variety of efflux transport systems for synthetic precursors of GCs, such as amino acids and neurotransmitters. Instead, the BCSFB functions as a major cerebral clearance system for GCs. In conclusion, transport of GCs at the BBB and BCSFB appears to be the key determinant of the cerebral levels of GCs, and changes in the transport characteristics may cause the abnormal distribution of GCs in the brain seen

  16. Lactate, Glucose and Oxygen Uptake in Human Brain During Recovery from Maximal Exercise

    DEFF Research Database (Denmark)

    Kojiro, I.; Schmalbruch, I.K.; Quistorff, B.

    1999-01-01

    Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake......Skeletal muscle, brain lactate uptake, brain oxygen uptake, energy metabolism, brain glucose uptake...

  17. Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA

    NARCIS (Netherlands)

    Bartels, A. L.; Willemsen, A. T. M.; Kortekaas, R.; de Jong, B. M.; de Vries, R.; de Klerk, O.; van Oostrom, J. C. H.; Portman, A.; Leenders, K. L.

    2008-01-01

    Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function

  18. Fractal Analysis of Brain Blood Oxygenation Level Dependent (BOLD) Signals from Children with Mild Traumatic Brain Injury (mTBI)

    Science.gov (United States)

    Dona, Olga; DeMatteo, Carol; Connolly, John F.

    2017-01-01

    Background Conventional imaging techniques are unable to detect abnormalities in the brain following mild traumatic brain injury (mTBI). Yet patients with mTBI typically show delayed response on neuropsychological evaluation. Because fractal geometry represents complexity, we explored its utility in measuring temporal fluctuations of brain resting state blood oxygen level dependent (rs-BOLD) signal. We hypothesized that there could be a detectable difference in rs-BOLD signal complexity between healthy subjects and mTBI patients based on previous studies that associated reduction in signal complexity with disease. Methods Fifteen subjects (13.4 ± 2.3 y/o) and 56 age-matched (13.5 ± 2.34 y/o) healthy controls were scanned using a GE Discovery MR750 3T MRI and 32-channel RF-coil. Axial FSPGR-3D images were used to prescribe rs-BOLD (TE/TR = 35/2000ms), acquired over 6 minutes. Motion correction was performed and anatomical and functional images were aligned and spatially warped to the N27 standard atlas. Fractal analysis, performed on grey matter, was done by estimating the Hurst exponent using de-trended fluctuation analysis and signal summation conversion methods. Results and Conclusions Voxel-wise fractal dimension (FD) was calculated for every subject in the control group to generate mean and standard deviation maps for regional Z-score analysis. Voxel-wise validation of FD normality across controls was confirmed, and non-Gaussian voxels (3.05% over the brain) were eliminated from subsequent analysis. For each mTBI patient, regions where Z-score values were at least 2 standard deviations away from the mean (i.e. where |Z| > 2.0) were identified. In individual patients the frequently affected regions were amygdala (p = 0.02), vermis(p = 0.03), caudate head (p = 0.04), hippocampus(p = 0.03), and hypothalamus(p = 0.04), all previously reported as dysfunctional after mTBI, but based on group analysis. It is well known that the brain is best modeled as a complex

  19. Caloric restriction increases ketone bodies metabolism and preserves blood flow in aging brain.

    Science.gov (United States)

    Lin, Ai-Ling; Zhang, Wei; Gao, Xiaoli; Watts, Lora

    2015-07-01

    Caloric restriction (CR) has been shown to increase the life span and health span of a broad range of species. However, CR effects on in vivo brain functions are far from explored. In this study, we used multimetric neuroimaging methods to characterize the CR-induced changes of brain metabolic and vascular functions in aging rats. We found that old rats (24 months of age) with CR diet had reduced glucose uptake and lactate concentration, but increased ketone bodies level, compared with the age-matched and young (5 months of age) controls. The shifted metabolism was associated with preserved vascular function: old CR rats also had maintained cerebral blood flow relative to the age-matched controls. When investigating the metabolites in mitochondrial tricarboxylic acid cycle, we found that citrate and α-ketoglutarate were preserved in the old CR rats. We suggest that CR is neuroprotective; ketone bodies, cerebral blood flow, and α-ketoglutarate may play important roles in preserving brain physiology in aging.

  20. Computational and in vitro studies of blast-induced blood-brain barrier disruption

    CERN Document Server

    Del Razo, Mauricio J; Meabon, James S; Huber, B Russell; Peskind, Elaine R; Banks, William A; Mourad, Pierre D; Leveque, Randall J; Cook, David G

    2015-01-01

    There is growing concern that blast-exposed individuals are at risk of developing neurological disorders later in life. Therefore, it is important to understand the dynamic properties of blast forces on brain cells, including the endothelial cells that maintain the blood-brain barrier (BBB), which regulates the passage of nutrients into the brain and protects it from toxins in the blood. To better understand the effect of shock waves on the BBB we have investigated an {\\em in vitro} model in which BBB endothelial cells are grown in transwell vessels and exposed in a shock tube, confirming that BBB integrity is directly related to shock wave intensity. It is difficult to directly measure the forces acting on these cells in the transwell container during the experiments, and so a computational tool has been developed and presented in this paper. Two-dimensional axisymmetric Euler equations with the Tammann equation of state were used to model the transwell materials, and a high-resolution finite volume method b...

  1. Molecular anatomy of interendothelial junctions in human blood-brain barrier microvessels.

    Directory of Open Access Journals (Sweden)

    Andrzej W Vorbrodt

    2004-07-01

    Full Text Available Immunogold cytochemical procedure was used to study the localization at the ultrastructural level of interendothelial junction-associated protein molecules in the human brain blood microvessels, representing the anatomic site of the blood-brain barrier (BBB. Ultrathin sections of Lowicryl K4M-embedded biopsy specimens of human cerebral cortex obtained during surgical procedures were exposed to specific antibodies, followed by colloidal gold-labeled secondary antibodies. All tight junction-specific integral membrane (transmembrane proteins--occludin, junctional adhesion molecule (JAM-1, and claudin-5--as well as peripheral zonula occludens protein (ZO-1 were highly expressed. Immunoreactivity of the adherens junction-specific transmembrane protein VE-cadherin was of almost similar intensity. Immunolabeling of the adherens junction-associated peripheral proteins--alpha-catenin, beta-catenin, and p120 catenin--although positive, was evidently less intense. The expression of gamma-catenin (plakoglobin was considered questionable because solitary immunosignals (gold particles appeared in only a few microvascular profiles. Double labeling of some sections made possible to observe strict colocalization of the junctional molecules, such as occludin and ZO-1 or JAM-1 and VE-cadherin, in the interendothelial junctions. We found that in human brain microvessels, the interendothelial junctional complexes contain molecular components specific for both tight and adherens junctions. It is assumed that the data obtained can help us find the immunodetectable junctional molecules that can serve as sensitive markers of normal or abnormal function of the BBB.

  2. Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

    Science.gov (United States)

    d'Avella, D; Cicciarello, R; Angileri, F F; Lucerna, S; La Torre, D; Tomasello, F

    1998-01-01

    The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

  3. Tight junctions at the blood brain barrier: physiological architecture and disease-associated dysregulation

    Directory of Open Access Journals (Sweden)

    Luissint Anny-Claude

    2012-11-01

    Full Text Available Abstract The Blood–brain barrier (BBB, present at the level of the endothelium of cerebral blood vessels, selectively restricts the blood-to-brain paracellular diffusion of compounds; it is mandatory for cerebral homeostasis and proper neuronal function. The barrier properties of these specialized endothelial cells notably depend on tight junctions (TJs between adjacent cells: TJs are dynamic structures consisting of a number of transmembrane and membrane-associated cytoplasmic proteins, which are assembled in a multimolecular complex and acting as a platform for intracellular signaling. Although the structural composition of these complexes has been well described in the recent years, our knowledge about their functional regulation still remains fragmentary. Importantly, pericytes, embedded in the vascular basement membrane, and perivascular microglial cells, astrocytes and neurons contribute to the regulation of endothelial TJs and BBB function, altogether constituting the so-called neurovascular unit. The present review summarizes our current understanding of the structure and functional regulation of endothelial TJs at the BBB. Accumulating evidence points to a correlation between BBB dysfunction, alteration of TJ complexes and progression of a variety of CNS diseases, such as stroke, multiple sclerosis and brain tumors, as well as neurodegenerative diseases like Parkinson’s and Alzheimer’s diseases. Understanding how TJ integrity is controlled may thus help improve drug delivery across the BBB and the design of therapeutic strategies for neurological disorders.

  4. Age-associated physiological and pathological changes at the blood-brain barrier: A review.

    Science.gov (United States)

    Erdő, Franciska; Denes, László; de Lange, Elizabeth

    2017-01-01

    The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood-brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood-brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication.

  5. Transport of carbamazepine and drug interactions at blood-brain barrier

    Institute of Scientific and Technical Information of China (English)

    Jing-jing SUN; Lin XIE; Xiao-dong LIU

    2006-01-01

    Aim: To investigate the characteristics of carbamazepine (CBZ) transport and drug interactions at the blood-brain barrier. Methods: Cultured rat brain microvascular endothelial cells (rBMEC) were used as an in vitro model of the blood-brain barrier (BBB). When cells became confluent, CBZ uptake over time was recorded by incubation of the cells in a medium containing 10 mg/L CBZ at 37 ℃. The steady-state uptake of CBZ by rBMEC was tested for different CBZ concentrations at 37 ℃. The effects of various agents on the steady-state uptake of CBZ and efflux of CBZ from rBMEC were also studied. Results: The uptake of CBZ by rBMEC was time- and concentration-dependent. The steady-state uptake occurred at 30 min for incubation. The steady-state uptake was significantly increased (P<0.01) by treatment with dinitrophenol. The co-administration of cyclosporine A significantly increased the steady-state uptake of CBZ by the rBMEC, whereas co-administration of olanzapine significantly decreased the uptake in a concentration- and temperature-dependent manner. The efflux of CBZ from rBMEC was inhibited by CsA. Conclusion: The transport of CBZ at the BBB is mediated by many transporters. Some specific ABC (ATP-binding cassette,ABC ) efflux transporters may be involved in the transport of CBZ. Drugs influence the transport of CBZ at the BBB in different ways.

  6. Blood-brain barrier changes with kainic acid-induced limbic seizures

    Energy Technology Data Exchange (ETDEWEB)

    Zucker, D.K.; Wooten, G.F.; Lothman, E.W.

    1983-02-01

    Rats were treated with kainic acid (KA) i.v. to produce increasingly severe limbic seizures that were monitored with a behavioral rating scale. At various times after the induction of seizures, the animals; blood-brain barriers (B-BB) were studied with alpha-(/sup 14/C)aminoisobutyric acid ((/sup 14/C)AIBA) autoradiography. Using optical density ratios, a coefficient was devised to assess the functional integrity of the B-BB in discrete anatomic regions and to quantitatively compare these measurements among different groups of experimental animals. In animals that exhibited only mild seizures, the B-BB was not different from controls. Animals with severe limbic seizures, however, showed alterations. For as long as 2 h after delivery of KA, the B-BB appeared normal; from 2 to 24 h, the permeability to (/sup 14/C)AIBA was markedly increased throughout the brain, especially in limbic regions; from 24 h to 7 days the B-BB returned to normal except for a small residual change in limbic structures. These findings were confirmed with Evans blue dye studies of the B-BB. A correlation between focal accentuation of B-BB alterations and neuropathologic changes was found. These experiments indicted that recurrent limbic seizures may lead to a breakdown in the B-BB independent of systemic metabolic derangements. Marked focal metabolic and electrical changes, however, occurred in several limbic structures several hours before the blood-brain barrier was altered.

  7. Global brain blood-oxygen level responses to autonomic challenges in obstructive sleep apnea.

    Directory of Open Access Journals (Sweden)

    Paul M Macey

    Full Text Available Obstructive sleep apnea (OSA is accompanied by brain injury, perhaps resulting from apnea-related hypoxia or periods of impaired cerebral perfusion. Perfusion changes can be determined indirectly by evaluation of cerebral blood volume and oxygenation alterations, which can be measured rapidly and non-invasively with the global blood oxygen level dependent (BOLD signal, a magnetic resonance imaging procedure. We assessed acute BOLD responses in OSA subjects to pressor challenges that elicit cerebral blood flow changes, using a two-group comparative design with healthy subjects as a reference. We separately assessed female and male patterns, since OSA characteristics and brain injury differ between sexes. We studied 94 subjects, 37 with newly-diagnosed, untreated OSA (6 female (age mean ± std: 52.1±8.1 yrs; apnea/hypopnea index [AHI]: 27.7±15.6 events/hr and 31 male 54.3±8.4 yrs; AHI: 37.4±19.6 events/hr, and 20 female (age 50.5±8.1 yrs and 37 male (age 45.6±9.2 yrs healthy control subjects. We measured brain BOLD responses every 2 s while subjects underwent cold pressor, hand grip, and Valsalva maneuver challenges. The global BOLD signal rapidly changed after the first 2 s of each challenge, and differed in magnitude between groups to two challenges (cold pressor, hand grip, but not to the Valsalva maneuver (repeated measures ANOVA, p<0.05. OSA females showed greater differences from males in response magnitude and pattern, relative to healthy counterparts. Cold pressor BOLD signal increases (mean ± adjusted standard error at the 8 s peak were: OSA 0.14±0.08% vs. Control 0.31±0.06%, and hand grip at 6 s were: OSA 0.08±0.03% vs. Control at 0.30±0.02%. These findings, indicative of reduced cerebral blood flow changes to autonomic challenges in OSA, complement earlier reports of altered resting blood flow and reduced cerebral artery responsiveness. Females are more affected than males, an outcome which may contribute to the sex

  8. Effects of blood-flow-restricted resistance training on muscle function in a 74-year-old male with sporadic inclusion body myositis

    DEFF Research Database (Denmark)

    Jørgensen, Anders Nørkær; Aagaard, P; Nielsen, J L

    2016-01-01

    Sporadic inclusion body myositis (sIBM) is a systemic disease that is characterized by substantial skeletal muscle weakness and muscle inflammation, leading to impaired physical function. The objective was to investigate the effect of low-load resistance exercise with concurrent partial blood flow...

  9. Effect of strength training with blood flow restriction on muscle power and submaximal strength in eumenorrheic women.

    Science.gov (United States)

    Gil, Ana L S; Neto, Gabriel R; Sousa, Maria S C; Dias, Ingrid; Vianna, Jeferson; Nunes, Rodolfo A M; Novaes, Jefferson S

    2017-03-01

    Blood flow restriction (BFR) training stimulates muscle size and strength by increasing muscle activation, accumulation of metabolites and muscle swelling. This method has been used in different populations, but no studies have evaluated the effects of training on muscle power and submaximal strength (SS) in accounted for the menstrual cycle. The aim of this study was to analyse the effect of strength training (ST) with BFR on the muscle power and SS of upper and lower limbs in eumenorrheic women. Forty untrained women (18-40 years) were divided randomly and proportionally into four groups: (i) high-intensity ST at 80% of 1RM (HI), (ii) low-intensity ST at 20% of 1RM combined with partial blood flow restriction (LI + BFR), (iii) low-intensity ST at 20% of 1RM (LI) and d) control group (CG). Each training group performed eight training sessions. Tests with a medicine ball (MB), horizontal jump (HJ), vertical jump (VJ), biceps curls (BC) and knee extension (KE) were performed during the 1st day follicular phase (FP), 14th day (ovulatory phase) and 26-28th days (luteal phase) of the menstrual cycle. There was no significant difference among groups in terms of the MB, HJ, VJ or BC results at any time point (P>0·05). SS in the KE exercise was significantly greater in the LI + BFR group compared to the CG group (P = 0·014) during the LP. Therefore, ST with BFR does not appear to improve the power of upper and lower limbs and may be an alternative to improve the SS of lower limbs of eumenorrheic women.

  10. Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

    Directory of Open Access Journals (Sweden)

    Benjamin S Bleier

    Full Text Available Utilization of neuropharmaceuticals for central nervous system(CNS disease is highly limited due to the blood-brain barrier(BBB which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

  11. Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

    Science.gov (United States)

    Bleier, Benjamin S; Kohman, Richie E; Feldman, Rachel E; Ramanlal, Shreshtha; Han, Xue

    2013-01-01

    Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

  12. Analysis of the effects of androgens and training on myostatin propeptide and follistatin concentrations in blood and skeletal muscle using highly sensitive Immuno PCR

    OpenAIRE

    2010-01-01

    Abstract Myostatin propeptide (MYOPRO) and follistatin (FOLLI) are potent myostatin inhibitors. In this study we analysed effects of training and androgens on MYOPRO and FOLLI concentrations in blood and skeletal muscle using Immuno PCR. Young healthy males performed either a 3-month endurance-training or a strength-training. Blood and biopsy samples were analysed. Training did not significantly affect MYOPRO and FOLLI concentrations in serum and muscle. To investigate whether tota...

  13. Over-expression of Slit2 induces vessel formation and changes blood vessel permeability in mouse brain

    Institute of Scientific and Technical Information of China (English)

    Hai-xiong HAN; Jian-guo GENG

    2011-01-01

    Aim:To investigate the effect of the axon guidance cue Slit2 on the density of blood vessels and permeability of the blood-brain barrier in mouse brain.Methods:hSlit2 transgenic mouse line was constructed,and the phenotypes of the mice were compared with wild-type mice in respect to the lateral ventricle (LV),ventricle pressure,and the choroids plexus.An in vivo Miles permeability assay and an amyloid-β permeability assay were used to assess the permeability of brain blood vessels.Brain vessel casting and intracerebral hemorrhage models were built to investigate vessel density in the transgenic mice.An in vitro permeability assay was used to test whether Slit2 could change the permeability and tight junctions of blood vessel endothelial cells.Results:Hydrocephalus occurred in some transgenic mice,and a significantly larger lateral ventricle area and significantly higher ventricle pressure were observed in the transgenic mice.The transgenic mice displayed changed construction of the choroids plexus,which had more micro vessels,dilated vessels,gaps between epithelial cells and endothelial cells than wild-type mice.Slit2 significantly increased brain vessel density and the permeability of brain vessels to large molecules.These blood vessels were more sensitive to cues that induce brain hemorrhage.At the cellular level,Slit2 disturbed the integrity of tight junctions in blood vessel endothelial cells and improved the permeability of the endothelial cell layer.Thus,it promoted the entry of amyloid-β peptides from the serum into the central nervous system,where they bound to neurons.Conclusion:Slit2 increases vessel density and permeability in the brains of transgenic mice.Thus,Slit2 induces numerous changes in brain vessels and the barrier system.

  14. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects.

    Science.gov (United States)

    Kanegawa, Naoki; Collste, Karin; Forsberg, Anton; Schain, Martin; Arakawa, Ryosuke; Jucaite, Aurelija; Lekander, Mats; Olgart Höglund, Caroline; Kosek, Eva; Lampa, Jon; Halldin, Christer; Farde, Lars; Varrone, Andrea; Cervenka, Simon

    2016-05-01

    Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation.

  15. Separation methods that are capable of revealing blood-brain barrier permeability.

    Science.gov (United States)

    Dash, Alekha K; Elmquist, William F

    2003-11-25

    The objective of this review is to emphasize the application of separation science in evaluating the blood-brain barrier (BBB) permeability to drugs and bioactive agents. Several techniques have been utilized to quantitate the BBB permeability. These methods can be classified into two major categories: in vitro or in vivo. The in vivo methods used include brain homogenization, cerebrospinal fluid (CSF) sampling, voltametry, autoradiography, nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), intracerebral microdialysis, and brain uptake index (BUI) determination. The in vitro methods include tissue culture and immobilized artificial membrane (IAM) technology. Separation methods have always played an important role as adjunct methods to the methods outlined above for the quantitation of BBB permeability and have been utilized the most with brain homogenization, in situ brain perfusion, CSF sampling, intracerebral microdialysis, in vitro tissue culture and IAM chromatography. However, the literature published to date indicates that the separation method has been used the most in conjunction with intracerebral microdialysis and CSF sampling methods. The major advantages of microdialysis sampling in BBB permeability studies is the possibility of online separation and quantitation as well as the need for only a small sample volume for such an analysis. Separation methods are preferred over non-separation methods in BBB permeability evaluation for two main reasons. First, when the selectivity of a determination method is insufficient, interfering substances must be separated from the analyte of interest prior to determination. Secondly, when large number of analytes is to be detected and quantitated by a single analytical procedure, the mixture must be separated to each individual component prior to determination. Chiral separation in particular can be essential to evaluate the stereo-selective permeation and distribution of agents into the

  16. Blood-Brain Barrier Abnormalities Caused by HIV-1 gp120: Mechanistic and Therapeutic Implications

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Louboutin

    2012-01-01

    Full Text Available The blood-brain barrier (BBB is compromised in many systemic and CNS diseases, including HIV-1 infection of the brain. We studied BBB disruption caused by HIV-1 envelope glycoprotein 120 (gp120 as a model. Exposure to gp120, whether acute [by direct intra-caudate-putamen (CP injection] or chronic [using SV(gp120, an experimental model of ongoing production of gp120] disrupted the BBB, and led to leakage of vascular contents. Gp120 was directly toxic to brain endothelial cells. Abnormalities of the BBB reflect the activity of matrix metalloproteinases (MMPs. These target laminin and attack the tight junctions between endothelial cells and BBB basal laminae. MMP-2 and MMP-9 were upregulated following gp120-injection. Gp120 reduced laminin and tight junction proteins. Reactive oxygen species (ROS activate MMPs. Injecting gp120 induced lipid peroxidation. Gene transfer of antioxidant enzymes protected against gp120-induced BBB abnormalities. NMDA upregulates the proform of MMP-9. Using the NMDA receptor (NMDAR-1 inhibitor, memantine, we observed partial protection from gp120-induced BBB injury. Thus, (1 HIV-envelope gp120 disrupts the BBB; (2 this occurs via lesions in brain microvessels, MMP activation and degradation of vascular basement membrane and vascular tight junctions; (3 NMDAR-1 activation plays a role in this BBB injury; and (4 antioxidant gene delivery as well as NMDAR-1 antagonists may protect the BBB.

  17. Anti-miR delivery strategies to bypass the blood-brain barrier in glioblastoma therapy

    Science.gov (United States)

    Kim, Dong Geon; Kim, Kang Ho; Seo, Yun Jee; Yang, Heekyoung; Marcusson, Eric G.; Son, Eunju; Lee, Kyoungmin; Sa, Jason K.; Lee, Hye Won; Nam, Do-Hyun

    2016-01-01

    Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method's efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models. PMID:27102443

  18. Polymeric nanoparticles assembled with microfluidics for drug delivery across the blood-brain barrier

    Science.gov (United States)

    Tavares, M. R.; de Menezes, L. R.; do Nascimento, D. F.; Souza, D. H. S.; Reynaud, F.; Marques, M. F. V.; Tavares, M. I. B.

    2016-07-01

    The blood-brain barrier (BBB) is a challenge in the treatment of some diseases, since it prevents many drugs from reaching therapeutic concentrations in the brain. In this context, there is a growing interest in nanoparticles for drug delivery, since they are able to cross this barrier and target the brain. The use of polymeric materials in the development of these nanoparticles has been extensively studied. It has already been demonstrated that these nanosystems have the ability to cross the BBB, which allows effective drug release into the brain. Biodegradable polymers provide a great advantage in the development of nanosystems, but modifications of the nanoparticles' surface is essential. The traditional batch methods lack precise control over the processes of nucleation and growth, resulting in poor control over final properties of the nanoparticles. Therefore, microfluidics could be used to achieve a better production environment for the fabrication of nano- structured drug delivery systems. This study provides a brief review of: the BBB, the polymeric nanoparticles with the ability to overcome the barrier, the properties of the most used polymeric matrices, and the nanostructured drug delivery systems assembled with microfluidics.

  19. Toward the restoration of hand use to a paralyzed monkey: brain-controlled functional electrical stimulation of forearm muscles.

    Directory of Open Access Journals (Sweden)

    Eric A Pohlmeyer

    Full Text Available Loss of hand use is considered by many spinal cord injury survivors to be the most devastating consequence of their injury. Functional electrical stimulation (FES of forearm and hand muscles has been used to provide basic, voluntary hand grasp to hundreds of human patients. Current approaches typically grade pre-programmed patterns of muscle activation using simple control signals, such as those derived from residual movement or muscle activity. However, the use of such fixed stimulation patterns limits hand function to the few tasks programmed into the controller. In contrast, we are developing a system that uses neural signals recorded from a multi-electrode array implanted in the motor cortex; this system has the potential to provide independent control of multiple muscles over a broad range of functional tasks. Two monkeys were able to use this cortically controlled FES system to control the contraction of four forearm muscles despite temporary limb paralysis. The amount of wrist force the monkeys were able to produce in a one-dimensional force tracking task was significantly increased. Furthermore, the monkeys were able to control the magnitude and time course of the force with sufficient accuracy to track visually displayed force targets at speeds reduced by only one-third to one-half of normal. Although these results were achieved by controlling only four muscles, there is no fundamental reason why the same methods could not be scaled up to control a larger number of muscles. We believe these results provide an important proof of concept that brain-controlled FES prostheses could ultimately be of great benefit to paralyzed patients with injuries in the mid-cervical spinal cord.

  20. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    Science.gov (United States)

    Anand, Prachi; O'Neil, Alison; Lin, Emily; Douglas, Trevor; Holford, Mandë

    2015-08-01

    The blood brain barrier (BBB) is often an insurmountable obstacle for a large number of candidate drugs, including peptides, antibiotics, and chemotherapeutic agents. Devising an adroit delivery method to cross the BBB is essential to unlocking widespread application of peptide therapeutics. Presented here is an engineered nanocontainer for delivering peptidic drugs across the BBB encapsulating the analgesic marine snail peptide ziconotide (Prialt®). We developed a bi-functional viral nanocontainer based on the Salmonella typhimurium bacteriophage P22 capsid, genetically incorporating ziconotide in the interior cavity, and chemically attaching cell penetrating HIV-Tat peptide on the exterior of the capsid. Virus like particles (VLPs) of P22 containing ziconotide were successfully transported in several BBB models of rat and human brain microvascular endothelial cells (BMVEC) using a recyclable noncytotoxic endocytic pathway. This work demonstrates proof in principle for developing a possible alternative to intrathecal injection of ziconotide using a tunable VLP drug delivery nanocontainer to cross the BBB.

  1. Effects of acetazolamide on cerebral blood flow and brain tissue oxygenation

    DEFF Research Database (Denmark)

    Lassen, N A; Friberg, L; Kastrup, J

    1987-01-01

    Oral administration of 1 g of acetazolamide to 8 normal subjects studied at sea level and in normoxia caused an acute increase in cerebral blood flow (CBF). During the subsequent prolonged oral treatment with 1 g of acetazolamide daily, CBF returned to normal within 2 days. The alveolar CO2 tension...... decreased gradually to 70% of the control value, indicating hyperventilation. At sea level hyperventilation will not increase brain oxygenation significantly in normal man, as the arterial oxygen content only increases minimally, while CBF is unchanged. At high altitude the beneficial effects...... of acetazolamide on the symptoms of acute mountain sickness may well be due to an improved oxygen supply to the brain, as hyperventilation will, at the low ambient PO2, cause a significant increase of the arterial oxygen content, while CBF presumably is unaffected by the drug. During hypoxia at high altitude...

  2. Delivery of Biologics Across the Blood-Brain Barrier Through Nanoencapsulation

    DEFF Research Database (Denmark)

    Bruun, Jonas

    Drug delivery through nanoencapsulation is a promising approach that offers systemic protection of the pharmaceutical and targeted delivery to the diseased tissue. Especially cancer therapeutic and gene-based medicine may benefit from the advantages offered by encapsulation in nanocarriers, since...... the off-target effect of anti-cancer drug often is severe and gene-based medicine have low systemic stability on its own. This thesis presents four different nanocarrier system with specific focus on delivery of small interfering RNA (siRNA) and cancer therapeutics. The first nanocarrier presented...... is a polymeric micelle made from an anionic triblock copolymer and was intended for delivery of drugs to the central nervous system (CNS), which is protected by the largely impermeable blood-brain barrier (BBB). In order to target the nanocarrier to the brain endothelial cells and obtain receptor...

  3. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia

    Directory of Open Access Journals (Sweden)

    Ted Menghsiung Hsu

    2014-05-01

    Full Text Available Both obesity and Alzheimer’s disease are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of Western diets, diets high in saturated fatty acids and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier degradation, and subsequent hippocampal damage and dementia pathology.

  4. Bioavailability of endomorphins and the blood-brain barrier--a review.

    Science.gov (United States)

    Perlikowska, Renata; Janecka, Anna

    2014-01-01

    Opioid peptides have the potential to be pharmaceutical agents for the treatment of pain because they modulate nociceptive pathways at supraspinal, spinal and peripheral levels. Unfortunately, peptides are generally hydrophilic compounds and therefore unable to cross the blood-brain barrier (BBB) by passive diffusion to reach the central nervous system (CNS) in an amount sufficient to activate appropriate receptors. Endomorphins (EMs) belong to the class of endogenous opioids eliciting the strongest analgesic effect, but only after direct administration to the CNS. Extensive research is in progress to better understand the relationships between EM structure and bioavailability. This article deals with the recent investigations that allow the design of stable and neuroactive EM analogs with enhanced brain passage and uptake.

  5. Cerebrolysin reduces blood-cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat.

    Science.gov (United States)

    Sharma, Hari Shanker; Zimmermann-Meinzingen, Sibilla; Johanson, Conrad E

    2010-06-01

    Traumatic brain injuries (TBIs) induce profound breakdown of the blood-brain and blood-cerebrospinal fluid barriers (BCSFB), brain pathology/edema, and sensory-motor disturbances. Because neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), and glial cell-derived neurotrophic factor (GDNF), are neuroprotective in models of brain and spinal cord injuries, we hypothesized that a combination of neurotrophic factors would enhance neuroprotective efficacy. In the present investigation, we examined the effects of Cerebrolysin, a mixture of different neurotrophic factors (Ebewe Neuro Pharma, Austria) on the brain pathology and functional outcome in a rat model of TBI. TBI was produced under Equithesin (3 mL/kg, i.p.) anesthesia by making a longitudinal incision into the right parietal cerebral cortex. Untreated injured rats developed profound disruption of the blood-brain barrier (BBB) to proteins, edema/cell injury, and marked sensory-motor dysfunctions on rota-rod and grid-walking tests at 5 h TBI. Intracerebroventricular administration of Cerebrolysin (10 or 30 microL) either 5 min or 1 h after TBI significantly reduced leakage of Evans blue and radioiodine tracers across the BBB and BCSFB, and attenuated brain edema formation/neuronal damage in the cortex as well as underlying subcortical regions. Cerebrolysin-treated animals also had improved sensory-motor functions. However, administration of Cerebrolysin 2 h after TBI did not affect these parameters significantly. These observations in TBI demonstrate that early intervention with Cerebrolysin reduces BBB and BCSFB permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits. Taken together, our observations suggest that Cerebrolysin has potential therapeutic value in TBI.

  6. Cellular Apoptosis and Blood Brain Barrier Permeability Changes in the Pre-Incubated Chicken Embryo’s Brain by Effect of Electromagnetic Fields

    Directory of Open Access Journals (Sweden)

    Sima Kalantari

    2015-02-01

    Full Text Available Background: Electromagnetic fields (EMF have teratogenic effects during the embryonic development. In current study, histopathological and physiological effects of sinusoidal EMF on the brain were investigated. We sought to determine the apoptosis level and changes in blood brain barrier permeability in brain tissue of pre-incubated white leghorn hen eggs in the field of EMF. Materials and Methods: In this experimental study, 300 healthy, fresh, and fertilized eggs (55-65 g were divided into experimental (3 groups, N=50, control (N=75 and sham (N=75 groups. Experimental eggs (inside the coil were exposed to 3 different intensities of 1.33, 2.66 and 7.32 mT and sham groups were also located inside the same coil but with no exposure, for 24 hrs before incubation. Control, sham and experimental groups were incubated in an incubator (38±0.5ºC, 60% humidity. Brains of 14 day old chicken embryos of all groups were removed, fixed in formalin (10%, stained with H & E and TUNEL, apoptotic cells were studied under light microscope. Brains of other embryos were prepared for scanning electron microscope. By injections of Evans blue, any possible changes in brain vessels were also investigated. Results: Our results showed electromagnetic fields have toxic effects on cell organelles and cell membranes. EMF would increase the level of cellular apoptosis in the brain. They also would tear up the blood vessels. Thereafter, they would affect the permeability of blood brain barrier of exposed chicken embryos. Conclusion: These findings suggest that electromagnetic fields induce different degrees of brain damages in chicken embryos brain tissue.

  7. Challenges in understanding the impact of blood pressure management on cerebral oxygenation in the preterm brain

    Directory of Open Access Journals (Sweden)

    Aminath eAzhan

    2012-12-01

    Full Text Available Systemic hypotension in preterm infants has been related to increased mortality, cerebrovascular lesions and neurodevelopmental morbidity. Treatment of hypotension with inotropic medications aims at preservation of end organ perfusion and oxygen delivery, especially the brain. The common inotropic medications in preterm infants include dopamine, dobutamine, adrenalin, with adjunctive use of corticosteroids in cases of refractory hypotension. Whether maintenance of mean arterial blood pressure (MAP by use of inotropic medication is neuroprotective or not remains unclear. This review explores the different inotropic agents and their effects on perfusion and oxygenation in the preterm brain, in clinical studies as well as in animal models. Dopamine and adrenalin, because of their -adrenergic vasoconstrictor actions, have raised concerns of reduction in cerebral blood flow (CBF. Several studies in hypotensive preterm infants have shown that dopamine elevates CBF together with increased MAP, in keeping with limited cerebro-autoregulation. Adrenaline is also effective in raising cerebral perfusion together with MAP in preterm infants. Experimental studies in immature animals show no cerebro-vasoconstrictive effects of dopamine or adrenaline, but demonstrate the consistent findings of increased cerebral perfusion and oxygenation with the use of dopamine, dobutamine and adrenaline, alongside with raised MAP. Both clinical and animal studies report the transitory effects of adrenaline in increasing plasma lactate, and blood glucose, which might render its use as a 2nd line therapy. To investigate the cerebral effects of inotropic agents in long-term outcome in hypotensive preterm infants, carefully designed prospective research possibly including preterm infants with permissive hypotension is required. Preterm animal models would be useful in investigating the relationship between the physiological effects of inotropes and histopathology outcomes in

  8. Obesity, type 2 diabetes, and impaired insulin-stimulated blood flow: role of skeletal muscle NO synthase and endothelin-1.

    Science.gov (United States)

    Reynolds, Leryn J; Credeur, Daniel P; Manrique, Camila; Padilla, Jaume; Fadel, Paul J; Thyfault, John P

    2017-01-01

    Increased endothelin-1 (ET-1) and reduced endothelial nitric oxide phosphorylation (peNOS) are hypothesized to reduce insulin-stimulated blood flow in type 2 diabetes (T2D), but studies examining these links in humans are limited. We sought to assess basal and insulin-stimulated endothelial signaling proteins (ET-1 and peNOS) in skeletal muscle from T2D patients. Ten obese T2D [glucose disposal rate (GDR): 6.6 ± 1.6 mg·kg lean body mass (LBM)(-1)·min(-1)] and 11 lean insulin-sensitive subjects (Lean GDR: 12.9 ± 1.2 mg·kg LBM(-1)·min(-1)) underwent a hyperinsulinemic-euglycemic clamp with vastus lateralis biopsies taken before and 60 min into the clamp. Basal biopsies were also taken in 11 medication-naïve, obese, non-T2D subjects. ET-1, peNOS (Ser1177), and eNOS protein and mRNA were measured from skeletal muscle samples containing native microvessels. Femoral artery blood flow was assessed by duplex Doppler ultrasound. Insulin-stimulated blood flow was reduced in obese T2D (Lean: +50.7 ± 6.5% baseline, T2D: +20.8 ± 5.2% baseline, P 0.05). Obese non-T2D subjects tended to also display elevated basal ET-1 (P = 0.06). In summary, higher basal skeletal muscle expression of ET-1 and reduced peNOS/eNOS may contribute to a reduced insulin-stimulated leg blood flow response in obese T2D patients.

  9. Effect of Acupuncture Signal after Brachial Plexus Blockade on Cerebral Blood Perfusion and Brain Cell Function

    Institute of Scientific and Technical Information of China (English)

    任永功; 郭长春; 贾少微

    2003-01-01

    Objective: Using single photon emission computed tomography (SPECT) to observe the influence of the up-transmitting of acupuncture signal into the brain in health volunteers whose nerve trunk was blocked by anesthetics. Methods: Thirty-one healthy volunteers were divided into two groups, the control group of 20 cases, and the brachial plexus blockade (BPB) group of 11 cases, with supraclavicular BPB route adopted. With the control group 2 acupoints were randomly selected (Hegu and Quchi of both sides), while with the BPB group Hegu and Quchi of anesthetic arm side were selected. Siemens ECAM/ICON SPECT system was used to conduct brain imaging using double imaging assay before acupuncture and 99mTc-ECD imaging agent during acupuncture for cerebral perfusion. The data were quantitatively analyzed by blood functional changing rate (BFCR%) mathematics model. Results: Before acupuncture, the control and BPB groups showed insignificant change by SPECT, but after electro-acupuncture (EA), the control group displayed improved motor and sensory cortex excitability in basal nuclei, contra-lateral thalamus, parietal and frontal lobe; while BPB group was characterized with reduction of the blood perfusion and cell function of contra-lateral thalamus of anesthetized arm. The difference between the two groups was significant (P<0.01). Conclusion: (1) After BPB, the up-transmitting of the acupuncture signal via upper limb into the brain, and its strength was impaired or blocked; (2) After BPB, the effect of acupuncture on cerebral perfusion and brain cell function of contra-lateral thalamus was impaired or blocked.

  10. Liposomes Coloaded with Elacridar and Tariquidar To Modulate the P-Glycoprotein at the Blood-Brain Barrier.

    Science.gov (United States)

    Nieto Montesinos, Rita; Béduneau, Arnaud; Lamprecht, Alf; Pellequer, Yann

    2015-11-01

    This study prepared three liposomal formulations coloaded with elacridar and tariquidar to overcome the P-glycoprotein-mediated efflux at the blood-brain barrier. Their pharmacokinetics, brain distribution, and impact on the model P-glycoprotein substrate, loperamide, were compared to those for the coadministration of free elacridar plus free tariquidar. After intravenous administration in rats, elacridar and tariquidar in conventional liposomes were rapidly cleared from the bloodstream. Their low levels in the brain did not improve the loperamide brain distribution. Although elacridar and tariquidar in PEGylated liposomes exhibited 2.6 and 1.9 longer half-lives than free elacridar and free tariquidar, respectively, neither their Kp for the brain nor the loperamide brain distribution was improved. However, the conjugation of OX26 F(ab')2 fragments to PEGylated liposomes increased the Kps for the brain of elacridar and tariquidar by 1.4- and 2.1-fold, respectively, in comparison to both free P-gp modulators. Consequently, the Kp for the brain of loperamide increased by 2.7-fold. Moreover, the plasma pharmacokinetic parameters and liver distribution of loperamide were not modified by the PEGylated OX26 F(ab')2 immunoliposomes. Thus, this formulation represents a promising tool for modulating the P-glycoprotein-mediated efflux at the blood-brain barrier and could improve the brain uptake of any P-glycoprotein substrate that is intended to treat central nervous system diseases.

  11. Blood-brain barrier models and their relevance for a successful development of CNS drug delivery systems: a review.

    Science.gov (United States)

    Bicker, Joana; Alves, Gilberto; Fortuna, Ana; Falcão, Amílcar

    2014-08-01

    During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood-brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood-brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood-brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is also discussed.

  12. Gap junction proteins in the blood-brain barrier control nutrient-dependent reactivation of Drosophila neural stem cells.

    Science.gov (United States)

    Spéder, Pauline; Brand, Andrea H

    2014-08-11

    Neural stem cells in the adult brain exist primarily in a quiescent state but are reactivated in response to changing physiological conditions. How do stem cells sense and respond to metabolic changes? In the Drosophila CNS, quiescent neural stem cells are reactivated synchronously in response to a nutritional stimulus. Feeding triggers insulin production by blood-brain barrier glial cells, activating the insulin/insulin-like growth factor pathway in underlying neural stem cells and stimulating their growth and proliferation. Here we show that gap junctions in the blood-brain barrier glia mediate the influence of metabolic changes on stem cell behavior, enabling glia to respond to nutritional signals and reactivate quiescent stem cells. We propose that gap junctions in the blood-brain barrier are required to translate metabolic signals into synchronized calcium pulses and insulin secretion.

  13. Purinergic receptor P2RY12-dependent microglial closure of the injured blood-brain barrier

    DEFF Research Database (Denmark)

    Lou, Nanhong; Takano, Takahiro; Pei, Yong;

    2016-01-01

    Microglia are integral functional elements of the central nervous system, but the contribution of these cells to the structural integrity of the neurovascular unit has not hitherto been assessed. We show here that following blood-brain barrier (BBB) breakdown, P2RY12 (purinergic receptor P2Y, G......-protein coupled, 12)-mediated chemotaxis of microglia processes is required for the rapid closure of the BBB. Mice treated with the P2RY12 inhibitor clopidogrel, as well as those in which P2RY12 was genetically ablated, exhibited significantly diminished movement of juxtavascular microglial processes and failed...

  14. Short-term low-intensity blood flow restricted interval training improves both aerobic fitness and muscle strength.

    Science.gov (United States)

    de Oliveira, M F M; Caputo, F; Corvino, R B; Denadai, B S

    2016-09-01

    The present study aimed to analyze and compare the effects of four different interval-training protocols on aerobic fitness and muscle strength. Thirty-seven subjects (23.8 ± 4 years; 171.7 ± 9.5 cm; 70 ± 11 kg) were assigned to one of four groups: low-intensity interval training with (BFR, n = 10) or without (LOW, n = 7) blood flow restriction, high-intensity interval training (HIT, n = 10), and combined HIT and BFR (BFR + HIT, n = 10, every session performed 50% as BFR and 50% as HIT). Before and after 4 weeks training (3 days a week), the maximal oxygen uptake (VO2max ), maximal power output (Pmax ), onset blood lactate accumulation (OBLA), and muscle strength were measured for all subjects. All training groups were able to improve OBLA (BFR, 16%; HIT, 25%; HIT + BFR, 22%; LOW, 6%), with no difference between groups. However, VO2max and Pmax improved only for BFR (6%, 12%), HIT (9%, 15%) and HIT + BFR (6%, 11%), with no difference between groups. Muscle strength gains were only observed after BFR training (11%). This study demonstrates the advantage of short-term low-intensity interval BFR training as the single mode of training able to simultaneously improve aerobic fitness and muscular strength.

  15. Probing Brain Oxygenation with Near Infrared spectroscopy, the Role of Carbon Dioxide and Blood Pressure

    CERN Document Server

    Gersten, Alexander

    2015-01-01

    The fundamentals of near infrared spectroscopy (NIRS) are reviewed. Among the major factors controlling the cerebral blood flow (CBF), the effect of PaCO2 is peculiar in that it violates autoregulatory CBF mechanisms and allows to explore the full range of the CBF. A simple physical model, with a four parameter formula, relating the CBF to PaCO2 is presented. It can be used to transform the fits of one animal to the fits of another one. It enable the use of rats data as monkeys data simply by rescaling the PaCO2 values and the CBF data. Controlled breathing can change the PaCO2. Experiments on human subjects relating the PaCO2 to rSO2, measured with brain oximeters, are presented. A simple model relating the mean blood pressure to CBF is worked out.

  16. Heat stress redistributes blood flow in arteries of the brain during dynamic exercise.

    Science.gov (United States)

    Sato, Kohei; Oue, Anna; Yoneya, Marina; Sadamoto, Tomoko; Ogoh, Shigehiko

    2016-04-01

    We hypothesized that heat stress would decrease anterior and posterior cerebral blood flow (CBF) during exercise, and the reduction in anterior CBF would be partly associated with large increase in extracranial blood flow (BF). Nine subjects performed 40 min of semirecumbent cycling at 60% of the peak oxygen uptake in hot (35°C; Heat) and thermoneutral environments (25°C; Control). We evaluated BF and conductance (COND) in the external carotid artery (ECA), internal carotid artery (ICA), and vertebral artery (VA) using ultrasonography. During the Heat condition, ICA and VA BF were significantly increased 10 min after the start of exercise (P brain arteries to exercise, which resulted in an alteration in the distribution of cardiac output. Moreover, a hyperthermia-induced increase in extracranial BF might compromise anterior CBF during exercise with heat stress.

  17. Human Umbilical Cord Blood Stem Cells: Rational for Use as a Neuroprotectant in Ischemic Brain Disease

    Directory of Open Access Journals (Sweden)

    Hadar Arien-Zakay

    2010-09-01

    Full Text Available The use of stem cells for reparative medicine was first proposed more than three decades ago. Hematopoietic stem cells from bone marrow, peripheral blood and human umbilical cord blood (CB have gained major use for treatment of hematological indications. CB, however, is also a source of cells capable of differentiating into various non-hematopoietic cell types, including neural cells. Several animal model reports have shown that CB cells may be used for treatment of neurological injuries. This review summarizes the information available on the origin of CB-derived neuronal cells and the mechanisms proposed to explain their action. The potential use of stem/progenitor cells for treatment of ischemic brain injuries is discussed. Issues that remain to be resolved at the present stage of preclinical trials are addressed.

  18. Laser speckle-imaging of blood microcirculation in the brain cortex of laboratory rats in stress

    Energy Technology Data Exchange (ETDEWEB)

    Vilensky, M A; Semyachkina-Glushkovskaya, Oxana V; Timoshina, P A; Kuznetsova, Jana V; Semyachkin-Glushkovskii, I A; Agafonov, Dmitry N; Tuchin, Valerii V

    2012-06-30

    The results of experimental approbation of the method of laser full-field speckle-imaging for monitoring the changes in blood microcirculation state of the brain cortex of laboratory rats under the conditions of developing stroke and administration of vasodilating and vasoconstrictive agents are presented. The studies aimed at the choice of the optimal conditions of speckle-image formation and recording were performed and the software implementing an adaptive algorithm for processing the data of measurements was created. The transfer of laser radiation to the probed region of the biotissue was implemented by means of a silica-polymer optical fibre. The problems and prospects of speckle-imaging of cerebral microcirculation of blood in laboratory and clinical conditions are discussed.

  19. Increased cerebral blood flow in MELAS shown by Tc-99m HMPAO brain SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Peng, N.J.; Tsay, D.G. [Department of Nuclear Medicine, Kaohsiung Veterans General Hospital, Kaohsiung (Taiwan); Liu, R.S. [Department of Nuclear Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei (Taiwan); Li, J.Y.; Kong, K.W. [Division of Neurology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung (Taiwan); Kwok, C.G.; Strauss, H.W. [Division of Nuclear Medicine, Department of Radiology, Stanford University Medical Center, CA (United States)

    2000-01-01

    We report cerebral SPECT studies on two siblings with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Tc-99m HMPAO brain SPECT was performed 8, 19 and 30 days after a stroke-like episode in one case and 10 days after a stroke-like episode, 6 h after a partial seizure and as a follow-up study in the other. Increased blood flow was seen in both these patients with stroke-like episodes due to MELAS. The cause of the increased blood flow is uncertain, but it may be related to the decreased pH created by local increase in lactic acid. (orig.)

  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. 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. Blood-brain barrier flux of aluminum, manganese, iron and other metals suspected to contribute to metal-induced neurodegeneration.

    Science.gov (United States)

    Yokel, Robert A

    2006-11-01

    The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc;{-} and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of

  3. Effects of GSM modulated radio-frequency electromagnetic radiation on permeability of blood-brain barrier in male & female rats.

    Science.gov (United States)

    Sırav, Bahriye; Seyhan, Nesrin

    2016-09-01

    With the increased use of mobile phones, their biological and health effects have become more important. Usage of mobile phones near the head increases the possibility of effects on brain tissue. This study was designed to investigate the possible effects of pulse modulated 900MHz and 1800MHz radio-frequency radiation on the permeability of blood-brain barrier of rats. Study was performed with 6 groups of young adult male and female wistar albino rats. The permeability of blood-brain barrier to intravenously injected evans blue dye was quantitatively examined for both control and radio-frequency radiarion exposed groups. For male groups; Evans blue content in the whole brain was found to be 0.08±0.01mg% in the control, 0.13±0.03mg% in 900MHz exposed and 0.26±0.05mg% in 1800MHz exposed animals. In both male radio-frequency radiation exposed groups, the permeability of blood-brain barrier found to be increased with respect to the controls (p0.01). However 900MHz pulse modulated radio-frequency exposure was found effective on the permeability of blood-brain barrier of female animals. Results have shown that 20min pulse modulated radio-frequency radiation exposure of 900MHz and 1800MHz induces an effect and increases the permeability of blood-brain barrier of male rats. For females, 900MHz was found effective and it could be concluded that this result may due to the physiological differences between female and male animals. The results of this study suggest that mobile phone radation could lead to increase the permeability of blood-brain barrier under non-thermal exposure levels. More studies are needed to demonstrate the mechanisms of that breakdown.

  4. The effect of butylphthalide on the brain edema, blood-brain barrier of rats after focal cerebral infarction and the expression of Rho A.

    Science.gov (United States)

    Hu, Jinyang; Wen, Qingping; Wu, Yue; Li, Baozhu; Gao, Peng

    2014-06-01

    The aim of this study was to explore the effect of butylphthalide on the brain edema, blood-brain barrier of rats of rats after focal cerebral infarction and the expression of Rho A. A total of 195 sprague-dawley male rats were randomly divided into control group, model group, and butylphthalide group (40 mg/kg, once a day, by gavage). The model was made by photochemical method. After surgery 3, 12, 24, 72, and 144 h, brain water content was done to see the effect of butylphthalide for the cerebral edema. Evans blue extravasation method was done to see the changes in blood-brain barrier immunohistochemistry, and Western blot was done to see the expression of Rho A around the infarction. Compared with the control group, the brain water content of model group and butylphthalide group rats was increased, the permeability of blood-brain barrier of model group and butylphthalide group rats was increased, and the Rho A protein of model group and butylphthalide group rats was increased. Compared with the model group, the brain water content of butylphthalide group rats was induced (73.67 ± 0.67 vs 74.14 ± 0.46; 74.89 ± 0.57 vs 75.61 ± 0.52; 77.49 ± 0.34 vs 79.33 ± 0.49; 76.31 ± 0.56 vs 78.01 ± 0.48; 72.36 ± 0.44 vs 73.12 ± 0.73; P edema, protect the blood-brain barrier, and decrease the expression of Rho A around the infarction.

  5. Adenosine receptor signaling modulates permeability of the blood-brain barrier.

    Science.gov (United States)

    Carman, Aaron J; Mills, Jeffrey H; Krenz, Antje; Kim, Do-Geun; Bynoe, Margaret S

    2011-09-14

    The blood-brain barrier (BBB) is comprised of specialized endothelial cells that form the capillary microvasculature of the CNS and is essential for brain function. It also poses the greatest impediment in the treatment of many CNS diseases because it commonly blocks entry of therapeutic compounds. Here we report that adenosine receptor (AR) signaling modulates BBB permeability in vivo. A(1) and A(2A) AR activation facilitated the entry of intravenously administered macromolecules, including large dextrans and antibodies to β-amyloid, into murine brains. Additionally, treatment with an FDA-approved selective A(2A) agonist, Lexiscan, also increased BBB permeability in murine models. These changes in BBB permeability are dose-dependent and temporally discrete. Transgenic mice lacking A(1) or A(2A) ARs showed diminished dextran entry into the brain after AR agonism. Following treatment with a broad-spectrum AR agonist, intravenously administered anti-β-amyloid antibody was observed to enter the CNS and bind β-amyloid plaques in a transgenic mouse model of Alzheimer's disease (AD). Selective AR activation resulted in cellular changes in vitro including decreased transendothelial electrical resistance, increased actinomyosin stress fiber formation, and alterations in tight junction molecules. These results suggest that AR signaling can be used to modulate BBB permeability in vivo to facilitate the entry of potentially therapeutic compounds into the CNS. AR signaling at brain endothelial cells represents a novel endogenous mechanism of modulating BBB permeability. We anticipate these results will aid in drug design, drug delivery and treatment options for neurological diseases such as AD, Parkinson's disease, multiple sclerosis and cancers of the CNS.

  6. Relationship between mercury concentrations in the blood with that in the muscle of four estuarine tropical fish species, Rio de Janeiro State, Brazil.

    Science.gov (United States)

    de Castro Rodrigues, Ana Paula; Maciel, Patrícia Oliveira; da Silva, Luiz César Cavalcanti Pereira; Almosny, Nádia Regina Pereira; Andreata, José Vanderli; Bidone, Edison Dausacker; Castilhos, Zuleica Carmen

    2011-03-01

    The aim of this work was to assess the relationship between mercury concentrations in the blood with that in muscle for non-invasive mercury contamination assessment in fish. At Ribeira Bay were collected 198 fishes of 4 species (Genidens genidens, Arius luniscutis, Haemulon steindachneri, Micropogonias furnieri). At Guanabara Bay were collected 84 fishes of 2 species (Genidens genidens, Micropogonias furnieri). Means of mercury concentrations in fish muscles in both areas were below 500 ng/g. The mean ratio, including all specimens of all species, for mercury in muscle-to-whole blood was 13.4:1, for muscle-to-erythrocytes, 6.5:1 and for erythrocytes-to-plasma, 6.5:1. Further studies are necessary to insure that blood could be used as an exposure biomarker, in order to assess mercury availability in aquatic ecosystems.

  7. Increased presence of FOXP3+ regulatory T cells in inflamed muscle of patients with active juvenile dermatomyositis compared to peripheral blood.

    Directory of Open Access Journals (Sweden)

    Yvonne Vercoulen

    Full Text Available Juvenile dermatomyositis (JDM is an immune-mediated inflammatory disease affecting the microvasculature of skin and muscle. CD4+ CD25+ FOXP3+ regulatory T cells (Tregs are key regulators of immune homeostasis. A role for Tregs in JDM pathogenesis has not yet been established. Here, we explored Treg presence and function in peripheral blood and muscle of JDM patients. We analyzed number, phenotype and function of Tregs in blood from JDM patients by flow cytometry and in vitro suppression assays, in comparison to healthy controls and disease controls (Duchenne's Muscular Dystrophy. Presence of Tregs in muscle was analyzed by immunohistochemistry. Overall, Treg percentages in peripheral blood of JDM patients were similar compared to both control groups. Muscle biopsies of new onset JDM patients showed increased infiltration of numbers of T cells compared to Duchenne's muscular dystrophy. Both in JDM and Duchenne's muscular dystrophy the proportion of FOXP3+ T cells in muscles were increased compared to JDM peripheral blood. Interestingly, JDM is not a self-remitting disease, suggesting that the high proportion of Tregs in inflamed muscle do not suppress inflammation. In line with this, peripheral blood Tregs of active JDM patients were less capable of suppressing effector T cell activation in vitro, compared to Tregs of JDM in clinical remission. These data show a functional impairment of Tregs in a proportion of patients with active disease, and suggest a regulatory role for Tregs in JDM inflammation.

  8. Inspiratory Muscle Training and Arterial Blood Oxygen Saturation in Patients With Chronic Obstructive Pulmonary Disease

    Directory of Open Access Journals (Sweden)

    Bakhshandeh Bavarsad

    2015-01-01

    Full Text Available Background One of the problems of the patients with chronic obstructive pulmonary disease (COPD is the weakness of the respiratory muscles that causes oxygen desaturation at rest and activity and decreases exercise tolerance. Objectives This study aimed to investigate the effect of inspiratory muscle training on arterial oxygen saturation (SPO2. Patients and Methods Forty patients with mild to very severe COPD were recruited for this study, which is a randomized control trail. The patients were randomized to IMT (inspiratory muscle training and control group. Training was performed with Respivol (a kind of inspiratory muscle trainer for 8 weeks (15 min/d for 6 d/week. SPSS software version 16 was used to analyze the data by performing independent t test, paired t test, and Fisher exact test. Results Results showed that, after 8 weeks of inspiratory muscle training, there was a little increase (but not statistically significant improvement in SPO2 (from 92.6 ± 8.71 % to 95.13 ± 7.08 %, with P = 0.06, whereas it remained unchanged in the control group (from 96.0 ± 3.46 % to 96.4 ± 3.35 % with P = 0.51. No statistically significant difference was seen between the two groups (P > 0.05. Conclusions Although inspiratory muscles training can prevent desaturation, which is caused by activity, it fails to improve it.

  9. Bacterial induction of Snail1 contributes to blood-brain barrier disruption

    Science.gov (United States)

    Kim, Brandon J.; Hancock, Bryan M.; Bermudez, Andres; Cid, Natasha Del; Reyes, Efren; van Sorge, Nina M.; Lauth, Xavier; Smurthwaite, Cameron A.; Hilton, Brett J.; Stotland, Aleksandr; Banerjee, Anirban; Buchanan, John; Wolkowicz, Roland; Traver, David; Doran, Kelly S.

    2015-01-01

    Bacterial meningitis is a serious infection of the CNS that results when blood-borne bacteria are able to cross the blood-brain barrier (BBB). Group B Streptococcus (GBS) is the leading cause of neonatal meningitis; however, the molecular mechanisms that regulate bacterial BBB disruption and penetration are not well understood. Here, we found that infection of human brain microvascular endothelial cells (hBMECs) with GBS and other meningeal pathogens results in the induction of host transcriptional repressor Snail1, which impedes expression of tight junction genes. Moreover, GBS infection also induced Snail1 expression in murine and zebrafish models. Tight junction components ZO-1, claudin 5, and occludin were decreased at both the transcript and protein levels in hBMECs following GBS infection, and this repression was dependent on Snail1 induction. Bacteria-independent Snail1 expression was sufficient to facilitate tight junction disruption, promoting BBB permeability to allow bacterial passage. GBS induction of Snail1 expression was dependent on the ERK1/2/MAPK signaling cascade and bacterial cell wall components. Finally, overexpression of a dominant-negative Snail1 homolog in zebrafish elevated transcription of tight junction protein–encoding genes and increased zebrafish survival in response to GBS challenge. Taken together, our data support a Snail1-dependent mechanism of BBB disruption and penetration by meningeal pathogens. PMID:25961453

  10. Microstructure and Cerebral Blood Flow within White Matter of the Human Brain: A TBSS Analysis.

    Directory of Open Access Journals (Sweden)

    Stéphanie Giezendanner

    Full Text Available White matter (WM fibers connect different brain regions and are critical for proper brain function. However, little is known about the cerebral blood flow in WM and its relation to WM microstructure. Recent improvements in measuring cerebral blood flow (CBF by means of arterial spin labeling (ASL suggest that the signal in white matter may be detected. Its implications for physiology needs to be extensively explored. For this purpose, CBF and its relation to anisotropic diffusion was analyzed across subjects on a voxel-wise basis with tract-based spatial statistics (TBSS and also across white matter tracts within subjects.Diffusion tensor imaging and ASL were acquired in 43 healthy subjects (mean age = 26.3 years.CBF in WM was observed to correlate positively with fractional anisotropy across subjects in parts of the splenium of corpus callosum, the right posterior thalamic radiation (including the optic radiation, the forceps major, the right inferior fronto-occipital fasciculus, the right inferior longitudinal fasciculus and the right superior longitudinal fasciculus. Furthermore, radial diffusivity correlated negatively with CBF across subjects in similar regions. Moreover, CBF and FA correlated positively across white matter tracts within subjects.The currently observed findings on a macroscopic level might reflect the metabolic demand of white matter on a microscopic level involving myelination processes or axonal function. However, the exact underlying physiological mechanism of this relationship needs further evaluation.

  11. Extraction of [99mTc]-d,l-HM-PAO across the blood-brain barrier

    DEFF Research Database (Denmark)

    Andersen, A R; Friberg, H; Knudsen, K B

    1988-01-01

    The initial extraction (E) across the blood-brain barrier (BBB) of [99mTc]-d,l-HM-PAO after intracarotid injection was measured in 14 Wistar rats and 6 patients using the double indicator, single injection method with Na-24 as the cotracer. In both series, cerebral blood flow (CBF) was measured...... using the initial slope of the xenon-133 washout curve after intracarotid bolus injection. In rats, bolus size (20 or 120 microliters), bolus type (saline or 10% albumin), or CBF were changed. First-pass extraction was dependent on CBF (p less than 0.001): With a small bolus of saline and at resting CBF...... the apparent extraction across brain capillaries. In patients using a bolus of 1 ml saline, E decreased linearly with increasing CBF (r = -0.81, p less than 0.001). For a CBF of 0.59 ml/g/min and an average apparent E of 0.72, an apparent PS product of 0.76 ml/g/min was calculated.(ABSTRACT TRUNCATED AT 250...

  12. Blood-brain barrier permeability mechanisms in view of quantitative structure-activity relationships (QSAR).

    Science.gov (United States)

    Bujak, Renata; Struck-Lewicka, Wiktoria; Kaliszan, Michał; Kaliszan, Roman; Markuszewski, Michał J

    2015-04-10

    The goal of the present paper was to develop a quantitative structure-activity relationship (QSAR) method using a simple statistical approach, such as multiple linear regression (MLR) for predicting the blood-brain barrier (BBB) permeability of chemical compounds. The "best" MLR models, comprised logP and either molecular mass (M) or isolated atomic energy (E(isol)), tested on a structurally diverse set of 66 compounds, is characterized the by correlation coefficients (R) around 0.8. The obtained models were validated using leave-one-out (LOO) cross-validation technique and the correlation coefficient of leave-one-out- R(LOO)(2) (Q(2)) was at least 0.6. Analysis of a case from legal medicine demonstrated informative value of our QSAR model. To best authors' knowledge the present study is a first application of the developed QSAR models of BBB permeability to case from the legal medicine. Our data indicate that molecular energy-related descriptors, in combination with the well-known descriptors of lipophilicity may have a supportive value in predicting blood-brain distribution, which is of utmost importance in drug development and toxicological studies.

  13. Effects of MDMA on blood glucose levels and brain glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Soto-Montenegro, M.L.; Vaquero, J.J.; Garcia-Barreno, P.; Desco, M. [Hospital General Universitario Gregorio Maranon, Laboratorio de Imagen, Medicina Experimental, Madrid (Spain); Arango, C. [Hospital General Gregorio Maranon, Departamento de Psiquiatria, Madrid (Spain); Ricaurte, G. [Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, MD (United States)

    2007-06-15

    This study was designed to assess changes in glucose metabolism in rats administered single or repeated doses of MDMA. Two different experiments were performed: (1) A single-dose study with four groups receiving 20 mg/kg, 40 mg/kg, saline or heat, and (2) a repeated-dose study with two groups receiving three doses, at intervals of 2 h, of 5 mg/kg or saline. Rats were imaged using a dedicated small-animal PET scanner 1 h after single-dose administration or 7 days after repeated doses. Glucose metabolism was measured in 12 cerebral regions of interest. Rectal temperature and blood glucose were monitored. Peak body temperature was reached 1 h after MDMA administration. Blood glucose levels decreased significantly after MDMA administration. In the single-dose experiment, brain glucose metabolism showed hyperactivation in cerebellum and hypo-activation in the hippocampus, amygdala and auditory cortex. In the repeated-dose experiment, brain glucose metabolism did not show any significant change at day 7. These results are the first to indicate that MDMA has the potential to produce significant hypoglycaemia. In addition, they show that MDMA alters glucose metabolism in components of the motor, limbic and somatosensory systems acutely but not on a long-term basis. (orig.)

  14. Comparative analysis of RNA-Seq data from brain and blood samples of Parkinson's disease.

    Science.gov (United States)

    Chatterjee, Paulami; Roy, Debjani

    2017-03-11

    Parkinson's disease (PD) is the second most common neurodegenerative disorders throughout the world. In order to search for PD biomarkers, we performed a system-level study of RNA-Seq data from PD brain and blood samples. Differentially expressed miRs of RNA-Seq data were subjected to generate the Co-expression networks. Three highly co-expressed clusters were identified based on their correlation coefficient values and fold change ratio. SM2miR drugs of the miRs contained in the three highly co-expressed clusters were identified, and drugs common among these clusters were selected. Co-expressed miRs not previously known to be associated with PD were identified from both the samples. Functional enrichment analyses of these miR targets were done, and the pathways common and unique to both the samples were identified. Thus, our study presents a comparative analysis of miRs, their associated pathways, and drugs from brain and blood samples of PD that may help in system level understanding of this disease. miRs identified from our study may serve as biomarkers for PD.

  15. Interaction of nanoparticles of ferric oxide with brain nerve terminals and blood platelets

    Science.gov (United States)

    Borisova, Tatiana; Krisanova, Natalia; Sivko, Roman; Borisov, Arseniy

    2012-07-01

    Nanoparticles of ferric oxide are the components of Lunar and Martian soil simulants. The observations suggest that exposure to Lunar soli simulant can be deleterious to human physiology and the components of lunar soil may be internalized by lung epithelium and may overcome the blood-brain barrier. The study focused on the effects of nanoparticles of ferric oxide on the functional state of rat brain nerve terminals (synaptosomes) and rabbit blood platelets. Using photon correlation spectroscopy, we demonstrated the binding of nanoparticles of ferric oxide with nerve terminals and platelets. Nanoparticles did not depolarize the plasma membrane of nerve terminals and platelets that was shown by fluorimetry with potential-sensitive fluorescent dye rhodamine 6G. Using pH-sensitive fluorescent dye acridine orange, we revealed that the acidification of synaptic vesicles of nerve terminals and secretory granules of platelets did not change in the presence of nanoparticles. The initial velocity of uptake of excitatory neurotransmitter glutamate was not influenced by nanoparticles of ferric oxide, whereas glutamate binding to nerve terminals was altered. Thus, it was suggested that nanoparticles of ferric oxide might disturb glutamate transport in the mammalian CNS.

  16. Impaired autoregulation of blood flow in skeletal muscle and subcutaneous tissue in long-term Type 1 (insulin-dependent) diabetic patients with microangiopathy

    DEFF Research Database (Denmark)

    Faris, I; Vagn Nielsen, H; Henriksen, O

    1983-01-01

    Autoregulation of blood flow was studied in skeletal muscle and subcutaneous tissue in seven Type 1 (insulin-dependent) diabetic patients (median age: 36 years) with nephropathy and retinopathy and in eight normal subjects of the same age. Blood flow was measured by the local 133Xe washout...

  17. Transgenic over-expression of slit2 enhances disruption of blood-brain barrier and increases cell death after traumatic brain injury in mice.

    Science.gov (United States)

    Li, Shuai; Li, Hang; He, Xiao-Fei; Li, Ge; Zhang, Qun; Liang, Feng-Ying; Jia, Huan-Huan; Li, Jiang-Chao; Huang, Ren; Pei, Zhong; Wang, Li-Jing; Zhang, Yu

    2016-09-19

    Traumatic brain injury (TBI) is the leading cause of mortality and disability among male adolescents and young adults; and mild traumatic brain injury is the most common type of traumatic brain injury. The disruption of blood-brain barrier (BBB) plays an important role in brain trauma. Previously, we have found that slit2, a member of slit protein family, increases permeability of BBB. In the present study, we examined the role of slit2 in the pathogenesis of mild TBI in a mouse model of micro TBI. Rhodamine BandPI (PropidiumIodide) staining were used to detect the permeability of BBB and cell death, respectively. The leakage of Rhodamine B and cell death were significantly increased in Slit2-Tg mice than in C57 control mice after micro TBI. The present results suggest that over expression of slit2 plays a detrimental role in the pathophysiology of mild TBI.

  18. The effects of Tanshinone IIA on blood-brain barrier and brain edema after transient middle cerebral artery occlusion in rats.

    Science.gov (United States)

    Tang, Chao; Xue, Hongli; Bai, Changlin; Fu, Rong; Wu, Anhua

    2010-12-01

    Disruption of blood-brain barrier (BBB) and edema formation play a key role in the development of neurological dysfunction after cerebral ischemia. In this study, the effects of Tanshinone IIA (Tan IIA), one of the active ingredients of Salvia miltiorrhiza root, on the BBB and brain edema after transient middle cerebral artery occlusion in rats were examined. Our study demonstrated that Tan IIA reduced brain infarct area, water content in the ischemic hemisphere. Furthermore, Tan IIA significantly decreased BBB permeability to Evans blue, suppressed the expression of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), inhibited the degradation of tight junction proteins zonula occludens-1 (ZO-1) and Occludin. These results demonstrated that Tan IIA was effective for attenuating the extent of brain edema formation in response to ischemia injury in rats, partly by Tan IIA's protective effect on the BBB. Our results may have implications in the treatment of brain edema in cerebral ischemia.

  19. Blood flow and muscle bio-energetics by 31P-nuclear magnetic resonance after local cold acclimation.

    Science.gov (United States)

    Savourey, G; Clerc, L; Vallerand, A L; Leftheriotis, G; Mehier, H; Bittel, J H

    1992-01-01

    To clarify the origin of local cold adaptation and to define precisely its influence on muscle bio-energetics during local exercise, five subjects were subjected to repeated 5 degrees C cold water immersion of the right hand and forearm. The first aim of our investigation was therefore carried out by measuring local skin temperatures and peripheral blood flow during a cold hand test (5 degrees C, 5 min) followed by a 10-min recovery period. The 31P by nuclear magnetic resonance (31PNMR) muscle bio-energetic changes, indicating possible heat production changes, were measured during the recovery period. The second aim of our investigation was carried out by measuring 31PNMR muscle bioenergetics during handgrip exercise (10% of the maximal voluntary contraction for 5 min followed by a 10-min recovery period) performed both at a comfortable ambient temperature (22 degrees C; E) and after a cold hand test (EC), before and after local cold adaptation. Local cold adaptation, confirmed by warmer skin temperatures of the extremities (+30%, P less than 0.05), was related more to an increased peripheral blood flow, as shown by the smaller decrease in systolic peak [-245 (SEM 30) Hz vs -382 (SEM 95) Hz, P less than 0.05] than to a change in local heat production, because muscle bioenergetics did not vary. Acute local cold immersion decreased the inorganic phosphate:phosphocreatine (PC) ratio during EC compared to E [+0.006 (SEM 0.010) vs +0.078 (SEM 0.002) before acclimation and +0.029 (SEM 0.002) vs +0.090 (SEM 0.002) after acclimation respectively, P less than 0.05] without significant change in the PC:beta-adenosine triphosphate ratio and pH. Local adaptation did not modify these results statistically. The recovery of PC during E increased after acclimation [9.0 (SEM 0.2) min vs 3.0 (SEM 0.4) min, P less than 0.05]. These results suggested that local cold adaptation is related more to peripheral blood flow changes than to increased metabolic heat production in the muscle.

  20. Generation of a High Resistance in vitro Blood-Brain-Barrier Model and Investigations of Brain-to-Blood Glutamate Efflux

    DEFF Research Database (Denmark)

    Helms, Hans Christian

    Blod-hjernebarrieren (blood-brain barrier, BBB) opretholder den generelle homeostase i hjernens væsker. BBB kan også spille en rolle i homeostasen for den eksitatoriske aminosyre, L-glutamat. In vitro modeller kan være effektive værktøjer til at få mekanistiske informationer om transcellulær...... polariseret transport i blod-til-hjerne-retningen med en KM på 138 ± 49 µM og Jmax på 28 ± 3.1 pmol • min-1 • cm-2 for L-glutamat. D-aspartat akkumuleredes i co-kulturerne, når det blev tilsat den basolaterale side. EAAT-1 ekspression var konstant og ensartet i modellen og i friskt isolerede kapillærer, mens...... ekspressionen af EAAT-2 og -3 var uklar. L-glutamat blev opkoncentreret i endothelcellerne indenfor 5 minutter af basolateral tilsætning. Optaget blev hæmmet af en generel EAAT-hæmmer og udviste Michaelis-Menten kinetik med Vmax på 31 ± 6 pmol • cm-2 • min-1 og KM på 36 ± 25 µM. Resultaterne viser, at BBB kan...

  1. The effect of regadenoson-induced transient disruption of the blood-brain barrier on temozolomide delivery to normal rat brain.

    Science.gov (United States)

    Jackson, Sadhana; Anders, Nicole M; Mangraviti, Antonella; Wanjiku, Teresia M; Sankey, Eric W; Liu, Ann; Brem, Henry; Tyler, Betty; Rudek, Michelle A; Grossman, Stuart A

    2016-02-01

    The blood-brain barrier (BBB) significantly reduces the delivery of many systemically administered agents to the central nervous system. Although temozolomide is the only chemotherapy to improve survival in patients with glioblastoma, its concentration in brain is only 20 % of that in blood. Regadenoson, an FDA approved adenosine receptor agonist used for cardiac stress testing, transiently disrupts rodent BBB allowing high molecular weight dextran (70 kD) to enter the brain. This study was conducted to determine if regadenoson could facilitate entry of temozolomide into normal rodent brain. Temozolomide (50 mg/kg) was administered by oral gavage to non-tumor bearing F344 rats. Two-thirds of the animals received a single dose of intravenous regadenoson 60-90 min later. All animals were sacrificed 120 or 360 min after temozolomide administration. Brain and plasma temozolomide concentrations were determined using HPLC/MS/MS. Brain temozolomide concentrations were significantly higher at 120 min when it was given with regadenoson versus alone (8.1 ± 2.7 and 5.1 ± 3.5 µg/g, P temozolomide administration. No differences were seen in plasma temozolomide concentrations with or without regadenoson. These results suggest co-administration of regadenoson with temozolomide results in 60% higher temozolomide levels in normal brain without affecting plasma concentrations. This novel approach to increasing intracranial concentrations of systemically administered agents has potential to improve the efficacy of chemotherapy in neuro-oncologic disorders.

  2. Determination of blood oxygenation in the brain by time-resolved reflectance spectroscopy: influence of the skin, skull, and meninges

    Science.gov (United States)

    Hielscher, Andreas H.; Liu, Hanli; Wang, Lihong; Tittel, Frank K.; Chance, Britton; Jacques, Steven L.

    1994-07-01

    Near infrared light has been used for the determination of blood oxygenation in the brain but little attention has been paid to the fact that the states of blood oxygenation in arteries, veins, and capillaries differ substantially. In this study, Monte Carlo simulations for a heterogeneous system were conducted, and near infrared time-resolved reflectance measurements were performed on a heterogeneous tissue phantom model. The model was made of a solid polyester resin, which simulates the tissue background. A network of tubes was distributed uniformly through the resin to simulate the blood vessels. The time-resolved reflectance spectra were taken with different absorbing solutions filled in the network. Based on the simulation and experimental results, we investigated the dependence of the absorption coefficient obtained from the heterogeneous system on the absorption of the actual absorbing solution filled in the tubes. We show that light absorption by the brain should result from the combination of blood and blood-free tissue background.

  3. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound.

    Science.gov (United States)

    Nance, Elizabeth; Timbie, Kelsie; Miller, G Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J; Woodworth, Graeme F; Hanes, Justin; Price, Richard J

    2014-09-10

    The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer's, Parkinson's and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a non-invasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPNs in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain.

  4. T Lymphocytes and Inflammatory Mediators in the Interplay between Brain and Blood in Alzheimer's Disease: Potential Pools of New Biomarkers

    Science.gov (United States)

    Mietelska-Porowska, Anna

    2017-01-01

    Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the main cause of dementia. The disease is among the leading medical concerns of the modern world, because only symptomatic therapies are available, and no reliable, easily accessible biomarkers exist for AD detection and monitoring. Therefore extensive research is conducted to elucidate the mechanisms of AD pathogenesis, which seems to be heterogeneous and multifactorial. Recently much attention has been given to the neuroinflammation and activation of glial cells in the AD brain. Reports also highlighted the proinflammatory role of T lymphocytes infiltrating the AD brain. However, in AD molecular and cellular alterations involving T cells and immune mediators occur not only in the brain, but also in the blood and the cerebrospinal fluid (CSF). Here we review alterations concerning T lymphocytes and related immune mediators in the AD brain, CSF, and blood and the mechanisms by which peripheral T cells cross the blood brain barrier and the blood-CSF barrier. This knowledge is relevant for better AD therapies and for identification of novel biomarkers for improved AD diagnostics in the blood and the CSF. The data will be reviewed with the special emphasis on possibilities for development of AD biomarkers.

  5. Altered blood-brain barrier permeability in rats with prehepatic portal hypertension turns to normal when portal pressure is lowered

    Institute of Scientific and Technical Information of China (English)

    Francisco Eizayaga; Camila Scorticati; Juan P Prestifilippo; Salvador Romay; Maria A Fernandez; José L Castro; Abraham Lemberg; Juan C Perazzo

    2006-01-01

    AIM: To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation, at 14 and 40 d after ligation when portal pressure is spontaneously normalized.METHODS: Adult male Wistar rats were divided into four groups: Group Ⅰ: Sham14d, sham operated; Group Ⅱ: PH14d, portal vein stenosis; (both groups were used 14 days after surgery); Group Ⅲ: Sham40d, Sham operated and Group Ⅳ: PH40d Portal vein stenosis (Groups Ⅱ and Ⅳ used 40 d after surgery). Plasma ammonia,plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected, were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded.RESULTS: Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high,and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished.When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished.CONCLUSION: The impairment of blood-brain barrier and subsequent normalization could be a mechanism involved in hepatic encephalopathy reversibility. Hemodynamic changes and ammonia could trigger blood-brain barrier alterations and its reestablishment.

  6. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Akihiko Urayama

    Full Text Available The impermeability of the adult blood-brain barrier (BBB to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

  7. A cord blood monocyte–derived cell therapy product accelerates brain remyelination

    Science.gov (United States)

    Buntz, Susan; Scotland, Paula; Xu, Li; Noeldner, Pamela; Patel, Sachit; Wollish, Amy; Gunaratne, Aruni; Gentry, Tracy; Matsushima, Glenn K.; Kurtzberg, Joanne; Balber, Andrew E.

    2016-01-01

    Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding–mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions. PMID:27699230

  8. Numerical study of a simple transcranial focused ultrasound system applied to blood-brain barrier opening.

    Science.gov (United States)

    Deffieux, Thomas; Konofagou, Elisa E

    2010-12-01

    In this paper, we investigate the focalization properties of single-element transducers at low frequencies (300 to 1000 kHz) through primate and human skulls. The study addresses the transcranial targeting involved in ultrasound- induced blood-brain barrier (BBB) opening with clinically relevant targets such as the hippocampus and the basal ganglia, which are typically affected by early Alzheimer's and Parkinson's disease, respectively. A finite-difference, timedomain simulation platform is used to solve the 3-D linear acoustic wave equation with CT-based acoustic maps of the skulls. The targeted brain structures were extracted from 3-D brain atlases registered with the skulls and used to virtually position and orient the transducers. The effect of frequency is first investigated and the targeting of the different structures is then tested. The frequency of 500 kHz provided the best tradeoff between phase aberrations and standing wave effects in the human case, whereas the frequency of 800 kHz was most suitable in the case of the primate skull. A fast periodic linear chirp method was developed and found capable of reducing the standing wave effects. Such a simple, affordable, and convenient system is concluded to be feasible for BBB opening in primates and humans and could thus allow for its broader impact and applications.

  9. Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound.

    Science.gov (United States)

    Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini; Zhang, Yongzhi; McDannold, Nathan

    2016-02-01

    The purpose of this study was to investigate the effects on the brain of multiple sessions of blood-brain barrier (BBB) disruption using focused ultrasound (FUS) in combination with micro-bubbles over a range of acoustic exposure levels. Six weekly sessions of FUS, using acoustical pressures between 0.66 and 0.80 MPa, were performed under magnetic resonance guidance. The success and degree of BBB disruption was estimated by signal enhancement of post-contrast T1-weighted imaging of the treated area. Histopathological analysis was performed after the last treatment. The consequences of repeated BBB disruption varied from no indications of vascular damage to signs of micro-hemorrhages, macrophage infiltration, micro-scar formations and cystic cavities. The signal enhancement on the contrast-enhanced T1-weighted imaging had limited value for predicting small-vessel damage. T2-weighted imaging corresponded well with the effects on histopathology and could be used to study treatment effects over time. This study demonstrates that repeated BBB disruption by FUS can be performed with no or limited damage to the brain tissue.

  10. Matrix metalloproteinase-9 expression and blood brain barrier permeability in the rat brain after cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Lifang Lei; Xiaohong Zi; Qiuyun Tu

    2008-01-01

    BACKGROUND: The integrity of the blood brain barrier (BBB) plays an important role in the patho-physiological process of cerebral ischemia/reperfusion injury. It has been recently observed that metalloproteinase-9 (MMP-9) is closely related to cerebral ischemia/reperfusion injuryOBJECTIVE: This study was designed to observe MMP-9 expression in the rat brain after cerebral ischemia/reperfusion injury and to investigate its correlation to BBB permeability.DESIGN, TIME AND SETTING: This study, a randomized controlled animal experiment, was performed at the Institute of Neurobiology, Central South University between September 2005 and March 2006.MATERIALS: Ninety healthy male SD rats, aged 3-4 months, weighing 200-280g, were used in the present study. Rabbit anti-rat MMP-9 polyclonal antibody (Boster, Wuhan, China) and Evans blue (Sigma, USA) were also used.METHODS: All rats were randomly divided into 9 groups with 10 rats in each group: normal control group, sham-operated group, and ischemia for 2 hours followed by reperfusion for 3,6,12 hours, 1,2,4 and 7 days groups. In the ischemia/reperfusion groups, rats were subjected to ischemia/reperfusion injury by suture occlusion of the right middle cerebral artery. In the sham-operated group, rats were merely subjected to vessel dissociation. In the normal control group, rats were not modeled.MAIN OUTCOME MEASURES: BBB permeability was assessed by determining the level of effusion of Evans blue. MMP-9 expression was detected by an immunohistochemical method.RESULTS: All 90 rats were included in the final analysis. BBB permeability alteration was closely correlated to ischemia/reperfusion time. BBB permeability began to increase at ischemia/reperfusion for 3 hours, then it gradually reached a peak level at ischemia/reperfusion for 1 day, and thereafter it gradually decreased. MMP-9 expression began to increase at ischemia/reperfusion for 3 hours, then gradually reached its peak level 2 days after perfusion, and thereafter

  11. Administration of sesamol improved blood-brain barrier function in streptozotocin-induced diabetic rats.

    Science.gov (United States)

    VanGilder, R L; Kelly, K A; Chua, M D; Ptachcinski, R L; Huber, Jason D

    2009-07-01

    Uncontrolled or poorly controlled blood glucose during diabetes is an important factor in worsened vascular function. While evidence suggests that hyperglycemia-induced oxidative stress plays a prominent role in development of microangiopathy of the retina, kidney, and nerves, the role oxidative stress plays on blood-brain barrier (BBB) function and structure has lagged behind. In this study, a natural antioxidant, sesamol, was administered to streptozotocin (STZ)-induced diabetic rats to examine the role that oxidative stress plays on BBB structure and function. Experiments were conducted at 56 days after STZ injection. Male Sprague-Dawley rats randomly were divided into four treatment groups CON--control; STZ--STZ-induced diabetes; CON + S--control + sesamol; STZ + S--STZ-induced diabetes + sesamol. Functional and structural changes to the BBB were measured by in situ brain perfusion and western blot analysis of changes in tight junction protein expression. Oxidative stress markers were visualized by fluorescent confocal microscopy and assayed by spectrophotometric analysis. Results demonstrated that the increased BBB permeability observed in STZ-induced diabetic rats was attenuated in STZ + S rats to levels observed in CON. Sesamol treatment reduced the negative impact of STZ-induced diabetes on tight junction protein expression in isolated cerebral microvessels. Oxidative stress markers were elevated in STZ as compared to CON. STZ + S displayed an improved antioxidant capacity which led to a reduced expression of superoxide and peroxynitrite and reduced lipid peroxidation. In conclusion, this study showed that sesamol treatment enhanced antioxidant capacity of the diabetic brain and led to decreased perturbation of hyperglycemia-induced changes in BBB structure and function.

  12. Early CT perfusion changes and blood-brain barrier permeability after aneurysmal subarachnoid hemorrhage

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Amanda; Bharatha, Aditya [University of Toronto, Department of Medical Imaging, Toronto, ON (Canada); De Oliveira Manoel, Airton Leonardo; Kouzmina, Ekaterina [St. Michael' s Hospital, Toronto (Canada); Burgers, Kyle; Lee, Ting [Robarts Research Institute, London (Canada); Macdonald, R.L. [St. Michael' s Hospital, Department of Neurosurgery, Toronto (Canada)

    2015-08-15

    Early brain injury (EBI) can occur within 72 h of aneurysmal subarachnoid hemorrhage (aSAH). The objective of this study was to determine if there are differences in early CTP parameters (<72 h) with respect to delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. We performed a prospective cohort study of aSAH patients admitted to a single tertiary care center. MTT, CBF and blood-brain barrier permeability (PS) were quantified with CTP within 72 h of aneurysm rupture. Primary outcomes were functional outcome by the Modified Rankin Scale (mRS) at 3 months and cerebral infarction. Secondary outcome was the development of DCI. Differences between early CTP parameters were determined with respect to primary and secondary outcomes. Fifty aSAH patients were included in the final analysis. MTT was significantly higher in patients who developed DCI (6.7 ± 1.2 vs 5.9 ± 1.0; p = 0.03) and cerebral infarction (7.0 ± 1.2 vs 5.9 ± 0.9; p = 0.007); however, no difference in MTT was found between patients with and without a poor outcome (mRS > 2). Early CBF and PS did not differ with respect to functional outcome, DCI, and cerebral infarction. Elevated MTT within 72 h of aneurysm rupture is associated with DCI and cerebral infarction but not with long-term functional outcome. Blood-brain barrier permeability, as assessed by CT perfusion, was not associated with DCI or worse outcome in this cohort. (orig.)

  13. Enhanced blood-brain barrier transmigration using a novel transferrin embedded fluorescent magneto-liposome nanoformulation

    Science.gov (United States)

    Ding, Hong; Sagar, Vidya; Agudelo, Marisela; Pilakka-Kanthikeel, Sudheesh; Subba Rao Atluri, Venkata; Raymond, Andrea; Samikkannu, Thangavel; Nair, Madhavan P.

    2014-02-01

    The blood-brain barrier (BBB) is considered as the primary impediment barrier for most drugs. Delivering therapeutic agents to the brain is still a big challenge to date. In our study, a dual mechanism, receptor mediation combined with external non-invasive magnetic force, was incorporated into ferrous magnet-based liposomes for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs), with a size of ˜10 nm, were synthesized and confirmed by TEM and XRD respectively. The classical magnetism assay showed the presence of the characteristic superparamagnetic property. These MNPs encapsulated in PEGylated fluorescent liposomes as magneto-liposomes (MLs) showed mono-dispersion, ˜130 ± 10 nm diameter, by dynamic laser scattering (DLS) using the lipid-extrusion technique. Remarkably, a magnetite encapsulation efficiency of nearly 60% was achieved. Moreover, the luminescence and hydrodynamic size of the MLs was stable for over two months at 4 ° C. Additionally, the integrity of the ML structure remained unaffected through 120 rounds of circulation mimicking human blood fluid. After biocompatibility confirmation by cytotoxicity evaluation, these fluorescent MLs were further embedded with transferrin and applied to an in vitro BBB transmigration study in the presence or absence of external magnetic force. Comparing with magnetic force- or transferrin receptor-mediated transportation alone, their synergy resulted in 50-100% increased transmigration without affecting the BBB integrity. Consequently, confocal microscopy and iron concentration in BBB-composed cells further confirmed the higher cellular uptake of ML particles due to the synergic effect. Thus, our multifunctional liposomal magnetic nanocarriers possess great potential in particle transmigration across the BBB and may have a bright future in drug delivery to the brain.

  14. Preparation of Silica Nanoparticles Loaded with Nootropics and Their In Vivo Permeation through Blood-Brain Barrier

    Directory of Open Access Journals (Sweden)

    Josef Jampilek

    2015-01-01

    Full Text Available The blood-brain barrier prevents the passage of many drugs that target the central nervous system. This paper presents the preparation and characterization of silica-based nanocarriers loaded with piracetam, pentoxifylline, and pyridoxine (drugs from the class of nootropics, which are designed to enhance the permeation of the drugs from the circulatory system through the blood-brain barrier. Their permeation was compared with non-nanoparticle drug substances (bulk materials by means of an in vivo model of rat brain perfusion. The size and morphology of the nanoparticles were characterized by transmission electron microscopy. The content of the drug substances in silica-based nanocarriers was analysed by elemental analysis and UV spectrometry. Microscopic analysis of visualized silica nanocarriers in the perfused brain tissue was performed. The concentration of the drug substances in the tissue was determined by means of UHPLC-DAD/HRMS LTQ Orbitrap XL. It was found that the drug substances in silica-based nanocarriers permeated through the blood brain barrier to the brain tissue, whereas bulk materials were not detected in the brain.

  15. Estimation of rat muscle blood flow by microdialysis probes perfused with ethanol, [14C]ethanol, and 3H2O

    DEFF Research Database (Denmark)

    Stallknecht, B; Donsmark, M; Enevoldsen, L H;

    1999-01-01

    We used the perfused rat hindquarter to evaluate whether the microdialysis ethanol technique can be used to qualitatively estimate nutritive skeletal muscle blood flow. Four microdialysis probes were inserted in different hindlimb muscles in each of 16 rats. Hindquarters were perfused at blood flow...... rates ranging from 0 to 21 ml. 100 g-1. min-1. The microdialysis probes were perfused at 2 microliter/min with perfusate containing ethanol, [14C]ethanol, and 3H2O. Within and between experiments outflow-to-inflow ratios (o/i) generally varied inversely with blood flow. When a low flow or no flow...... was maintained in hindquarters, o/i ratios first increased with time (for at least 60 min) and then leveled off. The long time constant impaired detection of rapid oscillations in blood flow, especially at low blood flow rates. Contractions per se apparently decreased o/i ratios independent of blood flow...

  16. Consequences of repeated blood-brain barrier disruption in football players.

    Directory of Open Access Journals (Sweden)

    Nicola Marchi

    Full Text Available The acknowledgement of risks for traumatic brain injury in American football players has prompted studies for sideline concussion diagnosis and testing for neurological deficits. While concussions are recognized etiological factors for a spectrum of neurological sequelae, the consequences of sub-concussive events are unclear. We tested the hypothesis that blood-brain barrier disruption (BBBD and the accompanying surge of the astrocytic protein S100B in blood may cause an immune response associated with production of auto-antibodies. We also wished to determine whether these events result in disrupted white matter on diffusion tensor imaging (DT scans. Players from three college football teams were enrolled (total of 67 volunteers. None of the players experienced a concussion. Blood samples were collected before and after games (n = 57; the number of head hits in all players was monitored by movie review and post-game interviews. S100B serum levels and auto-antibodies against S100B were measured and correlated by direct and reverse immunoassays (n = 15 players; 5 games. A subset of players underwent DTI scans pre- and post-season and after a 6-month interval (n = 10. Cognitive and functional assessments were also performed. After a game, transient BBB damage measured by serum S100B was detected only in players experiencing the greatest number of sub-concussive head hits. Elevated levels of auto-antibodies against S100B were elevated only after repeated sub-concussive events characterized by BBBD. Serum levels of S100B auto-antibodies also predicted persistence of MRI-DTI abnormalities which in turn correlated with cognitive changes. Even in the absence of concussion, football players may experience repeated BBBD and serum surges of the potential auto-antigen S100B. The correlation of serum S100B, auto-antibodies and DTI changes support a link between repeated BBBD and future risk for cognitive changes.

  17. L-tyrosine induces DNA damage in brain and blood of rats.

    Science.gov (United States)

    De Prá, Samira D T; Ferreira, Gabriela K; Carvalho-Silva, Milena; Vieira, Júlia S; Scaini, Giselli; Leffa, Daniela D; Fagundes, Gabriela E; Bristot, Bruno N; Borges, Gabriela D; Ferreira, Gustavo C; Schuck, Patrícia F; Andrade, Vanessa M; Streck, Emilio L

    2014-01-01

    Mutations in the tyrosine aminotransferase gene have been identified to cause tyrosinemia type II which is inherited in an autosomal recessive manner. Studies have demonstrated that an excessive production of ROS can lead to reactions with macromolecules, such as DNA, lipids, and proteins. Considering that the L-tyrosine may promote oxidative stress, the main objective of this study was to investigate the in vivo effects of L-tyrosine on DNA damage determined by the alkaline comet assay, in brain and blood of rats. In our acute protocol, Wistar rats (30 days old) were killed 1 h after a single intraperitoneal L-tyrosine injection (500 mg/kg) or saline. For chronic administration, the animals received two subcutaneous injections of L-tyrosine (500 mg/kg, 12-h intervals) or saline administered for 24 days starting at postnatal day (PD) 7 (last injection at PD 31), 12 h after the last injection, the animals were killed by decapitation. We observed that acute administration of L-tyrosine increased DNA damage frequency and damage index in cerebral cortex and blood when compared to control group. Moreover, we observed that chronic administration of L-tyrosine increased DNA damage frequency and damage index in hippocampus, striatum, cerebral cortex and blood when compared to control group. In conclusion, the present work demonstrated that DNA damage can be encountered in brain from animal models of hypertyrosinemia, DNA alterations may represent a further means to explain neurological dysfunction in this inherited metabolic disorder and to reinforce the role of oxidative stress in the pathophysiology of tyrosinemia type II.

  18. MSFD2A is critical for the formation and function of the blood brain barrier

    Science.gov (United States)

    Ben-Zvi, Ayal; Lacoste, Baptiste; Kur, Esther; Andreone, Benjamin J.; Mayshar, Yoav; Yan, Han; Gu, Chenghua

    2014-01-01

    The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the ‘blood brain barrier’ (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis)1–3. In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux4–6. While BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS7–10. A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here, we identify mechanisms governing the establishment of a functional BBB. First, using a novel embryonic tracer injection method, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic periods through adulthood, while maintaining the normal patterning of vascular networks. Electron microscopy examination reveals a dramatic increase in CNS endothelial cell vesicular transcytosis in Mfsd2a−/− mice, without obvious tight junction defects. Finally we show that MFSD2A endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify MFSD2A as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Further our findings may aid

  19. Mfsd2a is critical for the formation and function of the blood-brain barrier.

    Science.gov (United States)

    Ben-Zvi, Ayal; Lacoste, Baptiste; Kur, Esther; Andreone, Benjamin J; Mayshar, Yoav; Yan, Han; Gu, Chenghua

    2014-05-22

    The central nervous system (CNS) requires a tightly controlled environment free of toxins and pathogens to provide the proper chemical composition for neural function. This environment is maintained by the 'blood-brain barrier' (BBB), which is composed of blood vessels whose endothelial cells display specialized tight junctions and extremely low rates of transcellular vesicular transport (transcytosis). In concert with pericytes and astrocytes, this unique brain endothelial physiological barrier seals the CNS and controls substance influx and efflux. Although BBB breakdown has recently been associated with initiation and perpetuation of various neurological disorders, an intact BBB is a major obstacle for drug delivery to the CNS. A limited understanding of the molecular mechanisms that control BBB formation has hindered our ability to manipulate the BBB in disease and therapy. Here we identify mechanisms governing the establishment of a functional BBB. First, using a novel tracer-injection method for embryos, we demonstrate spatiotemporal developmental profiles of BBB functionality and find that the mouse BBB becomes functional at embryonic day 15.5 (E15.5). We then screen for BBB-specific genes expressed during BBB formation, and find that major facilitator super family domain containing 2a (Mfsd2a) is selectively expressed in BBB-containing blood vessels in the CNS. Genetic ablation of Mfsd2a results in a leaky BBB from embryonic stages through to adulthood, but the normal patterning of vascular networks is maintained. Electron microscopy examination reveals a dramatic increase in CNS-endothelial-cell vesicular transcytosis in Mfsd2a(-/-) mice, without obvious tight-junction defects. Finally we show that Mfsd2a endothelial expression is regulated by pericytes to facilitate BBB integrity. These findings identify Mfsd2a as a key regulator of BBB function that may act by suppressing transcytosis in CNS endothelial cells. Furthermore, our findings may aid in efforts

  20. Myeloperoxidase-derived oxidants induce blood-brain barrier dysfunction in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Andreas Üllen

    Full Text Available Peripheral leukocytes can exacerbate brain damage by release of cytotoxic mediators that disrupt blood-brain barrier (BBB function. One of the oxidants released by activated leukocytes is hypochlorous acid (HOCl formed via the myeloperoxidase (MPO-H2O2-Cl(- system. In the present study we examined the role of leukocyte activation, leukocyte-derived MPO and MPO-generated oxidants on BBB function in vitro and in vivo. In a mouse model of lipopolysaccharide (LPS-induced systemic inflammation, neutrophils that had become adherent released MPO into the cerebrovasculature. In vivo, LPS-induced BBB dysfunction was significantly lower in MPO-deficient mice as compared to wild-type littermates. Both, fMLP-activated leukocytes and the MPO-H2O2-Cl(- system inflicted barrier dysfunction of primary brain microvascular endothelial cells (BMVEC that was partially rescued with the MPO inhibitor 4-aminobenzoic acid hydrazide. BMVEC treatment with the MPO-H2O2-Cl(- system or activated neutrophils resulted in the formation of plasmalogen-derived chlorinated fatty aldehydes. 2-chlorohexadecanal (2-ClHDA severely compromised BMVEC barrier function and induced morphological alterations in tight and adherens junctions. In situ perfusion of rat brain with 2-ClHDA increased BBB permeability in vivo. 2-ClHDA potently activated the MAPK cascade at physiological concentrations. An ERK1/2 and JNK antagonist (PD098059 and SP600125, respectively protected against 2-ClHDA-induced barrier dysfunction in vitro. The current data provide evidence that interference with the MPO pathway could protect against BBB dysfunction under (neuroinflammatory conditions.

  1. Blood, pituitary, and brain renin-angiotensin systems and regulation of secretion of anterior pituitary gland.

    Science.gov (United States)

    Ganong, W F

    1993-07-01

    In addition to increasing blood pressure, stimulating aldosterone and vasopressin secretion, and increasing water intake, angiotensin II affects the secretion of anterior pituitary hormones. Some of these effects are direct. There are angiotensin II receptors on lactotropes and corticotropes in rats, and there may be receptors on thyrotropes and other secretory cells. Circulating angiotensin II reaches these receptors, but angiotensin II is almost certainly generated locally by the pituitary renin-angiotensin system as well. There are also indirect effects produced by the effects of brain angiotensin II on the secretion of hypophyseotropic hormones. In the anterior pituitary of the rat, the gonadotropes contain renin, angiotensin II, and some angiotensin-converting enzyme. There is debate about whether these cells also contain small amounts of angiotensinogen, but most of the angiotensinogen is produced by a separate population of cells and appears to pass in a paracrine fashion to the gonadotropes. An analogous situation exists in the brain. Neurons contain angiotensin II and probably renin, but most angiotensin-converting enzyme is located elsewhere and angiotensinogen is primarily if not solely produced by astrocytes. Angiotensin II causes secretion of prolactin and adrenocorticotropic hormone (ACTH) when added to pituitary cells in vitro. Paracrine regulation of prolactin secretion by angiotensin II from the gonadotropes may occur in vitro under certain circumstances, but the effects of peripheral angiotensin II on ACTH secretion appear to be mediated via the brain and corticotropin-releasing hormone (CRH). In the brain, there is good evidence that locally generated angiotensin II causes release of norepinephrine that in turn stimulates gonadotropin-releasing hormone-secreting neurons, increasing circulating luteinizing hormone. In addition, there is evidence that angiotensin II acts in the arcuate nuclei to increase the secretion of dopamine into the portal

  2. Disruption of the blood brain barrier following ALA mediated photodynamic therapy