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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. Regional blood flow in the normal and ischemic brain is controlled by arteriolar smooth muscle cell contractility and not by capillary pericytes

    OpenAIRE

    Hill, Robert A.; Tong, Lei; Yuan, Peng; Murikinati, Sasidhar; Gupta, Shobhana; Grutzendler, Jaime

    2015-01-01

    The precise regulation of cerebral blood flow is critical for normal brain function and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). Using optic...

  5. MUSCLE METABOLISM WITH BLOOD FLOW RESTRICTION IN CHRONIC FATIGUE SYNDROME

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    McCully, Kevin K; Smith, Sinclair; Rajaei, Sheeva; Leigh, John S.; Natelson, Benjamin H

    2003-01-01

    The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced blood flow and muscle oxidative metabolism. Patients with CFS according to CDC criteria (n=19) were compared to normal sedentary subjects (n = 11). Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle using 31P magnetic resonance spectroscopy (MRS). Muscle oxygen saturation and blood vo...

  6. The blood-brain barrier.

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    Obermeier, Birgit; Verma, Ajay; Ransohoff, Richard M

    2016-01-01

    In autoimmune neurologic disorders, the blood-brain barrier (BBB) plays a central role in immunopathogenesis, since this vascular interface is an entry path for cells and effector molecules of the peripheral immune system to reach the target organ, the central nervous system (CNS). The BBB's unique anatomic structure and the tightly regulated interplay of its cellular and acellular components allow for maintenance of brain homeostasis, regulation of influx and efflux, and protection from harm; these ensure an optimal environment for the neuronal network to function properly. In both health and disease, the BBB acts as mediator between the periphery and the CNS. For example, immune cell trafficking through the cerebral vasculature is essential to clear microbes or cell debris from neural tissues, while poorly regulated cellular transmigration can underlie or worsen CNS pathology. In this chapter, we focus on the specialized multicellular structure and function of the BBB/neurovascular unit and discuss how BBB breakdown can precede or be a consequence of neuroinflammation. We introduce the blood-cerebrospinal fluid barrier and include a brief aside about evolutionary aspects of barrier formation and refinements. Lastly, since restoration of barrier function is considered key to ameliorate neurologic disease, we speculate about new therapeutic avenues to repair a damaged BBB. PMID:27112670

  7. 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...

  8. 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

  9. 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.

  10. Vasodilator interactions in skeletal muscle blood flow regulation

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

    2012-01-01

    During exercise, oxygen delivery to skeletal muscle is elevated to meet the increased oxygen demand. The increase in blood flow to skeletal muscle is achieved by vasodilators formed locally in the muscle tissue, either on the intraluminal or the extraluminal side of the blood vessels. A number...... vasodilators are both stimulated by several compounds, eg. adenosine, ATP, acetylcholine, bradykinin, and are affected by mechanically induced signals, such as shear stress. NO and prostacyclin have also been shown to interact in a redundant manner where one system can take over when formation of the other...... 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...

  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. 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...... 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....... There is no single marker suitable for all purposes. A combination of different sized, visualizable dextrans and radiolabeled molecules currently seems to be the most appropriate approach for qualitative and quantitative assessment of barrier integrity....

  13. Recent advances in the brain-to-blood efflux transport across the blood-brain barrier.

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    Hosoya, Ken-ichi; Ohtsuki, Sumio; Terasaki, Tetsuya

    2002-11-01

    Elucidating the details of the blood-brain barrier (BBB) transport mechanism is a very important step towards successful drug targeting to the brain and understanding what happens in the brain. Although several brain uptake methods have been developed to characterize transport at the BBB, these are mainly useful for investigating influx transport across the BBB. In 1992, P-glycoprotein was found to act as an efflux pump for anti-cancer drugs at the BBB using primary cultured bovine brain endothelial cells. In order to determine the direct efflux transport from the brain to the circulating blood of exogenous compounds in vivo, the Brain Efflux Index method was developed to characterize several BBB efflux transport systems. Recently, we have established conditionally immortalized rat (TR-BBB) and mouse (TM-BBB) brain capillary endothelial cell lines from transgenic rats and mice harboring temperature-sensitive simian virus 40 large T-antigen gene to characterize the transport mechanisms at the BBB in vitro. TR-BBB and TM-BBB cells possess certain in vivo transport functions and express mRNAs for the BBB. Using a combination of newly developed in vivo and in vitro methods, we have elucidated the efflux transport mechanism at the BBB for neurosteroids, excitatory neurotransmitters, suppressive neurotransmitters, amino acids, and other organic anions to understand the physiological role played by the BBB as a detoxifying organ for the brain. PMID:12429456

  14. 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...... sympathetic vasoconstriction. ATP is released into plasma from erythrocytes and endothelial cells and the plasma concentration increases in both the feeding artery and the vein draining the contracting skeletal muscle. Adenosine also stimulates the formation of NO and prostaglandins, but the plasma adenosine...... 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...

  15. Blood-Brain Barrier Genomics, Proteomics, and New Transporter Discovery

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    Shusta, Eric V.

    2005-01-01

    Summary: The blood-brain barrier (BBB) is an impermeable cellular interface that physically separates the blood from the interstices of the brain. The endothelial cells lining the brain blood vessels form the principle barrier, and their unique phenotype is a consequence of dynamic interactions with several perivascular cell types present in the brain parenchyma. In addition, BBB dysfunction has been observed in the large majority of neurological diseases, but the causes of aberrant vascular ...

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

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    Nyberg, Michael Permin; Hellsten, Ylva

    2016-01-01

    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...... during exercise where systemic blood flow is not limited by cardiac output, thereby improving O2 delivery and allowing for an enhanced energy production from oxidative metabolism. The mechanisms underlying the increase in blood flow with regular physical activity include improved endothelial function...... 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....

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

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    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 ... forbrain (pyruvate and 3-hydroxybutyrate). Thus, long-term HF diet was associated with obesity, dyslipidemia, insulin resistance, andsignificantly altered mitochondrial function in skeletal muscle. Yet, brain mitochondria were unaffected. We suggest that therelative isolation of the brain due to the blood...

  18. Acute effects of electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate in the cat: an evaluation of safety.

    OpenAIRE

    Eyre, J A; Flecknell, P. A.; Kenyon, B R; Koh, T H; Miller, S.

    1990-01-01

    The influence of repeated high intensity electromagnetic stimulation of the brain on cortical activity, cortical blood flow, blood pressure and heart rate has been investigated in the cat, to evaluate the safety of the method. The observations have been made in preparations under propofol anaesthesia before, during and after periods of anoxia. Electromagnetic stimulation of the brain evoked activity in descending motor pathways and was recorded by activity in the median nerve and by muscle tw...

  19. 65zinc uptake from blood into brain and other tissues in the rat

    International Nuclear Information System (INIS)

    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

  20. Legs and Trunk Muscle Hypertrophy Following Walk Training with Restricted Leg Muscle Blood Flow

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    Mikako Sakamaki; Bemben, Michael G.; Takashi Abe

    2011-01-01

    We examined the effect of walk training combined with blood flow restriction (BFR) on the size of blood flow-restricted distal muscles, as well as, on the size of non-restricted muscles in the proximal limb and trunk. Nine men performed walk training with BFR and 8 men performed walk training alone. Training was conducted two times a day, 6 days/wk, for 3 wk using five sets of 2-min bouts (treadmill speed at 50 m/min), with a 1-min rest between bouts. After walk training with BFR, MRI-measure...

  1. 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...

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

    International Nuclear Information System (INIS)

    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−/− 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

  4. 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.

  5. 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...... recognized that neurotransmitter-mediated signalling has a key role in regulating cerebral blood flow, that much of this control is mediated by astrocytes, that oxygen modulates blood flow regulation, and that blood flow may be controlled by capillaries as well as by arterioles. These conceptual shifts...... in our understanding of cerebral blood flow control have important implications for the development of new therapeutic approaches....

  6. 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...

  7. 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

  8. The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

    Science.gov (United States)

    Hammerstad, J P; Pate, B D; Hewitt, K A; Chan, G L; Ruth, T J; Calne, D B

    1993-10-01

    The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain. PMID:8215248

  9. The Blood-Brain Barrier: An Engineering Perspective

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    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.

  10. KINESTHETIC IMAGERY TRAINING OF FORCEFUL MUSCLE CONTRACTIONS INCREASES BRAIN SIGNAL AND MUSCLE STRENGTH

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    Wan X Yao

    2013-09-01

    Full Text Available The purpose of this study was to compare the effect of training using internal imagery (IMI; also known as kinesthetic imagery or first person imagery with that of external imagery (EMI; also known as third-person visual imagery of strong muscle contractions on voluntary muscle strengthening. Eighteen young, healthy subjects were randomly assigned to one of three groups (6 in each group: internal motor imagery (IMI, external motor imagery (EMI, or a no-practice control (CTRL group. Training lasted for 6 weeks (~15 min/day, 5 days/week. The participants’ right arm elbow-flexion strength, muscle electrical activity and movement-related cortical potential (MRCP were evaluated before and after training. Only the IMI group showed significant strength gained (10.8% while the EMI (4.8% and CTRL (-3.3% groups did not. Only the IMI group showed a significant elevation in MRCP on scalp locations over both the primary motor (M1 and supplementary motor cortices (EMI group over M1 only and this increase was significantly greater than that of EMI and CTRL groups. These results suggest that training by IMI of forceful muscle contractions was effective in improving voluntary muscle strength without physical exercise. We suggest that the IMI training likely strengthened brain-to-muscle (BTM command that may have improved motor unit recruitment and activation, and led to greater muscle output. Training by internal motor imagery of forceful muscle contractions may change the activity level of cortical motor control network, which may translate into greater descending command to the target muscle and increase its strength.

  11. 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.

  12. 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 metabolism...... is well known, however endothelial cells may also play an important role through mediating brain-to-blood L-glutamate efflux. Expression of excitatory amino acid transporters has been demonstrated in brain endothelial cells of bovine, human, murine, rat and porcine origin. These can account for high......-glutamate, metabolism of L-glutamate and transport of metabolites or a combination of the two. However, both in vitro and in vivo studies have demonstrated blood-to-brain transport of L-glutamate, at least during pathological events. This review summarizes the current knowledge on the brain-to-blood L-glutamate efflux...

  13. Solubility of inert gases in dog blood and skeletal muscle.

    Science.gov (United States)

    Meyer, M; Tebbe, U; Piiper, J

    1980-03-01

    Solubility of H2, Ar, CH4 and SF6 was determined at 310 K (37 degrees C) in water, in saline (0.154 mol NaCl/l H2O), in plasma and whole blood of dogs, and in homogenates of the dog gastrocnemius muscle. The liquids were equilibrated with pure gases, and the dissolved gases were extracted and measured by gas chromatography as described previously (Meyer, M.: Pflügers Arch. 375, 161--165, 1978). In saline, the solubilities were 4% (SF6) to 15% (Ar) lower than in water. For dog blood the following mean values for the solubility coefficient (in mumol . 1(-1) . kPa-1) were found: for H2, 6.44; for Ar, 9.94; for CH4, 11.44; for SF6, 2.62. The red cell/plasma and the muscle/blood solubility ratios were near unity for H2, Ar and CH4 (ranging from 0.9 to 1.3); for SF6, however, they were much higher (about 2.1), apparently due to the high solubility of SF6 in hydrophobic substances (lipids). PMID:6247698

  14. 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.

  15. 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.

  16. Hemodynamic measurements in rat brain and human muscle using diffuse near-infrared absorption and correlation spectroscopies

    Science.gov (United States)

    Yu, Guoqiang; Durduran, Turgut; Furuya, D.; Lech, G.; Zhou, Chao; Chance, Britten; Greenberg, J. H.; Yodh, Arjun G.

    2003-07-01

    Measurement of concentration, oxygenation, and flow characteristics of blood cells can reveal information about tissue metabolism and functional heterogeneity. An improved multifunctional hybrid system has been built on the basis of our previous hybrid instrument that combines two near-infrared diffuse optical techniques to simultaneously monitor the changes of blood flow, total hemoglobin concentration (THC) and blood oxygen saturation (StO2). Diffuse correlation spectroscopy (DCS) monitors blood flow (BF) by measuring the optical phase shifts caused by moving blood cells, while diffuse photon density wave spectroscopy (DPDW) measures tissue absorption and scattering. Higher spatial resolution, higher data acquisition rate and higher dynamic range of the improved system allow us to monitor rapid hemodynamic changes in rat brain and human muscles. We have designed two probes with different source-detector pairs and different separations for the two types of experiments. A unique non-contact probe mounted on the back of a camera, which allows continuous measurements without altering the blood flow, was employed to in vivo monitor the metabolic responses in rat brain during KCl induced cortical spreading depression (CSD). A contact probe was used to measure changes of blood flow and oxygenation in human muscle during and after cuff occlusion or exercise, where the non-contact probe is not appropriate for monitoring the moving target. The experimental results indicate that our multifunctional hybrid system is capable of in vivo and non-invasive monitoring of the hemodynamic changes in different tissues (smaller tissues in rat brain, larger tissues in human muscle) under different conditions (static versus moving). The time series images of flow during CSD obtained by our technique revealed spatial and temporal hemodynamic changes in rat brain. Two to three fold longer recovery times of flow and oxygenation after cuff occlusion or exercise from calf flexors in a

  17. Brain magnetic resonance imaging with contrast dependent on blood oxygenation

    Energy Technology Data Exchange (ETDEWEB)

    Ogawa, S.; Lee, T.M.; Kay, A.R.; Tank, D.W. (AT and T Bell Laboratories, Murray Hill, NJ (United States))

    1990-12-01

    Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high yields, the authors demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complement other techniques that are attempting to provide position emission tomography-like measurements related to regional neural activity.

  18. Brain magnetic resonance imaging with contrast dependent on blood oxygenation

    International Nuclear Information System (INIS)

    Paramagnetic deoxyhemoglobin in venous blood is a naturally occurring contrast agent for magnetic resonance imaging (MRI). By accentuating the effects of this agent through the use of gradient-echo techniques in high yields, the authors demonstrate in vivo images of brain microvasculature with image contrast reflecting the blood oxygen level. This blood oxygenation level-dependent (BOLD) contrast follows blood oxygen changes induced by anesthetics, by insulin-induced hypoglycemia, and by inhaled gas mixtures that alter metabolic demand or blood flow. The results suggest that BOLD contrast can be used to provide in vivo real-time maps of blood oxygenation in the brain under normal physiological conditions. BOLD contrast adds an additional feature to magnetic resonance imaging and complement other techniques that are attempting to provide position emission tomography-like measurements related to regional neural activity

  19. Blood-brain transfer of Pittsburgh compound B in humans

    DEFF Research Database (Denmark)

    Gjedde, Albert; Aanerud, Joel; Braendgaard, Hans;

    2013-01-01

    In the labeled form, the Pittsburgh compound B (2-(4'-{N-methyl-[(11)C]}methyl-aminophenyl)-6-hydroxy-benzothiazole, [(11)C]PiB), is used as a biomarker for positron emission tomography (PET) of brain β-amyloid deposition in Alzheimer's disease (AD). The permeability of [(11)C]PiB in the blood......-brain barrier is held to be high but the permeability-surface area product and extraction fractions in patients or healthy volunteers are not known. We used PET to determine the clearance associated with the unidrectional blood-brain transfer of [(11)C]PiB and the corresponding cerebral blood flow rates in......-brain clearances of [(11)C]PiB in the patients....

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Paulo Roberto Correia

    2010-01-01

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

  2. 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.

  3. 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.

  4. 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.

  5. Postmortem Quetiapine Reference Concentrations in Brain and Blood

    DEFF Research Database (Denmark)

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

    2015-01-01

    Brain tissue is a useful alternative to blood in postmortem forensic investigations, but scarcity of information on reference concentrations in brain tissue makes interpretation challenging. Here we present a study of 43 cases where the antipsychotic drug quetiapine was quantified in brain tissue...... 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...

  6. Relationship between muscle oxygenation by NIRS and blood lactate

    International Nuclear Information System (INIS)

    The aim of the study was to investigate the relationship of muscle oxygenation in term of oxy-hemoglobin concentration change (ΔHbO2) 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 ΔHbO2 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, ΔHbO2 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 ΔHbO2 and the concurrency of crucial turning points between ΔHbO2 and BLA was revealed. This relationship between ΔHbO2 and BLA presented in the increasing load training suggested that ΔHbO2 might be capable for taking the place of the invasively measured parameter BLA. Considering that ΔHbO2 can be noninvasively measured by NIRS, ΔHbO2 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.

  7. 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.

  8. 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......, interstitial ATP has solely been described to induce vasoconstriction in skeletal muscle. To examine whether interstitial ATP induces vasodilation in skeletal muscle and to what extent this vasoactive effect is mediated by formation of nitric oxide (NO) and prostanoids, three different experimental models were...... studied. The rat gluteus maximus skeletal muscle model was used to study changes in local skeletal muscle hemodynamics. Superfused ATP at concentrations found during muscle contractions (1-10 µM) increased blood flow by up to 400%. In this model, the underlying mechanism was also examined by inhibition...

  9. 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.

  10. 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…

  11. 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...

  12. Structure and blood supply of motion neuro-muscles endings of skeletal muscles of rats of a different age

    Directory of Open Access Journals (Sweden)

    Popel S.L.

    2012-01-01

    Full Text Available Purpose of work consists in the study of structure ofthe neuro-muscles endings and their blood supply in ontogenesis. It is shown that at the level of the neuro-muscles endings there is the expressed blood-nerve barrier which is deter-mined by the structural features of wall of blood microvessels. In the early period of ontogenesis of structure of blood-nerve barrier immature, and his functional insufficiency is compensated by made distance of sources of blood supply, that provides the sufficient morphological isolation of axons from albumens and cellular components of blood. With age structure of blood-nerve barrier destruction as a result of strengthening and generalization reverse development processes which pass by apoptos. Intracellulary alteration of neurolemocytes during ontogenesis testifies to their active trophic function, and concentration of synaps blisters in the cytoplasm of separate terminals neurolemocytes requires сomprehension of their role in functioning of blood supply barrier at the level of neuro-muscles endings.

  13. 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.

  14. 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

    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...... 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...

  15. Spatiotemporal changes in blood-brain barrier permeability, cerebral blood flow, T2 and diffusion following mild traumatic brain injury.

    Science.gov (United States)

    Li, Wei; Watts, Lora; Long, Justin; Zhou, Wei; Shen, Qiang; Jiang, Zhao; Li, Yunxia; Duong, Timothy Q

    2016-09-01

    The blood-brain barrier (BBB) can be impaired following traumatic brain injury (TBI), however the spatiotemporal dynamics of BBB leakage remain incompletely understood. In this study, we evaluated the spatiotemporal evolution of BBB permeability using dynamic contrast-enhanced MRI and measured the volume transfer coefficient (K(trans)), a quantitative measure of contrast agent leakage across the blood and extravascular compartment. Measurements were made in a controlled cortical impact (CCI) model of mild TBI in rats from 1h to 7 days following TBI. The results were compared with cerebral blood flow, T2 and diffusion MRI from the same animal. Spatially, K(trans) changes were localized to superficial cortical layers within a 1mm thickness, which was dramatically different from the changes in cerebral blood flow, T2 and diffusion, which were localized to not only the superficial layers but also to brain regions up to 2.2mm from the cortical surface. Temporally, K(trans) changes peaked at day 3, similar to CBF and ADC changes, but differed from T2 and FA, whose changes peaked on day 2. The pattern of superficial cortical layer localization of K(trans) was consistent with patterns revealed by Evans Blue extravasation. Collectively, these results suggest that BBB disruption, edema formation, blood flow disturbance and diffusion changes are related to different components of the mechanical impact, and may play different roles in determining injury progression and tissue fate processes following TBI. PMID:27208495

  16. Blood-brain barrier and blood-cerebrospinal fluid barrier in normal and pathological conditions.

    Science.gov (United States)

    Ueno, Masaki; Chiba, Yoichi; Murakami, Ryuta; Matsumoto, Koichi; Kawauchi, Machi; Fujihara, Ryuji

    2016-04-01

    Blood-borne substances can invade into the extracellular spaces of the brain via endothelial cells in sites without the blood-brain barrier (BBB), and can travel through the interstitial fluid (ISF) of the brain parenchyma adjacent to non-BBB sites. It has been shown that cerebrospinal fluid (CSF) drains directly into the blood via the arachnoid villi and also into lymph nodes via the subarachnoid spaces of the brain, while ISF drains into the cervical lymph nodes through perivascular drainage pathways. In addition, the glymphatic pathway of fluids, characterized by para-arterial pathways, aquaporin4-dependent passage through astroglial cytoplasm, interstitial spaces, and paravenous routes, has been established. Meningeal lymphatic vessels along the superior sagittal sinus were very recently discovered. It is known that, in mice, blood-borne substances can be transferred to areas with intact BBB function, such as the medial regions of the hippocampus, presumably through leaky vessels in non-BBB sites. In the present paper, we review the clearance mechanisms of interstitial substances, such as amyloid-β peptides, as well as summarize models of BBB deterioration in response to different types of insults, including acute ischemia followed by reperfusion, hypertension, and chronic hypoperfusion. Lastly, we discuss the relationship between perivascular clearance and brain disorders. PMID:26920424

  17. 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...

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

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Langberg, H; Green, Sara Marie Ehrenreich;

    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...... with a rise in leg vascular conductance and microvascular haemoglobin volume, despite elevated systemic vascular resistance. 4. The parallel rise in calf muscle and peritendinous blood flow and fall in O2 saturation during exercise indicate that blood flow is coupled to oxidative metabolism in both tissue...... 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...

  19. Increased blood pressure can reduce fatigue of thenar muscles paralyzed after spinal cord injury

    NARCIS (Netherlands)

    Butler, JE; Ribot-Ciscar, E; Zijdewind, Inge; Thomas, CK

    2004-01-01

    The aim of this study was to evaluate whether increases in blood pressure, and presumably muscle perfusion pressure, improve the endurance of thenar muscles paralyzed chronically by cervical spinal cord injury (SCI). Resting mean arterial pressure (MAP) was low in all eight subjects (64 +/- 2 mmHg).

  20. Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis.

    Directory of Open Access Journals (Sweden)

    Federico Iovino

    Full Text Available Streptococcus pneumoniae (the pneumococcus is a Gram-positive bacterium and the predominant cause of bacterial meningitis. Meningitis is thought to occur as the result of pneumococci crossing the blood-brain barrier to invade the Central Nervous System (CNS; yet little is known about the steps preceding immediate disease development. To study the interactions between pneumococci and the vascular endothelium of the blood-brain barrier prior to meningitis we used an established bacteremia-derived meningitis model in combination with immunofluorescent imaging. Brain tissue of mice infected with S. pneumoniae strain TIGR4, a clinical meningitis isolate, was investigated for the location of the bacteria in relation to the brain vasculature in various compartments. We observed that S. pneumoniae adhered preferentially to the subarachnoid vessels, and subsequently, over time, reached the more internal cerebral areas including the cerebral cortex, septum, and choroid plexus. Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection. In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection. Our results imply that i the local immune system of the brain is activated immediately upon entry of bacteria into the bloodstream and that ii adhesion to the blood brain barrier is spatiotemporally controlled at different sites throughout the brain. These results provide new information on these two important steps towards the development of pneumococcal meningitis.

  1. Estrogen and insulin transport through the blood-brain barrier.

    Science.gov (United States)

    May, Aaron A; Bedel, Nicholas D; Shen, Ling; Woods, Stephen C; Liu, Min

    2016-09-01

    Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS. PMID:27182046

  2. 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)....

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

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  4. In vitro models of the blood-brain barrier

    DEFF Research Database (Denmark)

    Helms, Hans C; Abbott, N Joan; Burek, Malgorzata;

    2016-01-01

    The endothelial cells lining the brain capillaries separate the blood from the brain parenchyma. The endothelial monolayer of the brain capillaries serves both as a crucial interface for exchange of nutrients, gases, and metabolites between blood and brain, and as a barrier for neurotoxic compone...

  5. Electrical Stimulation of the Suprahyoid Muscles in Brain-injured Patients with Dysphagia: A Pilot Study

    OpenAIRE

    Beom, Jaewon; Kim, Sang Jun; Han, Tai Ryoon

    2011-01-01

    Objective To investigate the therapeutic effects of repetitive electrical stimulation of the suprahyoid muscles in brain-injured patients with dysphagia. Method Twenty-eight brain-injured patients who showed reduced laryngeal elevation and supraglottic penetration or subglottic aspiration during a videofluoroscopic swallowing study (VFSS) were selected. The patients received either conventional dysphagia management (CDM) or CDM with repetitive electrical stimulation of the suprahyoid muscles ...

  6. Interactions between Blood-Borne Streptococcus pneumoniae and the Blood-Brain Barrier Preceding Meningitis

    NARCIS (Netherlands)

    Iovino, Federico; Orihuela, Carlos J.; Moorlag, Henk E.; Molema, Grietje; Bijlsma, Jetta J. E.

    2013-01-01

    Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium and the predominant cause of bacterial meningitis. Meningitis is thought to occur as the result of pneumococci crossing the blood-brain barrier to invade the Central Nervous System (CNS); yet little is known about the steps pre

  7. 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.

  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. 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

  10. 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...

  11. 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.

  12. 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.

  13. 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. PMID:27208862

  14. 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

  15. 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.

  16. 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.

  17. Brain blood vessel segmentation using line-shaped profiles

    Science.gov (United States)

    Babin, Danilo; Pižurica, Aleksandra; De Vylder, Jonas; Vansteenkiste, Ewout; Philips, Wilfried

    2013-11-01

    Segmentation of cerebral blood vessels is of great importance in diagnostic and clinical applications, especially for embolization of cerebral aneurysms and arteriovenous malformations (AVMs). In order to perform embolization of the AVM, the structural and geometric information of blood vessels from 3D images is of utmost importance. For this reason, the in-depth segmentation of cerebral blood vessels is usually done as a fusion of different segmentation techniques, often requiring extensive user interaction. In this paper we introduce the idea of line-shaped profiling with an application to brain blood vessel and AVM segmentation, efficient both in terms of resolving details and in terms of computation time. Our method takes into account both local proximate and wider neighbourhood of the processed pixel, which makes it efficient for segmenting large blood vessel tree structures, as well as fine structures of the AVMs. Another advantage of our method is that it requires selection of only one parameter to perform segmentation, yielding very little user interaction.

  18. 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.

  19. 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.

  20. 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.

  1. 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...... years. The magnitudes of CMRO(2) and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions......, 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...

  2. Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery.

    Science.gov (United States)

    Oller-Salvia, Benjamí; Sánchez-Navarro, Macarena; Giralt, Ernest; Teixidó, Meritxell

    2016-08-22

    Brain delivery is one of the major challenges in drug development because of the high number of patients suffering from neural diseases and the low efficiency of the treatments available. Although the blood-brain barrier (BBB) prevents most drugs from reaching their targets, molecular vectors - known as BBB shuttles - offer great promise to safely overcome this formidable obstacle. In recent years, peptide shuttles have received growing attention because of their lower cost, reduced immunogenicity, and higher chemical versatility than traditional Trojan horse antibodies and other proteins. PMID:27188322

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

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

    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...

  4. 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.

  5. 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

  6. 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....... 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....

  7. Multiscale modeling and simulation of brain blood flow

    Science.gov (United States)

    Perdikaris, Paris; Grinberg, Leopold; Karniadakis, George Em

    2016-02-01

    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.

  8. 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.

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

    DEFF Research Database (Denmark)

    Nyberg, Michael Permin

    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...... that no single compound can explain exercise hyperemia and indicates that any condition associated with reduced oxygen delivery needs to be investigated independently. Physical activity can attenuate or even counteract the effects of essential hypertension and aging on vascular function and exercise hyperemia....

  10. 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.

  11. 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.

  12. 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. PMID:27156064

  13. 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.

  14. 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...... imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g...... on a pixel-by-pixel basis of cerebral perfusion, cerebral blood volume, and blood-brain barrier permeability....

  15. 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

  16. Regional blood flow and skeletal muscle energy status in endotoxemic rats

    International Nuclear Information System (INIS)

    Endotoxins induce muscle wasting in part as a result of depressed protein synthesis. To investigate whether these changes reflect impaired energy transduction, blood flow, O2 extraction, and high-energy phosphates in muscle and whole-body O2 consumption (Vo2) have been measured. Vo2 was measured for 6 h after an initial sublethal dose of endotoxin (Escherichia coli lipopolysaccharide 0.3 mg/100 g body wt sc) or saline and during 6 h after a second dose 24 h later. In fed or fasted rats, Vo2 was either increased or better maintained after endotoxin. In anesthetized fed rats 3-4 h after the second dose of endotoxin Vo2 was increased, and this was accompanied by increased blood flow measured by 57Co-labelled microspheres to liver (hepatic arterial supply), kidney, and perirenal brown adipose tissue and a 57 and 64% decrease in flow to back and hindlimb muscle, respectively, with no change in any other organ. Hindlimb arteriovenous O2 was unchanged, indicating markedly decreased aerobic metabolism in muscle, and the contribution of the hindlimb to whole-body Vo2 decreased by 46%. Adenosine 5'-triphosphate levels in muscle were unchanged in endotoxin-treated rats, and this was confirmed by topical nuclear magnetic resonance spectroscopy, which also showed muscle pH to be unchanged. These results show that, although there is decreased blood flow and aerobic oxidation in muscle, adenosine 5'-triphosphate availability does not appear to be compromised so that the endotoxin-induced muscle catabolism and decreased protein synthesis must reflex some other mechanism

  17. A Functional Requirement for Astroglia in Promoting Blood Vessel Development in the Early Postnatal Brain

    OpenAIRE

    Shang Ma; Hyo Jun Kwon; Zhen Huang

    2012-01-01

    Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in p...

  18. 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.

  19. In vivo interactions of magnetic nanoparticles with the blood-brain barrier

    International Nuclear Information System (INIS)

    Targeted drug delivery to the brain parenchyma, i.e., in brain tumor patients, by means of magnetically supported carrier delivery through the tight vascular endothelium of the blood-brain barrier is of critical biomedical importance. We were interested in delineating the first steps in successful brain drug delivery, which focuses on the interactions between magnetically guided yet freely blood circulating nanoparticles and the blood-brain barrier. We employed an in vivo model to quantitatively determine changes in cerebrovascular flow rate and volume during magnetically guided exposure of circulating nanoparticles.

  20. 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...

  1. 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

    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...

  2. 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...

  3. 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.......37 +/- 0.23 mM. Mean sprint time was unaltered after the first half, but longer (P sprint performance during the game was not correlated with muscle lactate...

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β

    OpenAIRE

    Kanekiyo, Takahisa; Liu, Chia-Chen; Shinohara, Mitsuru; Li, Jie; Bu, Guojun

    2012-01-01

    Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer’s disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood-brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-...

  9. 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.

  10. 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...

  11. Blood flow restricted and traditional resistance training performed to fatigue produce equal muscle hypertrophy.

    Science.gov (United States)

    Farup, J; de Paoli, F; Bjerg, K; Riis, S; Ringgard, S; Vissing, K

    2015-12-01

    This study investigated the hypertrophic potential of load-matched blood-flow restricted resistance training (BFR) vs free-flow traditional resistance training (low-load TRT) performed to fatigue. Ten healthy young subjects performed unilateral BFR and contralateral low-load TRT elbow flexor dumbbell curl with 40% of one repetition maximum until volitional concentric failure 3 days per week for 6 weeks. Prior to and at 3 (post-3) and 10 (post-10) days post-training, magnetic resonance imaging (MRI) was used to estimate elbow flexor muscle volume and muscle water content accumulation through training. Acute changes in muscle thickness following an early vs a late exercise bout were measured with ultrasound to determine muscle swelling during the immediate 0-48 h post-exercise. Total work was threefold lower for BFR compared with low-load TRT (P BRF and low-load TRT increased muscle volume by approximately 12% at post-3 and post-10 (P BRF (P < 0.05) in the early training phase. In conclusion, BFR and low-load TRT, when performed to fatigue, produce equal muscle hypertrophy, which may partly rely on transient exercise-induced increases in muscle water content. PMID:25603897

  12. 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

    2016-01-01

    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. PMID:27180729

  13. 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.

  14. Middle cerebral artery flow velocity and blood flow during exercise and muscle ischemia in humans

    DEFF Research Database (Denmark)

    Jørgensen, L G; Perko, M; Hanel, B;

    1992-01-01

    ," mechanoreceptors, and/or muscle "metaboreceptors" on cerebral perfusion. Ten healthy subjects performed two levels of dynamic exercise corresponding to a heart rate of 110 (range 89-134) and 148 (129-170) beats/min, respectively, and exhaustive one-legged static knee extension. Measurements were continued during 2......, they support the hypothesis that cerebral perfusion during exercise reflects an increase in brain activation that is independent of MAP, central command, and muscle metaboreceptors but is likely to depend on influence of mechanoreceptors....

  15. 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.

  16. 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.

  17. Measurement of blood flow volume of ocular muscles by Xe-133 clearance method

    International Nuclear Information System (INIS)

    The blood flow volume of the ocular muscles was measured in 8 normal volunteers and 12 cases with miscellaneous opthalmic diseases by Xe-133 clearance method. The average of blood flow volume in the normal subjects was 7.45 ± 2.07 ml/min/100 g, and the blood flow volume ratio of right eye to left eye was 0.94 ± 0.07. The blood flow volume of the ocular muscles was decreased in the cases with stenosis of the internal carotid artery (n = 4, 4.3 ± 2.1 ml/min/100 g), glaucoma (n = 3, 4.7 ± 4.1 ml/min/100 g), arterial scleroses (n = 2, 3.8 ± 0.2 ml/min/100 g) and Takayasu's disease (n = 2, 5.6 ± 0.4 ml/min/100 g), and was increased in the acute inflammatory disease (n = 2, 21.5 ± 2.5 ml/min/100 g). Measurement of the blood flow volume of the ocular muscles using Xe-133 clearance method is useful to evaluate the circulatory abnormality in the ophthalmic diseases. (author)

  18. Dyslipidemia and Blood-Brain Barrier Integrity in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Gene L. Bowman

    2012-01-01

    Full Text Available Background. Blood-brain barrier (BBB dysfunction may have a significant role in the pathogenesis of Alzheimer's disease (AD. Modifiable factors associated with BBB function may have therapeutic implication. This study tested the hypothesis that dyslipidemia is associated with BBB impairment in mild-to-moderate AD. Methods. Thirty-six subjects with AD were followed for 1 year. Fasting CSF and plasma were collected with clinical assessments at baseline and 12 months. BBB impairment was defined as CSF albumin index ≥9. Independent t-tests and linear regression assessed the relationship between plasma lipoproteins and BBB integrity. Results. Dyslipidemia was prevalent in 47% of the population, and in 75% of those with BBB impairment. Subjects with BBB impairment had significantly higher mean plasma triglyceride and lower HDL cholesterol (TG, P=0.007; HDL, P=0.043. Plasma triglycerides explained 22% of the variance in BBB integrity and remained significant after controlling for age, gender, ApoE-4 genotype, blood pressure, and statin use. Conclusion. Dyslipidemia is more prevalent in AD subjects with BBB impairment. Plasma triglyceride and HDL cholesterol may have a role in maintaining BBB integrity in mild-to-moderate Alzheimer's disease.

  19. 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.

  20. 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

  1. 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.

  2. Stress does not increase blood-brain barrier permeability in mice.

    Science.gov (United States)

    Roszkowski, Martin; Bohacek, Johannes

    2016-07-01

    Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood-brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood-brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood-brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood-brain barrier permeability. To additionally assess if stress could change blood-brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood-brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood-brain barrier permeability. PMID:27146513

  3. Acute responses of muscle protein metabolism to reduced blood flow reflect metabolic priorities for homeostasis.

    Science.gov (United States)

    Zhang, Xiao-Jun; Irtun, Oivind; Chinkes, David L; Wolfe, Robert R

    2008-03-01

    The present experiment was designed to measure the synthetic and breakdown rates of muscle protein in the hindlimb of rabbits with or without clamping the femoral artery. l-[ring-(13)C(6)]phenylalanine was infused as a tracer for measurement of muscle protein kinetics by means of an arteriovenous model, tracer incorporation, and tracee release methods. The ultrasonic flowmeter, dye dilution, and microsphere methods were used to determine the flow rates in the femoral artery, in the leg, and in muscle capillary, respectively. The femoral artery flow accounted for 65% of leg flow. A 50% reduction in the femoral artery flow reduced leg flow by 28% and nutritive flow by 26%, which did not change protein synthetic or breakdown rate in leg muscle. Full clamp of the femoral artery reduced leg flow by 42% and nutritive flow by 59%, which decreased (P < 0.05) both the fractional synthetic rate from 0.19 +/- 0.05 to 0.14 +/- 0.03%/day and fractional breakdown rate from 0.28 +/- 0.07 to 0.23 +/- 0.09%/day of muscle protein. Neither the partial nor full clamp reduced (P = 0.27-0.39) the intracellular phenylalanine concentration or net protein balance in leg muscle. We conclude that the flow threshold to cause a fall of protein turnover rate in leg muscle was a reduction of 30-40% of the leg flow. The acute responses of muscle protein kinetics to the reductions in blood flow reflected the metabolic priorities to maintain muscle homeostasis. These findings cannot be extrapolated to more chronic conditions without experimental validation. PMID:18089763

  4. 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...

  5. Protection of the blood-brain barrier by hypercapnia during acute hypertension

    International Nuclear Information System (INIS)

    The purpose of this study was to examine effects of hypercapnia on susceptibility of the blood-brain barrier to disruption during acute hypertension. Two methods were used to test the hypothesis that cerebral vasodilation during hypercapnia increases disruption of the blood-brain barrier. First, permeability of the blood-brain barrier was measured in anesthetized cats with 125I-labeled serum albumin. Severe hypertension markedly increased permeability of the blood-brain barrier during normocapnia, but not during hypercapnia. The protective effect of hypercapnia was not dependent on sympathetic nerves. Second, in anesthetized rats, permeability of the barrier was quantitated by clearance of fluorescent dextran. Disruption of the blood-brain barrier during hypertension was decreased by hypercapnia. Because disruption of the blood-brain barrier occurred primarily in pial venules, the authors also measured pial venular diameter and pressure. Acute hypertension increased pial venular pressure and diameter in normocapnic rats. Hypercapnia alone increased pial venular pressure and pial venular diameter, and acute hypertension during hypercapnia further increased venular pressure. The magnitude of increase in pial venular pressure during acute hypertension was significantly less in hypercapnic than in normocapnic rats. They conclude that hypercapnia protects the blood-brain barrier. Possible mechanisms of this effect include attenuation of the incremental increase in pial venular pressure by hypercapnia or a direct effect on the blood-brain barrier not related to venous pressure

  6. Heart Failure Impairs Muscle Blood Flow and Endurance Exercise Tolerance in COPD.

    Science.gov (United States)

    Oliveira, Mayron F; Arbex, Flavio F; Alencar, Maria Clara; Souza, Aline; Sperandio, Priscila A; Medeiros, Wladimir M; Mazzuco, Adriana; Borghi-Silva, Audrey; Medina, Luiz A; Santos, Rita; Hirai, Daniel M; Mancuso, Frederico; Almeida, Dirceu; O'Donnell, Denis E; Neder, J Alberto

    2016-08-01

    Heart failure, a prevalent and disabling co-morbidity of COPD, may impair cardiac output and muscle blood flow thereby contributing to exercise intolerance. To investigate the role of impaired central and peripheral hemodynamics in limiting exercise tolerance in COPD-heart failure overlap, cycle ergometer exercise tests at 20% and 80% peak work rate were performed by overlap (FEV1 = 56.9 ± 15.9% predicted, ejection fraction = 32.5 ± 6.9%; N = 16), FEV1-matched COPD (N = 16), ejection fraction-matched heart failure patients (N = 15) and controls (N = 12). Differences (Δ) in cardiac output (impedance cardiography) and vastus lateralis blood flow (indocyanine green) and deoxygenation (near-infrared spectroscopy) between work rates were expressed relative to concurrent changes in muscle metabolic demands (ΔO2 uptake). Overlap patients had approximately 30% lower endurance exercise tolerance than COPD and heart failure (p COPD. Blunted limb perfusion was related to greater muscle deoxygenation and lactate concentration in overlap (r = 0.78 and r = 0.73, respectively; p COPD and heart failure add to decrease exercising cardiac output and skeletal muscle perfusion to a greater extent than that expected by heart failure alone. Treatment strategies that increase muscle O2 delivery and/or decrease O2 demand may be particularly helpful to improve exercise tolerance in COPD patients presenting heart failure as co-morbidity. PMID:26790095

  7. Access of blood-borne vasoconstrictors to the arteriolar smooth muscle.

    Science.gov (United States)

    Lew, M J; Duling, B R

    1992-01-01

    In vitro experiments have shown that luminally applied water-soluble vasoactive materials have limited access to arteriolar smooth muscle cells, and as a result, the responses to such agents applied luminally are less than the responses to those applied adventitially. To determine the extent to which this 'compartmentation' influences arteriolar responsiveness to blood-borne water-soluble vasoconstrictors in vivo, we applied phenylephrine, vasopressin and angiotension II to arterioles in the hamster cheek pouch both by luminal perfusion, and by topical application to the arteriolar smooth muscle via micropipettes. The arterioles were about 2 orders of magnitude more sensitive to these water-soluble vasoconstrictors when they were applied topically than when they were applied luminally. In contrast, the arterioles were almost equally sensitive to the lipid-soluble alpha 1-adrenoceptor agonist SKF 89748-A applied by either route. The venular wall appears to be much less effective as a barrier than the arteriolar endothelium. Phenylephrine and vasopressin both elicited large arteriolar constrictions when perfused through venules in close proximity to the arteriole, and these constrictions were larger than those observed when the drug was applied to the arteriole's own lumen. Our observations confirm that the arteriolar endothelium can inhibit the direct access of water-soluble blood-borne agents to the arteriolar smooth muscle in vivo, and they suggest that the capillaries and venules could be the primary routes of access for water-soluble agents from the blood to the arteriolar smooth muscle. PMID:1391555

  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...... 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...

  9. 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.

  10. 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...

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

    Science.gov (United States)

    Boushel, Robert; Langberg, Henning; Gemmer, Carsten; Olesen, Jens; Crameri, Regina; Scheede, Celena; Sander, Michael; Kjær, Michael

    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 quantified by near infrared spectroscopy and indocyanine green in six healthy humans during dynamic knee extension exercise with and without combined pharmacological inhibition of NO synthase (NOS) and PG by l-NAME and indomethacin, respectively. Microdialysis was applied to determine interstitial release of PG. Compared to control, combined blockade resulted in a 5- to 10-fold lower muscle interstitial PG level. During control incremental knee extension exercise, mean blood flow in the quadriceps muscles rose from 10 ± 0.8 ml (100 ml tissue)−1 min−1 at rest to 124 ± 19, 245 ± 24, 329 ± 24 and 312 ± 25 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively. During inhibition of NOS and PG, blood flow was reduced to 8 ± 0.5 ml (100 ml tissue)−1 min−1 at rest, and 100 ± 13, 163 ± 21, 217 ± 23 and 256 ± 28 ml (100 ml tissue)−1 min−1 at 15, 30, 45 and 60 W, respectively (P < 0.05 vs. control). In conclusion, combined inhibition of NOS and PG reduced muscle blood flow during dynamic exercise in humans. These findings demonstrate an important synergistic role of NO and PG for skeletal muscle vasodilatation and hyperaemia during muscular contraction. PMID:12205200

  12. 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.

  13. 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.

  14. P03.09PHARMACOLOGICAL MODULATION OF BLOOD-BRAIN BARRIER: FUTURE STRATEGY FOR TREATMENT OF BRAIN TUMORS

    OpenAIRE

    Sardi, I.; Cardellicchio, S.; Iorio, A.L.; da Ros, M.; la Marca, G.; Giunti, L.; Massimino, M.; L. Genitori

    2014-01-01

    A prerequisite for the efficacy of chemotherapy is that it reaches the tumor mass at a therapeutic concentration. In brain tumors this phenomenon is hampered by the presence of the blood brain barrier (BBB) which limits the spread of chemotherapeutic agents within the brain. It is lately emerged as this Multi Drug Resistance (MDR) phenomenon is explained through the cooperation of P-glycoprotein (P-gp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), two “gatekeeper" transporters th...

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

    DEFF Research Database (Denmark)

    Tornabene, Erica; Brodin, Birger

    2016-01-01

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

  16. 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.

  17. Blood interference in fluorescence spectrum : Experiment, analysis and comparison with intraoperativemeasurements on brain tumor

    OpenAIRE

    Lowndes, Shannely

    2010-01-01

    The optical touch pointer (OTP), a fluorescence spectroscopy based system, assists brain surgeons during guided brain tumor resection in patients with glioblastoma multiforme (GBM). After recording and analyzing the autofluorescence spectrum of the tissue, it is possible to distinguish malignant from healthy brain tissue. A challenge during the intraoperative measurements is the interference of blood. If it gets in contact with the laser pointer, the blood blocks the light transmission to and...

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. Blood-Brain Barrier Breakdown Following Traumatic Brain Injury: A Possible Role in Posttraumatic Epilepsy

    Directory of Open Access Journals (Sweden)

    Oren Tomkins

    2011-01-01

    Full Text Available Recent animal experiments indicate a critical role for opening of the blood-brain barrier (BBB in the pathogenesis of post-traumatic epilepsy (PTE. This study aimed to investigate the frequency, extent, and functional correlates of BBB disruption in epileptic patients following mild traumatic brain injury (TBI. Thirty-seven TBI patients were included in this study, 19 of whom suffered from PTE. All underwent electroencephalographic (EEG recordings and brain magnetic resonance imaging (bMRI. bMRIs were evaluated for BBB disruption using novel quantitative techniques. Cortical dysfunction was localized using standardized low-resolution brain electromagnetic tomography (sLORETA. TBI patients displayed significant EEG slowing compared to controls with no significant differences between PTE and nonepileptic patients. BBB disruption was found in 82.4% of PTE compared to 25% of non-epileptic patients (P=.001 and could be observed even years following the trauma. The volume of cerebral cortex with BBB disruption was significantly larger in PTE patients (P=.001. Slow wave EEG activity was localized to the same region of BBB disruption in 70% of patients and correlated to the volume of BBB disrupted cortex. We finally present a patient suffering from early cortical dysfunction and BBB breakdown with a gradual and parallel resolution of both pathologies. Our findings demonstrate that BBB pathology is frequently found following mild TBI. Lasting BBB breakdown is found with increased frequency and extent in PTE patients. Based on recent animal studies and the colocalization found between the region of disrupted BBB and abnormal EEG activity, we suggest a role for a vascular lesion in the pathogenesis of PTE.

  4. Noninvasive monitoring of treatment response in a rabbit cyanide toxicity model reveals differences in brain and muscle metabolism

    Science.gov (United States)

    Kim, Jae G.; Lee, Jangwoen; Mahon, Sari B.; Mukai, David; Patterson, Steven E.; Boss, Gerry R.; Tromberg, Bruce J.; Brenner, Matthew

    2012-10-01

    Noninvasive near infrared spectroscopy measurements were performed to monitor cyanide (CN) poisoning and recovery in the brain region and in foreleg muscle simultaneously, and the effects of a novel CN antidote, sulfanegen sodium, on tissue hemoglobin oxygenation changes were compared using a sub-lethal rabbit model. The results demonstrated that the brain region is more susceptible to CN poisoning and slower in endogenous CN detoxification following exposure than peripheral muscles. However, sulfanegen sodium rapidly reversed CN toxicity, with brain region effects reversing more quickly than muscle. In vivo monitoring of multiple organs may provide important clinical information regarding the extent of CN toxicity and subsequent recovery, and facilitate antidote drug development.

  5. Blood-brain barrier permeability in rats exposed to electromagnetic fields used in wireless communication

    OpenAIRE

    Persson, Bertil R.; Leif G Salford; Brun, Arne

    1997-01-01

    iological effects of radio frequency electromagnetic fields (EMF) on the blood-brain barrier (BBB) have been studied in Fischer 344 rats of both sexes. The rats were not anaesthetised during the exposure. All animals were sacrificed by perfusion–fixation of the brains under chloralhydrate anaesthesia after the exposure. The brains were perfused with saline for 3–4 minutes, and thereafter perfusion fixed with 4% formaldehyde for 5–6 minutes. Whole coronal sections of the brains were d...

  6. 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.

  7. 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.

  8. The blood-brain barrier penetration and distribution of PEGylated fluorescein-doped magnetic silica nanoparticles in rat brain

    International Nuclear Information System (INIS)

    PEGylated PAMAM conjugated fluorescein-doped magnetic silica nanoparticles (PEGylated PFMSNs) have been synthesized for evaluating their ability across the blood-brain barrier (BBB) and distribution in rat brain. The obtained nanoparticles were characterized by transmission electron microscopy (TEM), thermal gravimetry analyses (TGA), zeta potential (ζ-potential) titration, and X-ray photoelectron spectroscopy (XPS). The BBB penetration and distribution of PEGylated PFMSNs and FMSNs in rat brain were investigated not only at the cellular level with Confocal laser scanning microscopy (CLSM), but also at the subcellular level with transmission electron microscopy (TEM). The results provide direct evidents that PEGylated PFMSNs could penetrate the BBB and spread into the brain parenchyma.

  9. Positron emission tomographic measurement of blood-to-brain and blood-to-tumor transport of 82Rb: the effect of dexamethasone and whole-brain radiation therapy

    International Nuclear Information System (INIS)

    Unidirectional blood-to-brain and blood-to-tumor transport rate constants for rubidium 82 were determined using dynamic positron emission tomography in patients with primary or metastatic brain tumors. Regional influx rate constants (K1) and plasma water volume (Vp) were estimated from the time course of blood and brain radioactivity following a bolus injection of tracer. Eight patients were studied before and 24 to 72 hours after treatment using pharmacological doses of dexamethasone, and 6 additional patients with metastatic brain tumors were studied before and within 60 to 90 minutes after 200- to 600-rad whole-brain radiation therapy. Steroid treatment was associated with a 9 to 48% decrease in tumor K1 and a 21% mean decrease in tumor Vp. No consistent changes in K1 or Vp were observed in control brain regions. Tumor K1 and Vp did not increase in patients undergoing whole-brain radiation therapy, all of whom were taking dexamethasone at the time of study. These data suggest that corticosteroids decrease the permeability of tumor capillaries to small hydrophilic molecules (including those of some chemotherapeutic agents) and that steroid pretreatment prevents acute, and potentially dangerous, increases in tumor capillary permeability following cranial irradiation

  10. 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

    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...

  11. The fibrinolytic system facilitates tumor cell migration across the blood-brain barrier in experimental melanoma brain metastasis

    International Nuclear Information System (INIS)

    Patients with metastatic tumors to the brain have a very poor prognosis. Increased metastatic potential has been associated with the fibrinolytic system. We investigated the role of the fibrinolytic enzyme plasmin in tumor cell migration across brain endothelial cells and growth of brain metastases in an experimental metastatic melanoma model. Metastatic tumors to the brain were established by direct injection into the striatum or by intracarotid injection of B16F10 mouse melanoma cells in C57Bl mice. The role of plasminogen in the ability of human melanoma cells to cross a human blood-brain barrier model was studied on a transwell system. Wild type mice treated with the plasmin inhibitor epsilon-aminocaproic acid (EACA) and plg-/- mice developed smaller tumors and survived longer than untreated wild type mice. Tumors metastasized to the brain of wild type mice treated with EACA and plg-/- less efficiently than in untreated wild type mice. No difference was observed in the tumor growth in any of the three groups of mice. Human melanoma cells were able to cross the human blood-brain barrier model in a plasmin dependent manner. Plasmin facilitates the development of tumor metastasis to the brain. Inhibition of the fibrinolytic system could be considered as means to prevent tumor metastasis to the brain

  12. 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...

  13. 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.

  14. Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain.

    OpenAIRE

    Kohen, R; Yamamoto, Y.; Cundy, K C; Ames, B N

    1988-01-01

    Carnosine, homocarnosine, and anserine are present in high concentrations in the muscle and brain of many animals and humans. However, their exact function is not clear. The antioxidant activity of these compounds has been examined by testing their peroxyl radical-trapping ability at physiological concentrations. Carnosine, homocarnosine, anserine, and other histidine derivatives all showed antioxidant activity. All of these compounds showing peroxyl radical-trapping activity were also electr...

  15. Restoration of grasp following paralysis through brain-controlled stimulation of muscles

    OpenAIRE

    Ethier, C.; Oby, E.R.; Bauman, M.J.; Miller, L.E.

    2012-01-01

    Patients with spinal cord injury lack the connections between brain and spinal cord circuits essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movement and to achieve a greater measure of independence in activities of daily living 1,2 . In typical systems, the patient uses residual proximal limb movements to trigger pre-pr...

  16. Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men

    OpenAIRE

    Fry, Christopher S.; Glynn, Erin L.; Drummond, Micah J.; Timmerman, Kyle L.; Fujita, Satoshi; Abe, Takashi; Dhanani, Shaheen; Volpi, Elena; Rasmussen, Blake B.

    2010-01-01

    The loss of skeletal muscle mass during aging, sarcopenia, increases the risk for falls and dependence. Resistance exercise (RE) is an effective rehabilitation technique that can improve muscle mass and strength; however, older individuals are resistant to the stimulation of muscle protein synthesis (MPS) with traditional high-intensity RE. Recently, a novel rehabilitation exercise method, low-intensity RE, combined with blood flow restriction (BFR), has been shown to stimulate mammalian targ...

  17. 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.

  18. 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

  19. Brain blood flow studies with single photon emission computed tomography in patients with plateau waves

    International Nuclear Information System (INIS)

    The authors studied brain blood flow with single photon emission computed tomography (SPECT) in two patients with plateau waves. The intracranial pressure and blood pressure were also monitored continuously in these patients. They included one patient with brain-tumor (rt. sphenoid ridge meningioma) and another with hydrocephalus after subarachnoid hemorrhage due to rupture of lt. internal carotid aneurysm. The intracranial pressure was monitored through an indwelling ventricular catheter attached to a pressure transducer. The blood pressure was recorded through an intraarterial catheter placed in the dorsalis pedis artery. Brain blood flow was studied with Headtome SET-011 (manufactured by Shimazu Co., Ltd.). For this flow measurement study, an intravenous injection of Xenon-133 of about 30 mCi was given via an antecubital vein. The position of the slice for the SPECT was selected so as to obtain information not only from the cerebral hemisphere but also from the brain stem : a cross section 25 deg over the orbito-meatal line, passing through the inferior aspect of the frontal horn, the basal ganglia, the lower recessus of the third ventricle and the brain stem. The results indicated that, in the cerebral hemisphere, plateau waves were accompanied by a decrease in blood flow, whereas, in the brain stem, the blood flow showed little change during plateau waves as compared with the interval phase between two plateau waves. These observations may explain why there is no rise in the blood pressure and why patients are often alert during plateau waves. (author)

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. P/Q-type and T-type voltage-gated calcium channels are involved in the contraction of mammary and brain blood vessels from hypertensive patients

    DEFF Research Database (Denmark)

    Thuesen, A D; Lyngsø, K S; Rasmussen, L;

    2016-01-01

    AIM: Calcium channel blockers are widely used in cardiovascular diseases. Besides L-type channels, T- and P/Q-type calcium channels are involved in the contraction of human renal blood vessels. It was hypothesized that T- and P/Q-type channels are involved in the contraction of human brain...... and mammary blood vessels. METHODS: Internal mammary arteries from bypass surgery patients and cerebral arterioles from patients with brain tumours with and without hypertension were tested in a myograph and perfusion set-up. PCR and immunohistochemistry were performed on isolated blood vessels. RESULTS...... labelling of mammary and cerebral arteries revealed the presence of Cav 2.1 in endothelial and smooth muscle cells. Cav 3.1 was also detected in mammary arteries. CONCLUSION: P/Q- and T-type Cav are present in human internal mammary arteries and in cerebral penetrating arterioles. P/Q- and T-type calcium...

  7. What is the correct value for the brain: blood partition coefficient for water

    Energy Technology Data Exchange (ETDEWEB)

    Herscovitch, P.; Raichle, M.E.

    1984-01-01

    A knowledge of the brain: blood partition coefficient (lambda) for water is usually required for the measurement of cerebral blood flow (CBF) with positron emission tomography (PET) and 0-15 labelled water. The correct calculation of this important parameter from the ratio of brain and blood water contents is reviewed, and the effect of physiological variations in these water contents on lambda is demonstrated. The currently accepted value for whole brain lambda is 0.95-0.96 ml/g, calculated from brain and blood water contents of 77g/100g and 80.5g/100g, respectively. However, this value for lambda is incorrect, because in the calculation the blood water content value was not adjusted for the density of blood. The correct value is 0.91 ml/g. Variations in brain or blood water content affect lambda. Over an hematocrit range of 25% to 55%, lambda varies from 0.86 to 0.93 ml/g, due to a decrease in blood water content. lambda changes with age, and varies regionally in the brain, as brain water content is inversely related to lipid and myelin content. The lambda of the human newborn brain, 1.10 ml/g, is considerably higher than in the adult. Differences in lambda between gray and white matter are well known. However, because of variations in water content, the lambda's of thalamus (0.88 ml/g) and caudate nucleus (0.96 ml/g) are less than that of cerebral cortex (0.99 ml/g), while the lambda of corpus callosum (0.89 ml/g) is greater than that of centrum semiovale (0.83 ml/g). These regional variations in lambda will assume more importance as PET resolution improves. The impact of using an incorrect lambda will depend upon the sensitivity of the particular CBF measurement technique to errors in lambda.

  8. Restraint Stress-Induced Morphological Changes at the Blood-Brain Barrier in Adult Rats

    OpenAIRE

    Petra eSántha; Szilvia eVeszelka; Zsófia eHoyk; Mária eMészáros; Walter, Fruzsina R.; Andrea E Tóth; Lóránd eKiss; András eKincses; Zita eOláh; György eSeprényi; Gabor eRakhely; András eDér; Magdolna ePákáski; Janos eKalman; Ágnes eKittel

    2016-01-01

    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 recognized 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 th...

  9. Understanding the rules of the road: proteomic approaches to interrogate the blood brain barrier

    OpenAIRE

    Torbett, Bruce E.; Baird, Andrew; Eliceiri, Brian P

    2015-01-01

    The blood brain barrier (BBB) is often regarded as a passive barrier that protects brain parenchyma from toxic substances, circulating leukocytes, while allowing the passage of selected molecules. Recently, a combination of molecular profiling techniques have characterized the constituents of the BBB based on in vitro models using isolated endothelial cells and ex vivo models analyzing isolated blood vessels. Characterization of gene expression profiles that are specific to the endothelium of...

  10. 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. PMID:25589747

  11. Comparison study of ferrofluid and powder iron oxide nanoparticle permeability across the blood-brain barrier.

    Science.gov (United States)

    Hoff, Dan; Sheikh, Lubna; Bhattacharya, Soumya; Nayar, Suprabha; Webster, Thomas J

    2013-01-01

    In the present study, the permeability of 11 different iron oxide nanoparticle (IONP) samples (eight fluids and three powders) was determined using an in vitro blood-brain barrier model. Importantly, the results showed that the ferrofluid formulations were statistically more permeable than the IONP powder formulations at the blood-brain barrier, suggesting a role for the presently studied in situ synthesized ferrofluid formulations using poly(vinyl) alcohol, bovine serum albumin, collagen, glutamic acid, graphene, and their combinations as materials which can cross the blood-brain barrier to deliver drugs or have other neurological therapeutic efficacy. Conversely, the results showed the least permeability across the blood-brain barrier for the IONP with collagen formulation, suggesting a role as a magnetic resonance imaging contrast agent but limiting IONP passage across the blood-brain barrier. Further analysis of the data yielded several trends of note, with little correlation between permeability and fluid zeta potential, but a larger correlation between permeability and fluid particle size (with the smaller particle sizes having larger permeability). Such results lay the foundation for simple modification of iron oxide nanoparticle formulations to either promote or inhibit passage across the blood-brain barrier, and deserve further investigation for a wide range of applications. PMID:23426527

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

    NARCIS (Netherlands)

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

    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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Next generation of non-mammalian blood-brain barrier models to study parasitic infections of the central nervous system

    OpenAIRE

    Siddiqui, Ruqaiyyah; Edwards-Smallbone, James; Flynn, Robin; Khan, Naveed Ahmed

    2012-01-01

    Transmigration of neuropathogens across the blood-brain barrier is a key step in the development of central nervous system infections, making it a prime target for drug development. The ability of neuropathogens to traverse the blood-brain barrier continues to inspire researchers to understand the specific strategies and molecular mechanisms that allow them to enter the brain. The availability of models of the blood-brain barrier that closely mimic the situation in vivo offers unprecedented o...

  18. 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.

  19. Selective permeabilization of the blood-brain barrier at sites of metastasis

    OpenAIRE

    Sibson, NR; Vallis, KA; Hamilton, A.; Seymour, L.; Anthony, DC; Connell, JJ; Chatain, G

    2013-01-01

    BACKGROUND: Effective chemotherapeutics for primary systemic tumors have limited access to brain metastases because of the blood-brain barrier (BBB). The aim of this study was to develop a strategy for specifically permeabilizing the BBB at sites of cerebral metastases. METHODS: BALB/c mice were injected intracardially to induce brain metastases. After metastasis induction, either tumor necrosis factor (TNF) or lymphotoxin (LT) was administered intravenously, and 2 to 24 hours later gadoliniu...

  20. Blood-Brain Barrier Active Efflux Transporters: ATP-Binding Cassette Gene Family

    OpenAIRE

    Löscher, Wolfgang; Potschka, Heidrun

    2005-01-01

    Summary: The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lip...

  1. 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......(-1), P > 0.05; 85% W(max) 88 +/- 31 vs. -9 +/- 25 nmol x 100 g(-1) x min(-1), P contracting than adjacent to resting muscle irrespective of exercise intensity. Thus specific exercises can induce "spot lipolysis...... 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...

  2. Pressure passive cerebral blood flow and breakdown of the blood-brain barrier in experimental fetal asphyxia

    DEFF Research Database (Denmark)

    Lou, H C; Lassen, N A; Tweed, W A;

    1979-01-01

    reaching CBF values up to 6 times normal at normal MABP of about 60 to 70 mmHg, and severe ischemia reaching CBF values close to zero in large cortical areas at MABP of 30 mmHg. CVP remained essentially unchanged at 10--15 mmHg. The severe and prolonged asphyxia rendered the blood-brain barrier leaky...

  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. Changes in extracellular muscle volume affect heart rate and blood pressure responses to static exercise

    Science.gov (United States)

    Baum, K.; Essfeld, D.; Stegemann, J.

    To investigate the effect of μg-induced peripheral extracellular fluid reductions on heart rate and blood pressure during isometric exercise, six healthy male subjects performed three calf ergometer test with different extracellular volumes of working muscles. In all tests, body positions during exercise were identical (supine with the knee joint flexed to 900). After a pre-exercise period of 25 min, during which calf volumes were manipulated, subjects had to counteract an external force of 180 N for 5 min. During the pre-exercise period three different protocols were applied. Test A: Subjects rested in the exercise position; test B: Body position was the same as in A but calf volume was increased by venous congestion (cuffs inflated to 80 mm Hg); test C: Calf volumes were decreased by a negative hydrostatic pressure (calves about 40 cm above heart level with the subjects supine). To clamp the changed calf volumes in tests B and C, cuffs were inflated to 300 mm Hg 5 min before the onset of exercise. This occlusion was maintained until termination of exercise. Compared to tests A and B, the reduced volume of test C led to significant increases in heart rate and blood pressure during exercise. Oxygen uptake did not exceed resting levels in B and C until cuffs were deflated, indicating that exclusively calf muscles contributed to the neurogenic peripheral drive. It is concluded that changes in extracellular muscle volume have to be taken into account when comparing heart rate and blood pressure during lg- and μg- exercise.

  5. Muscle activation, blood lactate, and perceived exertion responses to changing resistance training programming variables.

    Science.gov (United States)

    Hiscock, Daniel J; Dawson, Brian; Donnelly, Cyril J; Peeling, Peter

    2016-08-01

    Ratings of perceived exertion (RPE: 0-10) during resistance training with varying programming demands were examined. Blood lactate (BLa) and muscle activation (using surface electromyography: EMG) were measured as potential mediators of RPE responses. Participants performed three sets of single arm (preferred side) bicep curls at 70% of 1 repetition maximum over 4 trials: Trial (A) 3 sets × 8 repetitions × 120 s recovery between sets; (B) 3 sets × 8 repetitions × 240 s recovery; (C) 3 sets × maximum number of repetitions (MNR) × 120 s recovery; (D) 3 sets × MNR × 240 s recovery. Overall body (RPE-O) and active muscle (RPE-AM) perceptual responses were assessed following each set in each trial. Biceps brachii and brachioradialis muscle EMG was measured during each set for each trial. RPE-O and RPE-AM were not different between Trial A (3.5 ± 1 and 6 ± 1, respectively) and Trial B (3.5 ± 1 and 5.5 ± 1, respectively) (p < .05). However, RPE-AM was significantly greater in Trial C (7.5 ± 1.5) and Trial D (7.5 ± 1.5) than in Trial B (p < .05). There were no significant differences in muscle activation or BLa between trials; however, work rate (tonnage/min) was greater in Trials C and D compared to Trial B. In conclusion, BLa and muscle activation were not related to RPE, but resistance training variables, such as work rate, may impact on RPE when intensity (%1RM) and the number of sets completed remain constant. PMID:26267339

  6. Endoscopic-assisted minimally invasive resection of a papillary muscle blood cyst in an adult patient.

    Science.gov (United States)

    Okamoto, Kazuma; Kudo, Mikihiko; Hayashi, Kanako; Shimizu, Hideyuki

    2016-02-01

    We describe endoscopic-assisted minimally invasive resection of a blood cyst originating from the papillary muscle that caused severe mitral regurgitation and necessitated mitral valve replacement in an active adult woman, as well as a review of the relevant literature. An endoscopic view increases the visibility of the surgical target and facilitates a precise observation of the tumour and dissection at the appropriate layer. The On-X mechanical valve was chosen for mitral valve repair to minimize thromboembolic risk. This patient additionally benefited from endoscopic-assisted right minithoracotomy in terms of both cosmetic and functional aspects. PMID:26586675

  7. 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.

  8. 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

    2016-09-01

    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. PMID:27349679

  9. Spatial mapping of blood flow and oxygen consumption in the human calf muscle using near-infrared spectroscopy

    Science.gov (United States)

    Fantini, Sergio; Hoimes, Matthew L.; Casavola, Claudia; Franceschini, Maria-Angela

    2001-05-01

    We have designed a new optical probe to perform spatially resolved measurements of blood flow and oxygen consumption over an area of about 4 x 4 cm2 of the lateral gastrocnemius muscle (calf muscle) of human subjects. The blood flow and the oxygen consumption were measured non- invasively with frequency-domain, near-infrared spectroscopy from the maximum rate of increase of the oxy- and deoxy- hemoglobin concentrations in the muscle during venous occlusion. In a preliminary test on one subject, involving measurements at rest and after exercise, we have found that the spatial variability of the measured blood flow and oxygen consumption is significantly greater than the variability of repeated measurements at a given tissue location. We have also observed a strong spatial dependence of the exercise-induced increase in blood flow and oxygen consumption.

  10. Lactography as an approach to monitor glucose metabolism on-line in brain and muscle.

    Science.gov (United States)

    Korf, J; de Boer, J

    1990-01-01

    1. Thus far metabolic processes in the intact animal (or man) have been studied either by the analysis of body fluids, of biopsies, of tissue obtained post mortem or by techniques, requiring dedicated and expensive equipment (such as positron emission tomography or magnetic resonance spectroscopy). 2. Here we describe a relatively simple and inexpensive technique, that can be applied in vivo to study metabolism in brain regions and muscle in the freely moving rat and in human peripheral tissue. 3. The method is based on microdialysis allowing continuous sampling from the extracellular space, the enzymatic conversion of lactate and the on-line detection of fluorescent NADH. 4. Examples of the application of our technique include the monitoring of lactate efflux from various brain regions of behaving animals under a variety of stress exposures, during ischemia or hypoxia and drug treatments. 5. The results indicate that in brain lactate is not exclusively formed under hypoxia and that neuronal activation leads also to lactate formation, possibly due to the compartmentation of both the involved enzymes and the energy metabolism. 6. The increase of lactate formation in contracting or ischemic muscle or during exercise could also be followed on-line in the rat, suggesting that our approach allows the continuous monitoring of anaerobic metabolism in man e.g. during traumatic or arteriosclerotic limb ischemia or lactic acidosis in shock states. 7. The principle of our approach can easily be adapted to other metabolites, thus enabling to monitor other metabolic pathways in vivo as well. PMID:2276411

  11. Creatine supplementation in the aging population: effects on skeletal muscle, bone and brain.

    Science.gov (United States)

    Gualano, Bruno; Rawson, Eric S; Candow, Darren G; Chilibeck, Philip D

    2016-08-01

    This narrative review aims to summarize the recent findings on the adjuvant application of creatine supplementation in the management of age-related deficits in skeletal muscle, bone and brain metabolism in older individuals. Most studies suggest that creatine supplementation can improve lean mass and muscle function in older populations. Importantly, creatine in conjunction with resistance training can result in greater adaptations in skeletal muscle than training alone. The beneficial effect of creatine upon lean mass and muscle function appears to be applicable to older individuals regardless of sex, fitness or health status, although studies with very old (>90 years old) and severely frail individuals remain scarce. Furthermore, there is evidence that creatine may affect the bone remodeling process; however, the effects of creatine on bone accretion are inconsistent. Additional human clinical trials are needed using larger sample sizes, longer durations of resistance training (>52 weeks), and further evaluation of bone mineral, bone geometry and microarchitecture properties. Finally, a number of studies suggest that creatine supplementation improves cognitive processing under resting and various stressed conditions. However, few data are available on older adults, and the findings are discordant. Future studies should focus on older adults and possibly frail elders or those who have already experienced an age-associated cognitive decline. PMID:27108136

  12. 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.

  13. 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.

  14. Cocaine postmortem distribution in three brain structures: a comparison with whole blood and vitreous humour.

    Science.gov (United States)

    Carvalho, Virginia M; Fukushima, André R; Fontes, Luiz R; Fuzinato, Daniela V; Florio, Jorge C; Chasin, Alice A M

    2013-04-01

    The presence of cocaine (COC) in fluids or tissues does not prove that death was due to drug consumption and the interpretation of postmortem concentrations is more complex than attempts at making such correlations in the living. The purpose of this study was to investigate the distribution of cocaine and its metabolite benzoylecgonine in brain and compare with whole blood and vitreous humour. The distribution in three brain structures (prefrontal cortex, basal ganglia and cerebellum) was homogeneous. There is a strong correlation for cocaine concentrations between vitreous humour and brain, vitreous humour and whole blood, and whole blood and brain in overdose cases. In addition, the comparison of COC/benzoylecgonine (BE) ratios in different experimental specimens proved to be more appropriate for evaluating cocaine-related death than individual drug values. These findings suggest that the comparison of cocaine levels in different compartments is essential to assess the cause of death. PMID:23472791

  15. [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.

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

    Directory of Open Access Journals (Sweden)

    Katarzyna Bozek

    2014-05-01

    Full Text Available 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 by superior cognition, their muscular performance might be markedly inferior to that of chimpanzees and macaque monkeys.

  17. In vivo two-photon imaging measuring the blood-brain barrier permeability during early postnatal brain development in rodent

    Science.gov (United States)

    Shi, Lingyan; Rodríguez-Contreras, Adrián.

    2016-03-01

    The blood-brain barrier (BBB) is a unique structure between the cerebral blood circulation and the delicate neural environment that is important in regulating the movement of molecules and ions involved in brain development and function. However, little is known about the physiological permeability of molecules and ions across the BBB during brain development. In this study we applied an innovative approach to examine the development of BBB properties quantitatively. Two-photon microscopy was employed to measure BBB permeability in real time in vivo. Vascular growth and specific interactions between astrocyte end feet and microvessels were studied by using a combination of IB4 histochemistry, immunohistochemistry, confocal microscopy and 3D analysis.

  18. In vitro screening of nanomedicines through the blood brain barrier: A critical review.

    Science.gov (United States)

    Aparicio-Blanco, Juan; Martín-Sabroso, Cristina; Torres-Suárez, Ana-Isabel

    2016-10-01

    The blood-brain barrier accounts for the high attrition rate of the treatments of most brain disorders, which therefore remain one of the greatest health-care challenges of the twenty first century. Against this background of hindrance to brain delivery, nanomedicine takes advantage of the assembly at the nanoscale of available biomaterials to provide a delivery platform with potential to raising brain levels of either imaging or therapeutic agents. Nevertheless, to prevent later failure due to ineffective drug levels at the target site, researchers have been endeavoring to develop a battery of in vitro screening procedures that can predict earlier in the drug discovery process the ability of these cutting-edge drug delivery platforms to cross the blood-brain barrier for biomedical purposes. This review provides an in-depth analysis of the currently available in vitro blood-brain barrier models (both cell-based and non-cell-based) with the focus on their suitability for understanding the biological brain distribution of forthcoming nanomedicines. The relationship between experimental factors and underlying physiological assumptions that would ultimately lead to a more predictive capacity of their in vivo performance, and those methods already assayed for the evaluation of the brain distribution of nanomedicines are comprehensively discussed. PMID:27392291

  19. 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.

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

    Science.gov (United States)

    Peterson, Sarah H; Ackerman, Joshua T; Costa, Daniel P

    2016-08-01

    Mercury (Hg) biomonitoring and toxicological risk assessments for marine mammals commonly sample different tissues, making comparisons with 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. The authors 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). The results indicate that THg concentrations in blood or muscle can be translated to the other tissue type using the equations developed but that THg concentrations in hair were generally a poor index of internal THg concentrations except during the end of fasting periods. Environ Toxicol Chem 2016;35:2103-2110. © 2016 SETAC. PMID:26757244

  1. Cerebral blood volume measured using near-infrared spectroscopy and radiolabels in the immature lamb brain.

    Science.gov (United States)

    Barfield, C P; Yu, V Y; Noma, O; Kukita, J; Cussen, L J; Oates, A; Walker, A M

    1999-07-01

    Near-infrared spectroscopy (NIRS) is a technique that is increasingly being used for the noninvasive measurement of cerebral blood volume (CBV) in newborn infants, but it has not been fully validated against established methods. These experiments in immature lambs (gestation 92+/-1 d, mean+/-SEM) compared CBV measured using NIRS-derived estimates of oxygenated Hb (n = 5) with CBV estimated with radiolabeled indicators (125I-labeled serum albumin and 51Cr-labeled red blood cells, n = 10). Total brain CBV (mL/100 g tissue) measured using NIRS was 2.5+/-0.2 compared with 2.5+/-0.2 using radiolabels (NS). Regional tissue plasma, red blood cells, and whole blood volumes from radiolabels varied significantly (p cerebellum > cortex > brain stem = midbrain > white matter. Regional plasma and red blood cell distributions were similar to whole blood, being highest in choroid plexus (13.0+/-1.6 and 3.2+/-0.9, respectively), and least in white matter (0.8+/-0.1 and 0, respectively). These data from the immature lamb brain indicate that total CBV measured with NIRS is essentially identical with the volumes obtained using intravascular radiolabels. Among cerebral regions, white matter contributes little to the global blood volume measured with NIRS because its red blood cell content is very low. PMID:10400134

  2. 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 ...

  3. Regional cerebral blood flow and brain atrophy in senile dementia of Alzheimer type (SDAT)

    International Nuclear Information System (INIS)

    To investigate the relationship between the reduction of cerebal blood flow and brain atrophy in SDAT, these were measured in 13 cases of senile dementia of Alzheimer type, and compared to 15 cases of multi-infarct Dementia, 39 cases of lacunar infarction without dementia (non-demented CVD group) and 69 cases of aged normal control. Brain atrophy was evaluated by two-dimensional method on CT film by digitizer and regional cerebral blood flow (rCBF) was measured by 133Xe inhalation method. The degree of brain atrophy in SDAT was almost similar of that of MID. But it was more severe than that of non-demented group. MID showed the lowest rCBF among these groups. SDAT showed significantly lower rCBF than that of aged control, but rCBF in SDAT was equal to that of lacunar stroke without dementia. Focal reduction of cerebral blood flow in bilateral fronto-parietal and left occipital regions were observed in SDAT. Verbal intelligence score (Hasegawa's score) correlated with rCBF and brain atrophy index in MID, and a tendency of correlation between rCBF and brain atrophy in MID was also observed. However, there was no correlation among those indices in SDAT. These findings suggest that the loss of brain substance dose not correspond to the reduction of rCBF in SDAT and simultaneous measurement of rCBF and brain atrophy was useful to differ SDAT from MID. (author)

  4. 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.

  5. 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

  6. Increased blood-brain transfer in a rabbit model of acute liver failure

    International Nuclear Information System (INIS)

    The blood-to-brain transfer of [14C]alpha-aminoisobutyric acid was investigated by quantitative autoradiography in normal rabbits and rabbits with acute liver failure induced by the selective hepatotoxin galactosamine. The blood-to-brain transfer of alpha-aminoisobutyric acid was similar in control animals and animals 2 and 7 h after galactosamine injections, but was increased five- to tenfold in certain gray-matter areas of the brain in animals 11 and 18 h after galactosamine treatment. No detectable differences in white-matter uptake of [14C]alpha-aminoisobutyric acid were found between the control and treated groups. The increase in alpha-aminoisobutyric acid transfer within the gray-matter areas suggested that a general or nonspecific increase in brain capillary permeability occurred in these areas. No clinical signs of early hepatic encephalopathy were observed in the treated rabbits, except for 1 animal from the 18-h postgalactosamine group. Thus, enhanced blood-brain transfer of alpha-aminoisobutyric acid preceded the development of overt hepatic encephalopathy. The distribution of radioactivity after the intravenous administration of [14C]galactosamine showed that virtually none of the hepatotoxin localized in the brain, suggesting that the drug itself does not have a direct effect upon the blood-brain barrier or the brain. The increased uptake of alpha-aminoisobutyric acid at 11 and 18 h implies that the transfer of other solutes would also be enhanced, that central nervous system homeostasis would be compromised, and that the resulting changes in brain fluid composition could contribute to or cause hepatic encephalopathy

  7. Glucagon-like peptide-1 inhibits blood-brain glucose transfer in humans

    DEFF Research Database (Denmark)

    Lerche, Susanne; Brock, Birgitte; Rungby, Jørgen;

    2008-01-01

    demonstrated that a hormone involved in postprandial glucose regulation also limits glucose delivery to brain tissue and hence provides a possible regulatory mechanism for the link between plasma glucose and brain glucose. Because GLP-1 reduces glucose uptake across the intact blood-brain barrier at normal...... glycemia, GLP-1 may also protect the brain by limiting intracerebral glucose fluctuation when plasma glucose is increased.......OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has many effects on glucose homeostasis, and GLP-1 receptors are broadly represented in many tissues including the brain. Recent research in rodents suggests a protective effect of GLP-1 on brain tissue. The mechanism is unknown. We therefore tested...

  8. Influence of erythrocyte oxygenation and intravascular ATP on resting and exercising skeletal muscle blood flow in humans with mitochondrial myopathy

    DEFF Research Database (Denmark)

    Jeppesen, Tina D; Vissing, John; González-Alonso, José

    2012-01-01

    Oxygen (O(2)) extraction is impaired in exercising skeletal muscle of humans with mutations of mitochondrial DNA (mtDNA), but the muscle hemodynamic response to exercise has never been directly investigated. This study sought to examine the extent to which human skeletal muscle perfusion can...... increase without reductions in blood oxygenation and to determine whether erythrocyte O(2) off-loading and related ATP vascular mechanisms are impaired in humans with mutations of mtDNA. Leg vascular hemodynamic, oxygenation and ATP were investigated in ten patients with mtDNA mutations and ten matched...... healthy control subjects: 1) at rest during normoxia, hypoxia, hyperoxia and intra-femoral artery ATP infusion, and 2) during passive and dynamic one-legged knee-extensor exercises. At rest, blood flow (LBF), femoral arterial and venous blood oxygenation and plasma ATP were similar in the two groups...

  9. 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

  10. Review of lithium effects on brain and blood.

    Science.gov (United States)

    Young, Wise

    2009-01-01

    Clinicians have long used lithium to treat manic depression. They have also observed that lithium causes granulocytosis and lymphopenia while it enhances immunological activities of monocytes and lymphocytes. In fact, clinicians have long used lithium to treat granulocytopenia resulting from radiation and chemotherapy, to boost immunoglobulins after vaccination, and to enhance natural killer activity. Recent studies revealed a mechanism that ties together these disparate effects of lithium. Lithium acts through multiple pathways to inhibit glycogen synthetase kinase-3beta (GSK3 beta). This enzyme phosphorylates and inhibits nuclear factors that turn on cell growth and protection programs, including the nuclear factor of activated T cells (NFAT) and WNT/beta-catenin. In animals, lithium upregulates neurotrophins, including brain-derived neurotrophic factor (BDNF), nerve growth factor, neurotrophin-3 (NT3), as well as receptors to these growth factors in brain. Lithium also stimulates proliferation of stem cells, including bone marrow and neural stem cells in the subventricular zone, striatum, and forebrain. The stimulation of endogenous neural stem cells may explain why lithium increases brain cell density and volume in patients with bipolar disorders. Lithium also increases brain concentrations of the neuronal markers n-acetyl-aspartate and myoinositol. Lithium also remarkably protects neurons against glutamate, seizures, and apoptosis due to a wide variety of neurotoxins. The effective dose range for lithium is 0.6-1.0 mM in serum and >1.5 mM may be toxic. Serum lithium levels of 1.5-2.0 mM may have mild and reversible toxic effects on kidney, liver, heart, and glands. Serum levels of >2 mM may be associated with neurological symptoms, including cerebellar dysfunction. Prolonged lithium intoxication >2 mM can cause permanent brain damage. Lithium has low mutagenic and carcinogenic risk. Lithium is still the most effective therapy for depression. It "cures" a third

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. Accelerated leucine decarboxylation in the rat brain in relation to increased blood ammonia levels during acute hepatic failure.

    Directory of Open Access Journals (Sweden)

    Shiota,Tetsuya

    1984-06-01

    Full Text Available Leucine decarboxylation in rat brain was investigated during acute hepatic failure, induced by partial hepatectomy after carbon tetrachloride (CCl4 pretreatment of rats. These rats presented metabolic alkalosis, and had significantly higher levels of arterial blood and brain ammonia than control and CCl4-treated rats. Brain leucine decarboxylation was elevated in rats with hepatic failure. This alteration correlated with arterial blood ammonia concentrations, and probably with elevated brain ammonia levels, as brain ammonia levels were directly related to arterial blood ammonia.

  16. The in vitro blood-brain barrier model under OGD condition

    DEFF Research Database (Denmark)

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

    of therapies to treat this devastating disease. Materials and Methods - Primary cultures of endothelial cells from bovine brain microvessels were cocultured with rat astrocytes in transwell inserts. At day 11, cells were treated with 4h of OGD by changing the culture medium with glucose-free medium......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...... the wall of brain capillaries. The restrictive nature of the BBB is due to the presence of tight junctions, which seal the paracellular space, a low number of endocytotic vesicles and the presence of efflux transporters, resulting in a very tight layer. Ischemic insult and the subsequent reperfusion...

  17. 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 ...

  18. Could Cord Blood Cell Therapy Reduce Preterm Brain Injury?

    OpenAIRE

    Li, Jingang; McDonald, Courtney A.; Fahey, Michael C.; Jenkin, Graham; Miller, Suzanne L.

    2014-01-01

    Major advances in neonatal care have led to significant improvements in survival rates for preterm infants, but this occurs at a cost, with a strong causal link between preterm birth and neurological deficits, including cerebral palsy (CP). Indeed, in high-income countries, up to 50% of children with CP were born preterm. The pathways that link preterm birth and brain injury are complex and multifactorial, but it is clear that preterm birth is strongly associated with damage to the white matt...

  19. 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.

  20. 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.

  1. 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.

  2. A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain.

    Directory of Open Access Journals (Sweden)

    Shang Ma

    Full Text Available Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in promoting angiogenesis throughout the central nervous system. To determine the roles that astrocytes may play during brain angiogenesis, we employ genetic approaches to inhibit astrogliogenesis during perinatal corticogenesis and examine its effects on brain vessel development. We find that conditional deletion from glial progenitors of orc3, a gene required for DNA replication, dramatically reduces glial progenitor cell number in the subventricular zone and astrocytes in the early postnatal cerebral cortex. This, in turn, results in severe reductions in both the density and branching frequency of cortical blood vessels. Consistent with a delayed growth but not regression of vessels, we find neither significant net decreases in vessel density between different stages after normalizing for cortical expansion nor obvious apoptosis of endothelial cells in these mutants. Furthermore, concomitant with loss of astroglial interactions, we find increased endothelial cell proliferation, enlarged vessel luminal size as well as enhanced cytoskeletal gene expression in pericytes, which suggests compensatory changes in vascular cells. Lastly, we find that blood vessel morphology in mutant cortices recovers substantially at later stages, following astrogliosis. These results thus implicate a functional requirement for astroglia in promoting blood vessel growth during brain development.

  3. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    Directory of Open Access Journals (Sweden)

    Sharabi Shirley

    2016-03-01

    Full Text Available Electroporation-based therapies such as electrochemotherapy (ECT and irreversible electroporation (IRE are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This model can be used for individual treatment planning.

  4. A statistical model describing combined irreversible electroporation and electroporation-induced blood-brain barrier disruption

    OpenAIRE

    Sharabi Shirley; Kos Bor; Last David; Guez David; Daniels Dianne; Harnof Sagi; Mardor Yael; Miklavcic Damijan

    2016-01-01

    Background Electroporation-based therapies such as electrochemotherapy (ECT) and irreversible electroporation (IRE) are emerging as promising tools for treatment of tumors. When applied to the brain, electroporation can also induce transient blood-brain-barrier (BBB) disruption in volumes extending beyond IRE, thus enabling efficient drug penetration. The main objective of this study was to develop a statistical model predicting cell death and BBB disruption induced by electroporation. This m...

  5. Enhanced blood-brain barrier transmigration using a novel Transferrin-embedded fluorescent magnetoliposome nanoformulation

    OpenAIRE

    Ding, Hong; Sagar, Vidya; Agudelo, Marisela; Pilakka-Kanthikeel, Sudheesh; Atluri, Venkata Subba Rao; Raymond, Andrea; Thangavel, Samikkannu; Nair, Madhavan P.

    2014-01-01

    Blood-brain barrier (BBB) is considered as the primary impediment barrier for most of drugs. Delivering therapeutic agents to brain is still a big challenge by now. In our study, a dual mechanism, receptor mediation combining with external non-invasive magnetic force, was incorporated together into ferrous magnet-based liposome for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs) with size of ~ 10 nm were synthesized and confirmed by TEM and XRD respectively. The c...

  6. Computational Prediction of Blood-Brain Barrier Permeability Using Decision Tree Induction

    OpenAIRE

    Jörg Huwyler; Felix Hammann; Claudia Suenderhauf

    2012-01-01

    Predicting blood-brain barrier (BBB) permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was co...

  7. Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

    OpenAIRE

    Lakhan, Shaheen E.; Kirchgessner, Annette; Tepper, Deborah; Leonard, Aidan

    2013-01-01

    Ischemic stroke continues to be one of the most challenging diseases in translational neurology. Tissue plasminogen activator (tPA) remains the only approved treatment for acute ischemic stroke, but its use is limited to the first hours after stroke onset due to an increased risk of hemorrhagic transformation over time resulting in enhanced brain injury. In this review we discuss the role of matrix metalloproteinases (MMPs) in blood-brain barrier (BBB) disruption as a consequence of ischemic ...

  8. 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

    Petroleum products with low content of aromatics have been increasingly used during the past years. This study investigates tissue disposition of dearomatised white spirit. In addition, brain neurotransmitter concentrations were measured. Male rats were exposed by inhalation to 0, 400 (2.29 mg...... 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...

  9. 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

  10. 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.

  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. 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. PMID:26551768

  13. 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

  14. Repair of astrocytes, blood vessels, and myelin in the injured brain: possible roles of blood monocytes

    OpenAIRE

    Jeong, Hey-Kyeong; Ji, Kyung-min; Kim, Jun; Jou, Ilo; Joe, Eun-hye

    2013-01-01

    Inflammation in injured tissue has both repair functions and cytotoxic consequences. However, the issue of whether brain inflammation has a repair function has received little attention. Previously, we demonstrated monocyte infiltration and death of neurons and resident microglia in LPS-injected brains (Glia. 2007. 55:1577; Glia. 2008. 56:1039). Here, we found that astrocytes, oligodendrocytes, myelin, and endothelial cells disappeared in the damage core within 1–3 d and then re-appeared at 7...

  15. Core modular blood and brain biomarkers in social defeat mouse model for post traumatic stress disorder

    OpenAIRE

    Yang, Ruoting; Daigle Jr, Bernie J; Muhie, Seid Y; Hammamieh, Rasha; Jett, Marti; Petzold, Linda; Francis J Doyle

    2013-01-01

    Abstract Background Post-traumatic stress disorder (PTSD) is a severe anxiety disorder that affects a substantial portion of combat veterans and poses serious consequences to long-term health. Consequently, the identification of diagnostic and prognostic blood biomarkers for PTSD is of great interest. Previously, we assessed genome-wide gene expression of seven brain regions and whole blood in a social defeat mouse model subjected to various stress co...

  16. 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.

  17. An ex Vivo Model for Evaluating Blood-Brain Barrier Permeability, Efflux, and Drug Metabolism.

    Science.gov (United States)

    Hellman, Karin; Aadal Nielsen, Peter; Ek, Fredrik; Olsson, Roger

    2016-05-18

    The metabolism of drugs in the brain is difficult to study in most species because of enzymatic instability in vitro and interference from peripheral metabolism in vivo. A locust ex vivo model that combines brain barrier penetration, efflux, metabolism, and analysis of the unbound fraction in intact brains was evaluated using known drugs. Clozapine was analyzed, and its major metabolites, clozapine N-oxide (CNO) and N-desmethylclozapine (NDMC), were identified and quantified. The back-transformation of CNO into clozapine observed in humans was also observed in locusts. In addition, risperidone, citalopram, fluoxetine, and haloperidol were studied, and one preselected metabolite for each drug was analyzed, identified, and quantified. Metabolite identification studies of clozapine and midazolam showed that the locust brain was highly metabolically active, and 18 and 14 metabolites, respectively, were identified. The unbound drug fraction of clozapine, NDMC, carbamazepine, and risperidone was analyzed. In addition, coadministration of drugs with verapamil or fluvoxamine was performed to evaluate drug-drug interactions in all setups. All findings correlated well with the data in the literature for mammals except for the stated fact that CNO is a highly blood-brain barrier permeant compound. Overall, the experiments indicated that invertebrates might be useful for screening of blood-brain barrier permeation, efflux, metabolism, and analysis of the unbound fraction of drugs in the brain in early drug discovery. PMID:26930271

  18. 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.

  19. 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.

  20. 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

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    Sitvanit Haziza

    2015-08-01

    Full Text Available 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

  3. 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

  4. Differential oxidative stress and DNA damage in rat brain regions and blood following chronic arsenic exposure.

    Science.gov (United States)

    Mishra, D; Flora, S J S

    2008-05-01

    Chronic arsenic poisoning caused by contaminated drinking water is a wide spread and worldwide problem particularly in India and Bangladesh. One of the possible mechanisms suggested for arsenic toxicity is the generation of reactive oxygen species (ROS). The present study was planned 1) to evaluate if chronic exposure to arsenic leads to oxidative stress in blood and brain - parts of male Wistar rats and 2) to evaluate which brain region of the exposed animals was more sensitive to oxidative injury. Male Wistar rats were exposed to arsenic (50A ppm sodium arsenite in drinking water) for 10A months. The brain was dissected into five major parts, pons medulla, corpus striatum, cortex, hippocampus, and cerebellum. A number of biochemical variables indicative of oxidative stress were studied in blood and different brain regions. Single-strand DNA damage using comet assay was also assessed in lymphocytes. We observed a significant increase in blood and brain ROS levels accompanied by the depletion of GSH/GSSG ratio and glucose-6-phosphate dehydrogenase (G6PD) activity in different brain regions of arsenic-exposed rats. Chronic arsenic exposure also caused significant single-strand DNA damage in lymphocytes as depicted by comet with a tail in arsenic-exposed cells compared with the control cells. On the basis of results, we concluded that the cortex region of the brain was more sensitive to oxidative injury compared with the other regions studied. The present study, thus, leads us to suggest that arsenic induces differential oxidative stress in brain regions with cortex followed by hippocampus and causes single-strand DNA damage in lymphocytes.

  5. Effect of floorball training on blood lipids, body composition, muscle strength, and functional capacity of elderly men

    DEFF Research Database (Denmark)

    Petersen, Jacob Vorup; Pedersen, Mogens Theisen; Melcher, Pia Grethe Sandfeld;

    2016-01-01

    the effect of floorball training on blood lipids, muscle strength, body composition, and functional capacity of men aged 65-76 years. Thirty-nine recreational active men were randomized into a floorball group (FG; n = 22) or petanque group (PG; n = 17), in which training was performed 1 h twice a week for 12...

  6. AMYLOID BETA ACCUMULATION IN HIV-1-INFECTED BRAIN: THE ROLE OF THE BLOOD BRAIN BARRIER

    OpenAIRE

    András, Ibolya E.; Toborek, Michal

    2012-01-01

    In recent years we face an increase in the aging of the HIV-1-infected population, which is not only due to effective antiretroviral therapy but also to new infections among older people. Even with the use of the antiretroviral therapy, HIV-associated neurocognitive disorders represent an increasing problem as the HIV-1-infected population ages. Increased amyloid beta (Aβ) deposition is characteristic of HIV-1-infected brains, and it has been hypothesized that brain vascular dysfunction contr...

  7. Toward Eradicating HIV Reservoirs in the Brain: Inhibiting P-glycoprotein at the Blood-Brain Barrier with Prodrug Abacavir Dimers

    OpenAIRE

    Namanja, Hilda A.; Emmert, Dana; Davis, David A.; Campos, Christopher; Miller, David S.; Hrycyna, Christine A.; Chmielewski, Jean

    2011-01-01

    Eradication of HIV reservoirs in the brain necessitates penetration of antiviral agents across the blood-brain barrier (BBB), a process limited by drug efflux proteins such as P-glycoprotein (P-gp) at the membrane of brain capillary endothelial cells. We present an innovative chemical strategy toward the goal of therapeutic brain penetration of the P-gp substrate and anti-viral agent abacavir, in conjunction with a traceless tether. Dimeric prodrugs of abacavir were designed to have two funct...

  8. Sensitivity analysis aimed at blood vessels detection using interstitial optical tomography during brain needle biopsy procedures.

    Science.gov (United States)

    Pichette, Julien; Goyette, Andréanne; Picot, Fabien; Tremblay, Marie-Andrée; Soulez, Gilles; Wilson, Brian C; Leblond, Frédéric

    2015-11-01

    A brain needle biopsy procedure is performed for suspected brain lesions in order to sample tissue that is subsequently analysed using standard histopathology techniques. A common complication resulting from this procedure is brain hemorrhaging from blood vessels clipped off during tissue extraction. Interstitial optical tomography (iOT) has recently been introduced by our group as a mean to assess the presence of blood vessels in the vicinity of the needle. The clinical need to improve safety requires the detection of blood vessels within 2 mm from the outer surface of the needle, since this distance is representative of the volume of tissue that is aspirated durirng tissue extraction. Here, a sensitivity analysis is presented to establish the intrinsic detection limits of iOT based on simulations and experiments using brain tissue phantoms. It is demonstrated that absorbers can be detected with diameters >300 μm located up to >2 mm from the biopsy needle core for bulk optical properties consistent with brain tissue. PMID:26600990

  9. 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.

  10. Examining the Uptake of Central Nervous System Drugs and Candidates across the Blood-Brain Barrier.

    Science.gov (United States)

    Summerfield, Scott G; Zhang, Yanyan; Liu, Houfu

    2016-08-01

    Assessing the equilibration of the unbound drug concentrations across the blood-brain barrier (Kp,uu) has progressively replaced the partition coefficient based on the ratio of the total concentration in brain tissue to blood (Kp). Here, in vivo brain distribution studies were performed on a set of central nervous system (CNS)-targeted compounds in both rats and P-glycoprotein (P-gp) genetic knockout mice. Several CNS drugs are characterized by Kp,uu values greater than unity, inferring facilitated uptake across the rodent blood-brain barrier (BBB). Examples are shown in which Kp,uu also increases above unity on knockout of P-gp, highlighting the composite nature of this parameter with respect to facilitated BBB uptake, efflux, and passive diffusion. Several molecules with high Kp,uu values share common structural elements, whereas uptake across the BBB appears more prevalent in the CNS-targeted drug set than the chemical templates being generated within the current lead optimization paradigm. Challenges for identifying high Kp,uu compounds are discussed in the context of acute versus steady-state data and cross-species differences. Evidently, there is a need for better predictive models of human brain Kp,uu. PMID:27194478

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

    NARCIS (Netherlands)

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

    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

  12. 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

  13. 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

  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. Reproductive hormones regulate the selective permeability of the blood-brain barrier

    OpenAIRE

    Wilson, Andrea C.; Clemente, Luca; Liu, Tianbing; Bowen, Richard L.; Meethal, Sivan Vadakkadath; Atwood, Craig S.

    2008-01-01

    Reproductive hormones regulate the selective permeability of the blood-brain barrier : Current address: Department of Biochemistry, Colorado State University, CO, USA. (Clemente, Luca) correspondence: Corresponding author. University of Wisconsin-Madison Medical School, Wm S. Middleton Memorial VA (GRECC 11G), 2500 Overlook Terrace, Madison, WI 53705, USA. Tel.: +1 608 256 1901x11664; fax: +1 608 280 7291. (Atw...

  16. On ultrasound-induced microbubble oscillation in a capillary blood vessel and its implications for the blood-brain barrier

    Science.gov (United States)

    Wiedemair, W.; Tuković, Ž.; Jasak, H.; Poulikakos, D.; Kurtcuoglu, V.

    2012-02-01

    The complex interaction between an ultrasound-driven microbubble and an enclosing capillary microvessel is investigated by means of a coupled, multi-domain numerical model using the finite volume formulation. This system is of interest in the study of transient blood-brain barrier disruption (BBBD) for drug delivery applications. The compliant vessel structure is incorporated explicitly as a distinct domain described by a dedicated physical model. Red blood cells (RBCs) are taken into account as elastic solids in the blood plasma. We report the temporal and spatial development of transmural pressure (Ptm) and wall shear stress (WSS) at the luminal endothelial interface, both of which are candidates for the yet unknown mediator of BBBD. The explicit introduction of RBCs shapes the Ptm and WSS distributions and their derivatives markedly. While the peak values of these mechanical wall parameters are not affected considerably by the presence of RBCs, a pronounced increase in their spatial gradients is observed compared to a configuration with blood plasma alone. The novelty of our work lies in the explicit treatment of the vessel wall, and in the modelling of blood as a composite fluid, which we show to be relevant for the mechanical processes at the endothelium.

  17. P-glycoprotein activity in the blood-brain barrier is affected by virus-induced neuroinflammation and antipsychotic treatment

    NARCIS (Netherlands)

    Doorduin, Janine; de Vries, Erik F. J.; Dierckx, Rudi A.; Klein, Hans C.

    2014-01-01

    A large percentage of schizophrenic patients respond poorly to antipsychotic treatment. This could be explained by inefficient drug transport across the blood-brain barrier due to P-glycoprotein mediated efflux. P-glycoprotein activity and expression in the blood-brain barrier can be affected by inf

  18. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier?

    Directory of Open Access Journals (Sweden)

    Tina Sartorius

    Full Text Available It is a matter of debate whether impaired insulin action originates from a defect at the neural level or impaired transport of the hormone into the brain. In this study, we aimed to investigate the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.Insulin, glucose and albumin concentrations were determined in 160 paired human serum and cerebrospinal fluid (CSF samples. Additionally, insulin was applied in young and aged mice by subcutaneous injection or intracerebroventricularly to circumvent the blood-brain barrier. Insulin action and cortical activity were assessed by Western blotting and electrocorticography radiotelemetric measurements.In humans, CSF glucose and insulin concentrations were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Western blot analysis in murine whole brain lysates revealed impaired phosphorylation of AKT (P-AKT in aged mice following peripheral insulin stimulation whereas P-AKT was comparable to levels in young mice after intracerebroventricular insulin application. As readout for insulin action in the brain, insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. When insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.This study discloses age-dependent changes in insulin CSF/serum ratios in humans. In the elderly, cerebral insulin resistance might be partially attributed to an impaired transport of insulin into the central nervous system.

  19. Blood brain barrier dysfunction and delayed neurological deficits in mild traumatic brain injury induced by blast shock waves.

    Science.gov (United States)

    Shetty, Ashok K; Mishra, Vikas; Kodali, Maheedhar; Hattiangady, Bharathi

    2014-01-01

    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 (TJ) 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 (CTE) 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. PMID:25165433

  20. 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.

  1. Immunological changes in human blood and skeletal muscle in response to physical exercise

    OpenAIRE

    Malm, Christer

    2001-01-01

    Pysical exercise is essential for maintaining normal function of skeletal muscle. Muscle tissue also has a remarkable capacity for adaptation to changes in physical demand. In fact, without stimulation from physical activity, muscle tissue will atrophy. The mechanisms responsible for increases or decreases in muscle function are to a large extent not known. According to current opinions, one consequence of physical exercise can be muscle cell damage and inflammation. The inf...

  2. 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.

  3. 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.

  4. 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.

  5. The blood-brain barrier in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, L; Tfelt-Hansen, P

    2008-01-01

    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......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...... with special emphasize on the triptans and calcitonin gene-related peptide (CGRP). The human experimental headache model, especially the use of glycerol trinitrate (the nitric oxide model), and experiences with CGRP administrations utilize the systemic administration of the agonists with effects on other...

  6. 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

  7. Blood-brain barrier transport of short proline-rich antimicrobial peptides.

    Science.gov (United States)

    Stalmans, Sofie; Wynendaele, Evelien; Bracke, Nathalie; Knappe, Daniel; Hoffmann, Ralf; Peremans, Kathelijne; Polis, Ingeborgh; Burvenich, Christian; De Spiegeleer, Bart

    2014-04-01

    Infections by antibiotic-resistant bacteria are becoming a great risk for human health, leading to an urgent need for new efficient antibacterial therapies. The short, proline-rich antimicrobial peptides from insects gained a lot of interest as a potential antibacterial treatment, having a low toxicity profile and being mainly active against Gram-negative bacteria. To know whether these antimicrobial peptides can be used for the treatment of cerebral infections, the blood-brain barrier transport characteristics of these peptides were investigated. This study describes the results of the in vivo blood-brain barrier experiments in mice, as well as the in vitro metabolic stability in mouse plasma and brain of apidaecin Api137, oncocin, drosocin and drosocin Pro5Hyp. The four investigated peptides showed a significant influx into the brain with a K(in) ranging between 0.37 and 0.86 µL/g x min and brain distribution volumes of 19.6 to 25.8 µL/g. Only for drosocin, a significant efflux was determined, with a k(out) of 0.22 min(-1). After entering the brain, oncocin was for approximately 80% trapped in the endothelial cells, while the other peptides reached the brain parenchyma for about 70%. All peptides were stable in plasma and brain during the experiments, with estimated metabolic half-lives ranging between 47 min and 637 min. We conclude that the investigated short, proline-rich antimicrobial peptides show an influx into the brain, which make them a promising antibacterial treatment of cerebral infections.

  8. Reliability of the Modified Ashworth Scale in the Assessment of Plantarflexor Muscle Spasticity in Patients with Traumatic Brain Injury.

    Science.gov (United States)

    Allison, S. C.; And Others

    1996-01-01

    This attempt to determine the reliability of the Modified Ashworth Scale for assessing the severity of muscle spasticity for ankle plantarflexors in 30 patients with traumatic brain injury concluded that the reliability was minimally adequate to support the scale's continued use. Interrater reliability was less than that previously reported for…

  9. Next generation of non-mammalian blood-brain barrier models to study parasitic infections of the central nervous system

    Science.gov (United States)

    Siddiqui, Ruqaiyyah; Edwards-Smallbone, James; Flynn, Robin; Khan, Naveed Ahmed

    2012-01-01

    Transmigration of neuropathogens across the blood-brain barrier is a key step in the development of central nervous system infections, making it a prime target for drug development. The ability of neuropathogens to traverse the blood-brain barrier continues to inspire researchers to understand the specific strategies and molecular mechanisms that allow them to enter the brain. The availability of models of the blood-brain barrier that closely mimic the situation in vivo offers unprecedented opportunities for the development of novel therapeutics. PMID:21921682

  10. 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.

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. Acute arginine supplementation fails to improve muscle endurance or affect blood pressure responses to resistance training.

    Science.gov (United States)

    Greer, Beau K; Jones, Brett T

    2011-07-01

    Dietary supplement companies claim that arginine supplements acutely enhance skeletal muscular endurance. The purpose of this study was to determine whether acute arginine α-ketoglutarate supplementation (AAKG) will affect local muscle endurance of the arm and shoulder girdle or the blood pressure (BP) response to anaerobic exercise. Twelve trained college-aged men (22.6 ± 3.8 years) performed 2 trials of exercise separated by at least 1 week. At 4 hours before, and 30 minutes before exercise, a serving of an AAKG supplement (3,700 mg arginine alpha-ketoglutarate per serving) or placebo was administered. Resting BP was assessed pre-exercise after 16 minutes of seated rest, and 5 and 10 minutes postexercise. Three sets each of chin-ups, reverse chin-ups, and push-ups were performed to exhaustion with 3 minutes of rest between each set. Data were analyzed using repeated-measures analysis of variance and paired t-tests. The AAKG supplementation did not improve muscle endurance or significantly affect the BP response to anaerobic work. Subjects performed fewer total chin-ups (23.75 ± 6.38 vs. 25.58 ± 7.18) and total trial repetitions (137.92 ± 28.18 vs. 141.08 ± 28.57) in the supplement trial (p ≤ 0.05). Subjects executed fewer reverse chin-ups (5.83 ± 1.85 vs. 6.75 ± 2.09) during set 2 after receiving the supplement as compared to the placebo (p AAKG supplementation may hinder muscular endurance, the use of these supplements before resistance training should be questioned. PMID:21399536

  18. 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...... was released as (13)CO(2) with 100%+/-24%, 86%+/-15%, and 87%+/-30% at rest with and without lactate infusion and during exercise, respectively. The contribution of systemic lactate to cerebral energy expenditure was 8%+/-2%, 19%+/-4%, and 27%+/-4% for the respective conditions. In conclusion, systemic lactate...... 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....

  19. 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.

  20. 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.

  1. High muscle blood flow in man: is maximal O2 extraction compromised?

    Science.gov (United States)

    Richardson, R S; Poole, D C; Knight, D R; Kurdak, S S; Hogan, M C; Grassi, B; Johnson, E C; Kendrick, K F; Erickson, B K; Wagner, P D

    1993-10-01

    During conventional cycle ergometry, as work rate (WR) is increased toward maximum, O2 extraction increases hyperbolically, typically achieving values of 80-90% at peak O2 uptake (VO2). In contrast, studies using isolated knee-extensor exercise report much higher mass-specific blood flows (Q) and lower maximal O2 extractions (approximately 70%), which have been interpreted as transit time limitation to O2 movement out of the muscle capillary. However, maximal achievable WR levels during conventional cycle ergometry are generally reached (over 10-15 min) after rapid increases in WR, whereas the reported knee-extensor studies have used only more lengthy protocols (45 min). The duration of these protocols may have prevented the attainment of high WR levels and thus high O2 extraction ratios. Accordingly, this investigation examined leg Q and O2 extraction responses during single-leg knee-extensor exercise incremented rapidly (steps of 15-25 W per 2- to 3-min interval), which produced fatigue in 13-15 min. Q and muscle VO2 increased linearly with WR to fatigue with Q-WR and VO2-WR slopes similar to those reported in previous knee-extensor studies. However, with the use of this protocol, very high maximal achievable WR [99 +/- 6 (SE) W] and muscle Q (385 +/- 26 ml.min-1 x 100 g-1) levels were attained, some 80% greater than previously reported. An O2 extraction of 84.6 +/- 2.1% was reached, giving a maximal VO2 of 60.2 +/- 5.8 ml.min-1 x 100 g-1. We conclude that, even under the high Q conditions of single-leg knee-extensor exercise, O2 extraction does not reach a plateau on the basis of short transit times and that previous conclusions to the contrary reflect failure to attain sufficiently high WR levels. Maximal VO2, Q, and O2 extraction in this model have yet to be defined. PMID:8282650

  2. 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

  3. Kinetics of creatine in blood and brain after intraperitoneal injection in the rat.

    Science.gov (United States)

    Perasso, Luisa; Cupello, Aroldo; Lunardi, Gian Luigi; Principato, Cristina; Gandolfo, Carlo; Balestrino, Maurizio

    2003-06-01

    Creatine has in recent years raised the interest of the neurologist, because it has been used in children with hereditary disorders of creatine metabolism and because experimental data suggest that it may exert a protective effect against various neurological diseases including stroke. Moreover, it is widely used as a nutritional supplement. It is well known that creatine crosses the blood-brain barrier with difficulty, however its accumulation into the brain after systemic administration is still not completely known. In the present experiments we studied its accumulation into rat brain tissue after intraperitoneal (i.p.) single or repeated injections. After a single injection of 160 mg/kg, radioactively labelled creatine (14C-creatine) entered the brain to a limited extent. It reached a plateau value of around 70 microM above baseline, that remained stable for at least 9 h. This amount of exogenous creatine obviously added to the endogenous creatine store. This increase is a minor one, since endogenous creatine has a brain concentration of about 10 mM. In accordance with this conclusion, when single or repeated injections of unlabelled ('cold') creatine were administered to rats, no sizable increase could be measured with high-performance liquid chromatography in the brain levels of either this compound or its phosphorylated derivative, phosphocreatine. Although our data clearly show some passage of serum creatine into the brain, other strategies are needed to improve passage of creatine across the blood-brain barrier in a way that it may be suitable to treat acute conditions like stroke. PMID:12742622

  4. 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.

  5. 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

  6. Sex Steroids Influence Brain-Derived Neurotropic Factor Secretion From Human Airway Smooth Muscle Cells.

    Science.gov (United States)

    Wang, Sheng-Yu; Freeman, Michelle R; Sathish, Venkatachalem; Thompson, Michael A; Pabelick, Christina M; Prakash, Y S

    2016-07-01

    Brain derived neurotropic factor (BDNF) is emerging as an important player in airway inflammation, remodeling, and hyperreactivity. Separately, there is increasing evidence that sex hormones contribute to pathophysiology in the lung. BDNF and sex steroid signaling are thought to be intricately linked in the brain. There is currently little information on BDNF and sex steroid interactions in the airway but is relevant to understanding growth factor signaling in the context of asthma in men versus women. In this study, we assessed the effect of sex steroids on BDNF expression and secretion in human airway smooth muscle (ASM). Human ASM was treated with estrogen (E2 ) or testosterone (T, 10 nM each) and intracellular BDNF and secreted BDNF measured. E2 and T significantly reduced secretion of BDNF; effects prevented by estrogen and androgen receptor inhibitor, ICI 182,780 (1 μM), and flutamide (10 μM), respectively. Interestingly, no significant changes were observed in intracellular BDNF mRNA or protein expression. High affinity BDNF receptor, TrkB, was not altered by E2 or T. E2 (but not T) significantly increased intracellular cyclic AMP levels. Notably, Epac1 and Epac2 expression were significantly reduced by E2 and T. Furthermore, SNARE complex protein SNAP25 was decreased. Overall, these novel data suggest that physiologically relevant concentrations of E2 or T inhibit BDNF secretion in human ASM, suggesting a potential interaction of sex steroids with BDNF in the airway that is different from brain. The relevance of sex steroid-BDNF interactions may lie in their overall contribution to airway diseases such as asthma. J. Cell. Physiol. 231: 1586-1592, 2016. © 2015 Wiley Periodicals, Inc. PMID:26566264

  7. 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. PMID:27374823

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

    International Nuclear Information System (INIS)

    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. (paper)

  9. 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.

  10. 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

  11. Cellular response of the blood-brain barrier to injury: Potential biomarkers and therapeutic targets for brain regeneration.

    Science.gov (United States)

    Tenreiro, M M; Ferreira, R; Bernardino, L; Brito, M A

    2016-07-01

    Endothelial cells are the main component of the blood-brain barrier (BBB), a vital structure for maintaining brain homeostasis that is seriously disrupted in various neurological pathologies. Therefore, vascular-targeted therapies may bring advantages for the prevention and treatment of brain disorders. In this sense, novel methods to identify and evaluate endothelial damage have been developed and include the detection of circulating endothelial cells, endothelial progenitor cells, endothelial microparticles and exosomes. These cells and cellular structures have been documented in numerous diseases, and increasingly in neurodegenerative disorders, which have led many to assume that they can either be possible biomarkers or tools of repair. Therefore, the purpose of this review is to discuss available data on BBB endothelial damage occurring in two pathologies of the central nervous system, Alzheimer's disease and stroke, which exemplify conditions where chronic and acute vascular damage occur, respectively. The ultimate goal is to identify useful biomarkers and/or therapeutic tools in the healthy and diseased brain that can be used for the treatment of neurodegenerative diseases where BBB permeability and integrity are impaired. PMID:26996728

  12. Cerebral circulation, metabolism, and blood-brain barrier of rats in hypocapnic hypoxia

    Energy Technology Data Exchange (ETDEWEB)

    Beck, T.; Krieglstein, J.

    1987-03-01

    The effects of hypoxic hypoxia on physiological variables, cerebral circulation, cerebral metabolism, and blood-brain barrier were investigated in conscious, spontaneously breathing rats by exposing them to an atmosphere containing 7% O/sub 2/. Hypoxia affected a marked hypotension, hypocapnia and alkalosis. Cortical tissue high-energy phosphates and glucose content were not affected by hypoxia, glucose 6-phosphate lactate, and pyruvate levels were significantly increased. Blood-brain barrier permeability, regional brain glucose content and lumped constant were not changed by hypoxia. Local cerebral glucose utilization (LCGU) rose by 40-70% of control values in gray matter and by 80-90% in white matter. Under hypoxia, columns of increased and decreased LCGU and were detectable in cortical gray matter. Color-coded (/sup 14/C)2-deoxy-D-glucose autoradiograms of rat brain are shown. Local cerebral blood flow (LCBF) increased by 50-90% in gray matter and by up to 180% in white matter. Coupling between LCGU and LCBF in hypoxia remained unchanged. The data suggests a stimulation of glycolysis, increased glucose transport into the cell, and increased hexokinase activity. The physiological response of gray and white matter to hypoxia obviously differs. Uncoupling of the relation between LCGU and LCBF does not occur.

  13. 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).

  14. 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.

  15. 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.

  16. [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.

  17. 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.

  18. Muscle size and arterial stiffness after blood flow-restricted low-intensity resistance training in older adults.

    Science.gov (United States)

    Yasuda, T; Fukumura, K; Fukuda, T; Uchida, Y; Iida, H; Meguro, M; Sato, Y; Yamasoba, T; Nakajima, T

    2014-10-01

    Previous studies have shown that blood flow-restricted low-intensity resistance training (BFR-RT) causes muscle hypertrophy while maintaining arterial function in young adults. We examined the effects of BFR-RT on muscle size and arterial stiffness in older adults. Healthy subjects (ages 61-84 years) were divided into BFR-RT (n = 9) or non-training control (CON; n = 10) groups. The BFR-RT group performed 20% and 30%, respectively, of one-repetition maximal (1-RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR-RT group wore elastic cuffs (120-270 mmHg) on both legs during training. Magnetic resonance imaging-measured muscle cross-sectional area (CSA), 1-RM strength, chair stand (CS) test, and cardio-ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before and 3-5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors (6.5%), and gluteus maximus (4.4%), leg extension and leg press 1-RM strength (26.1% and 33.4%), and CS performance (18.3%) improved (P testing, there were no changes in both two groups. In conclusion, BFR-RT improves muscle CSA as well as maximal muscle strength, but does not negatively affect arterial stiffness or humeral coagulation factors in older adults. PMID:23730848

  19. 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.

  20. Insulin Detemir is Not Transported Across the Blood-Brain Barrier

    OpenAIRE

    Banks, William A.; Morley, John E.; Lynch, Jessica L.; Lynch, Kristin M.; Mooradian, Arshag D.

    2010-01-01

    Insulin detemir has a different profile of action on the central nervous system (CNS) than human insulin. It has been hypothesized that this is caused by an altered ability of insulin detemir to cross the blood-brain barrier (BBB). Here, we measured the permeability of the BBB to insulin detemir. We labeled insulin detemir with radioactive iodine (I-Det) and examined its ability to cross the BBB of the mouse. Permeation was assessed after intravenous injection and by brain perfusion in the pr...

  1. In Situ Blood-Brain Barrier Permeability of a C-10 Paclitaxel Carbamate

    OpenAIRE

    Ballatore, Carlo; Zhang, Bin; Trojanowski, John Q.; Lee, Virginia M.-Y.; Smith, Amos B.

    2008-01-01

    We report the synthesis and blood-brain barrier (BBB) permeability of 14C-CNDR-29, a paclitaxel C-10 carbamate derivative shown to be devoid of P-glycoprotein (Pgp)-interactions, in an in situ mouse brain perfusion model, in comparison with 14C-paclitaxel. The results presented reveal a 3–4 fold higher BBB-permeability for the C-10 modified taxane compared to paclitaxel. These results support the notion that circumvention of Pgp-mediated efflux can lead to higher BBB-permeability. Further stu...

  2. 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.

  3. Mitochondrial energetic metabolism perturbations in skeletal muscles and brain of zebrafish (Danio rerio) exposed to low concentrations of waterborne uranium

    International Nuclear Information System (INIS)

    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 μg 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 μg/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.

  4. 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.

  5. Optically enhanced blood-brain-barrier crossing of plasmonic-active nanoparticles in preclinical brain tumor animal models

    Science.gov (United States)

    Yuan, Hsiangkuo; Wilson, Christy M.; Li, Shuqin; Fales, Andrew M.; Liu, Yang; Grant, Gerald; Vo-Dinh, Tuan

    2014-02-01

    Nanotechnology provides tremendous biomedical opportunities for cancer diagnosis, imaging, and therapy. In contrast to conventional chemotherapeutic agents where their actual target delivery cannot be easily imaged, integrating imaging and therapeutic properties into one platform facilitates the understanding of pharmacokinetic profiles, and enables monitoring of the therapeutic process in each individual. Such a concept dubbed "theranostics" potentiates translational research and improves precision medicine. One particular challenging application of theranostics involves imaging and controlled delivery of nanoplatforms across blood-brain-barrier (BBB) into brain tissues. Typically, the BBB hinders paracellular flux of drug molecules into brain parenchyma. BBB disrupting agents (e.g. mannitol, focused ultrasound), however, suffer from poor spatial confinement. It has been a challenge to design a nanoplatform not only acts as a contrast agent but also improves the BBB permeation. In this study, we demonstrated the feasibility of plasmonic gold nanoparticles as both high-resolution optical contrast agent and focalized tumor BBB permeation-inducing agent. We specifically examined the microscopic distribution of nanoparticles in tumor brain animal models. We observed that most nanoparticles accumulated at the tumor periphery or perivascular spaces. Nanoparticles were present in both endothelial cells and interstitial matrices. This study also demonstrated a novel photothermal-induced BBB permeation. Fine-tuning the irradiating energy induced gentle disruption of the vascular integrity, causing short-term extravasation of nanomaterials but without hemorrhage. We conclude that our gold nanoparticles are a powerful biocompatible contrast agent capable of inducing focal BBB permeation, and therefore envision a strong potential of plasmonic gold nanoparticle in future brain tumor imaging and therapy.

  6. 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, J L;

    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 uni...

  7. 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...

  8. 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.

  9. 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

  10. 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 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...... 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...

  11. 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.

  12. Cellular Apoptosis and Blood Brain Barrier Permeability Changes in the Pre-Incubated Chicken Embryo’s Brain by Effect of Electromagnetic Fields

    OpenAIRE

    Sima Kalantari; Mohammad Reza Bigdeli; Maryam Shams-Lahijani

    2015-01-01

    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 ...

  13. 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

  14. Tailored delivery of analgesic ziconotide across a blood brain barrier model using viral nanocontainers

    OpenAIRE

    Prachi Anand; Alison O’Neil; Emily Lin; Trevor Douglas; Mandë Holford

    2015-01-01

    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 nanocon...

  15. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

    OpenAIRE

    Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Julie E Simpson; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E.; Hirst, Mark C; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J.; Romero, Ignacio Andres

    2014-01-01

    Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-15...

  16. The Effects of Psychostimulant Drugs on Blood Brain Barrier Function and Neuroinflammation

    OpenAIRE

    Kousik, Sharanya M.; T. Celeste eNapier; Carvey, Paul M.

    2012-01-01

    The blood brain barrier (BBB) is a highly dynamic interface between the central nervous system (CNS) and periphery. The BBB is comprised of a number of components and is part of the larger neuro(glio)vascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicoti...

  17. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

    OpenAIRE

    Renée J Turner; Sharp, Frank R.

    2016-01-01

    Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen...

  18. Diffuse optical correlation tomography of cerebral blood flow during cortical spreading depression in rat brain

    Science.gov (United States)

    Zhou, Chao; Yu, Guoqiang; Furuya, Daisuke; Greenberg, Joel; Yodh, Arjun; Durduran, Turgut

    2006-02-01

    Diffuse optical correlation methods were adapted for three-dimensional (3D) tomography of cerebral blood flow (CBF) in small animal models. The image reconstruction was optimized using a noise model for diffuse correlation tomography which enabled better data selection and regularization. The tomographic approach was demonstrated with simulated data and during in-vivo cortical spreading depression (CSD) in rat brain. Three-dimensional images of CBF were obtained through intact skull in tissues(~4mm) deep below the cortex.

  19. 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), ...

  20. The Role of Lumbar Sympathetic Nerves in Regulation of Blood Flow to Skeletal Muscle during Anaphylactic Hypotension in Anesthetized Rats.

    Directory of Open Access Journals (Sweden)

    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.

  1. Management of initial orthostatic hypotension: lower body muscle tensing attenuates the transient arterial blood pressure decrease upon standing from squatting

    OpenAIRE

    Go-Schön, Ingeborg K.; Kim, Yu-Sok; Linzer, Mark; van Lieshout, Johannes J.; Wieling, Wouter; Krediet, C. T. Paul

    2007-01-01

    Abstract Initial orthostatic hypotension (IOH) comprises symptoms of cerebral hypoperfusion caused by an abnormally large transient mean arterial blood pressure (MAP) decrease 5-15 s after arising from a supine, sitting or squatting position. Few treatment options are available. We set out to test the hypothesis that lower body muscle tensing (LBMT) attenuates IOH after rising from squatting and its symptoms in daily life. Thirteen IOH patients (9 males, 27 years) rose twice from s...

  2. 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.

  3. 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.

  4. Human blood-brain barrier insulin-like growth factor receptor

    International Nuclear Information System (INIS)

    Insulin-like growth factor (IGF)-1 and IGF-2, may be important regulatory molecules in the CNS. Possible origins of IGFs in brain include either de novo synthesis or transport of circulating IGFs from blood into brain via receptor mediated transcytosis mechanisms at the brain capillary endothelial wall, ie, the blood-brain barrier (BBB). In the present studies, isolated human brain capillaries are used as an in vitro model system of the human BBB and the characteristics of IGF-1 or IGF-2 binding to this preparation were assessed. The total binding of IGF-2 at 37 degrees C exceeded 130% per mg protein and was threefold greater than the total binding for IGF-1. However, at 37 degrees C nonsaturable binding equaled total binding, suggesting that endocytosis is rate limiting at physiologic temperatures. Binding studies performed at 4 degrees C slowed endocytosis to a greater extent than membrane binding, and specific binding of either IGF-1 or IGF-2 was detectable. Scatchard plots for either peptide were linear and the molar dissociation constant of IGF-1 and IGF-2 binding was 2.1 +/- 0.4 and 1.1 +/- 0.1 nmol/L, respectively. Superphysiologic concentrations of porcine insulin inhibited the binding of both IGF-1 (ED50 = 2 micrograms/mL) and IGF-2 (ED50 = 0.5 microgram/mL). Affinity cross linking of 125I-IGF-1, 125I-IGF-2, and 125I-insulin to isolated human brain capillaries was performed using disuccinimidylsuberate (DSS). These studies revealed a 141 kd binding site for both IGF-1 and IGF-2, and a 133 kd binding site for insulin

  5. Blood-compatible poly(2-methoxyethyl acrylate) for the adhesion and proliferation of endothelial and smooth muscle cells.

    Science.gov (United States)

    Sato, Chikako; Aoki, Makiko; Tanaka, Masaru

    2016-09-01

    Thrombus formation presents a serious hindrance in the development of functional artificial blood vessels, especially those with a small diameter. Endothelialization can prevent thrombus formation; however, the adhesion of endothelial cells to existing polymer materials is generally weak. Therefore, polymers that have both anti-thrombotic and endothelialization properties do not currently exist. We previously reported that platelets do not adhere to poly(2-methoxyethyl acrylate) (PMEA) or poly(tetrahydrofurfuryl acrylate)(PTHFA). Here, we investigated whether endothelial cells and smooth muscle cells, both of which are blood vessel components, could adhere to these synthetic polymers. Polyethylene terephthalate films were coated with PMEA and PTHFA using a spin-coater. Human umbilical vein endothelial cells or aorta smooth muscle cells were seeded on the polymer surfaces, after which we analyzed the number of adherent cells, their morphologies and vinculin expression. We found that both endothelial and smooth muscle cells adhered to PMEA and PTHFA, while platelets did not. We propose that, by using PMEA and PTHFA with no modifications, it should be possible to develop artificial blood vessels with both anti-thrombotic and endothelialization properties. In addition, we discuss the mechanism of selective cell adhesion in PMEA and PTHFA. PMID:27285730

  6. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

    Directory of Open Access Journals (Sweden)

    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

  7. Modelling blood flow and metabolism in the piglet brain during hypoxia-ischaemia: simulating brain energetics.

    Science.gov (United States)

    Moroz, Tracy; Hapuarachchi, Tharindi; Bainbridge, Alan; Price, David; Cady, Ernest; Baer, Ether; Tachtsidis, Ilias; Broad, Kevin; Ezzati, Mojgan; Robertson, Nicola J; Thomas, David; Golay, Xavier; Cooper, Chris E

    2013-01-01

    We have developed a computational model to simulate hypoxia-ischaemia (HI) in the neonatal piglet brain. It has been extended from a previous model by adding the simulation of carotid artery occlusion and including pH changes in the cytoplasm. Here, simulations from the model are compared with near-infrared spectroscopy (NIRS) and phosphorus magnetic resonance spectroscopy (MRS) measurements from two piglets during HI and short-term recovery. One of these piglets showed incomplete recovery after HI, and this is modelled by considering some of the cells to be dead. This is consistent with the results from MRS and the redox state of cytochrome-c-oxidase as measured by NIRS. However, the simulations do not match the NIRS haemoglobin measurements. The model therefore predicts that further physiological changes must also be taking place if the hypothesis of dead cells is correct.

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

    Directory of Open Access Journals (Sweden)

    Amard J Abcejo

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

  9. Brain Atrophy, Anti-Smooth Muscle Antibody and Cognitive Impairment: An Association Study.

    Science.gov (United States)

    Giulia, Paroni; Michele, Lauriola; Andrea, Fontana; Grazia, D'Onofrio; Filomena, Ciccone; Francesco, Paris; Leandro, Cascavilla; Maria, Urbano; Carolina, Gravina; Massimiliano, Copetti; Antonio, Greco

    2016-08-01

    Cortical atrophy, neuronal loss, beta-amyloid deposition, neuritic plaques, and neurofibrillary tangles are neuropathological key features in the Alzheimer's disease (AD). Antibodies against beta-amyloid, neurotransmitters, microvascular endothelium components and microglial cells have been detected in AD serum suggesting that AD could be another autoimmune disease and provides a link between vascular pathology, endothelium dysfunction and neuronal cells death. Aim of the present study was to evaluate the association between autoantibody profile and cognitive impairment in geriatric patients, accounting for ApoE genotype as a potential confounding factor. Three hundred and forty-four geriatric patients, attending the clinic for the cognitive decline, underwent a biochemical and immunological profile, chest X-ray, cerebral computed tomography scan and complete cognitive evaluation. All patients were also screened for the ApoE genotype. A significantly higher prevalence of Anti-Smooth Muscle Antibody (ASMA) positivity was found in 89/204 (43.63%) patients with diagnosed neuroradiological signs of cerebral atrophy compared with 15/140 (10.71%) patients without the condition (pbrain atrophy and with the presence of ASMA positivity. Our results shows a strong association between brain atrophy and ASMA positivity and are consistent with several studies that focused attention on the mechanisms of endothelial immune response in the development of dementia. PMID:27493830

  10. 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...

  11. 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.

  12. Carbenoxolone does not cross the blood brain barrier: an HPLC study

    Directory of Open Access Journals (Sweden)

    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.

  13. 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.

  14. Vascular endothelial growth factors enhance the permeability of the mouse blood-brain barrier.

    Directory of Open Access Journals (Sweden)

    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.

  15. 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

  16. Blood-brain barrier alterations provide evidence of subacute diaschisis in an ischemic stroke rat model.

    Directory of Open Access Journals (Sweden)

    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.

  17. Blood-brain barrier proteomics: towards the understanding of neurodegenerative diseases.

    Science.gov (United States)

    Karamanos, Yannis; Gosselet, Fabien; Dehouck, Marie-Pierre; Cecchelli, Roméo

    2014-11-01

    The blood-brain barrier (BBB) regulates the passage of endogenous and exogenous compounds and thus contributes to the brain homeostasis with the help of well-known proteins such as tight junction proteins, plasma membrane transporters and metabolic barrier proteins. In the last decade, proteomics have emerged as supplementary tools for BBB research. The development of proteomic technologies has provided several means to extend knowledge on the BBB and to investigate additional routes for the bypass of this barrier. Proteomics approaches have been used in vivo and also using in vitro BBB models to decipher the physiological characteristics and, under stress conditions, to understand the molecular mechanisms of brain diseases. This work has demonstrated that both quantitative global and targeted proteomics approaches are powerful and provide significant information on the brain microvessel endothelium. However, current knowledge is only partial and it is necessary to increase the studies using proteomics tools that will provide additional information concerning brain pathologies or BBB metabolism. Highly sensitive, accurate and specific protein quantification by quantitative targeted proteomics appears as an essential methodology for human BBB studies. PMID:25446619

  18. Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo.

    Directory of Open Access Journals (Sweden)

    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.

  19. Cell-Penetrating Peptides Selectively Cross the Blood-Brain Barrier In Vivo.

    Science.gov (United States)

    Stalmans, Sofie; Bracke, Nathalie; Wynendaele, Evelien; Gevaert, Bert; Peremans, Kathelijne; Burvenich, Christian; Polis, Ingeborgh; De Spiegeleer, Bart

    2015-01-01

    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.

  20. Blood-brain barrier transport of cationized immunoglobulin G: Enhanced delivery compared to native protein

    Energy Technology Data Exchange (ETDEWEB)

    Triguero, D.; Buciak, J.B.; Yang, J.; Pardridge, W.M.

    1989-06-01

    IgG molecules are potential neuropharmaceuticals that may be used for therapeutic or diagnostic purposes. However, IgG molecules are excluded from entering brain, owing to a lack of transport of these plasma proteins through the brain capillary wall, or blood-brain barrier (BBB). The possibility of enhanced IgG delivery through the BBB by cationization of the proteins was explored in the present studies. Native bovine IgG molecules were cationized by covalent coupling of hexamethylenediamine and the isoelectric point was raised to greater than 10.7 based on isoelectric focusing studies. Native and cationized IgG molecules were radiolabeled with /sup 125/I and chloramine T. Cationized IgG, but not native IgG, was rapidly taken up by isolated bovine brain microvessels, which were used as an in vitro model system of the BBB. Cationized IgG binding was time and temperature dependent and was saturated by increasing concentrations of unlabeled cationized IgG (dissociation constant of the high-affinity binding site, 0.90 +/- 0.37 microM; Bmax, 1.4 +/- 0.4 nmol per mg of protein). In vivo studies documented enhanced brain uptake of 125I-labeled cationized IgG relative to (3H)albumin, and complete transcytosis of the 125I-labeled cationized IgG molecule through the BBB and into brain parenchyma was demonstrated by thaw-mount autoradiography of frozen sections of rat brain obtained after carotid arterial infusions of 125I-labeled cationized IgG. These studies demonstrate that cationization of IgG molecules greatly facilitates the transport of these plasma proteins through the BBB in vivo, and this process may provide a new strategy for IgG delivery through the BBB.

  1. 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.

  2. Effects of blood-flow-restricted resistance training on muscle function in a 74-year-old male with sporadic inclusion body myositis: a case report

    DEFF Research Database (Denmark)

    Jørgensen, A N; 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...

  3. 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 metabo...

  4. Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain

    OpenAIRE

    Lochhead, Jeffrey J; McCaffrey, Gwen; Sanchez-Covarrubias, Lucy; Finch, Jessica D.; DeMarco, Kristin M; Quigley, Colleen E.; Davis, Thomas P.; Ronaldson, Patrick T

    2011-01-01

    Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain ba...

  5. Abnormal blood-brain barrier permeability in normal appearing white matter in multiple sclerosis investigated by MRI

    DEFF Research Database (Denmark)

    Cramer, Stig Præstekær; Simonsen, Helle Juhl; Frederiksen, Jette Lautrup Battistini;

    2013-01-01

    To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics.......To investigate whether blood-brain barrier (BBB) permeability is disrupted in normal appearing white matter in MS patients, when compared to healthy controls and whether it is correlated with MS clinical characteristics....

  6. Conjunctival microcirculatory blood flow is altered but not abolished in brain dead patients: a prospective observational study

    OpenAIRE

    Tamosuitis, Tomas; Pranskunas, Andrius; Balciuniene, Neringa; Pilvinis, Vidas; Boerma, E Christiaan

    2016-01-01

    Background The conjunctival microcirculation has potential as a window to cerebral perfusion due to related blood supply, close anatomical proximity and easy accessibility for microcirculatory imaging technique, such as sidestream dark field (SDF) imaging. Our study aims to evaluate conjunctival and sublingual microcirculation in brain dead patients and to compare it with healthy volunteers in two diametrically opposed conditions: full stop versus normal arterial blood supply to the brain. Me...

  7. 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.

  8. 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.

  9. 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

  10. Changes in blood-brain permeability resulting from d-amphetamine, 6-hydroxydopamine and pimozide measured by a new technique

    Energy Technology Data Exchange (ETDEWEB)

    Braun, U.; Graun, G.; Sargent, T. III

    1980-01-01

    A new technique is described for measurement of diffusion across the blood-brain barrier using intraventricularly administered /sup 68/Ga-EDTA, and determining loss from the brain with a scintillation camera. Repeated injections via permanent cannulas showed that the diffusion half-time was reduced to 50% of control values after intraventricular d-amphetamine and 6-hydroxydopamine; pimozide had no effect.

  11. Change and clinical significance of cerebral blood flow after concussion of brain detected with three-dimensional transcranial Doppler

    Institute of Scientific and Technical Information of China (English)

    肖兴义; 薛关生; 许国珍; 尹晓梅

    2003-01-01

    @@ From April 1995 to October 1999, 135 patients with concussion of brain were examined with threedimensional transcranial Doppler (3D-TCD) and the change of cerebral blood flow in various phases was analyzed to evaluate the effect of 3D-TCD on diagnosis and therapy of brain concussion.

  12. 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...

  13. Ethanol and Acetaldehyde After Intraperitoneal Administration to Aldh2-Knockout Mice-Reflection in Blood and Brain Levels.

    Science.gov (United States)

    Jamal, Mostofa; Ameno, Kiyoshi; Tanaka, Naoko; Ito, Asuka; Takakura, Ayaka; Kumihashi, Mitsuru; Kinoshita, Hiroshi

    2016-05-01

    This paper reports, for the first time, on the analysis of ethanol (EtOH) and acetaldehyde (AcH) concentrations in the blood and brains of Aldh2-knockout (Aldh2-KO) and C57B6/6J (WT) mice. Animals were administrated EtOH (1.0, 2.0 or 4.0 g/kg) or 4-methylpyrazole (4-MP, 82 mg/kg) plus AcH (50, 100 or 200 mg/kg) intraperitoneally. During the blood tests, samples from the orbital sinus of the eye were collected. During the brain tests, dialysates were collected every 5 min (equal to a 15 µl sample) from the striatum using in vivo brain microdialysis. Samples were collected at 5, 10, 15, 20, 25, 30 and 60 min intervals post-EtOH and -AcH injection, and then analyzed by head-space GC. In the EtOH groups, high AcH levels were found in the blood and brains of Aldh2-KO mice, while only small traces of AcH were seen in the blood and brains of WT mice. No significant differences in EtOH levels were observed between the WT and the Aldh2-KO mice for either the EtOH dose. EtOH concentrations in the brain were comparable to the EtOH concentrations in the blood, but the AcH concentrations in the brain were four to five times lower compared to the AcH concentrations in the blood. In the AcH groups, high AcH levels were found in both WT and Aldh2-KO mice. Levels reached a sharp peak at 5 min and then quickly declined for 60 min. Brain AcH concentrations were almost equal to the concentrations found in the blood, where the AcH concentrations were approximately two times higher in the Aldh2-KO mice than in the WT mice, both in the blood and the brain. Our results suggest that systemic EtOH and AcH administration can cause a greater increase in AcH accumulation in the blood and brains of Aldh2-KO mice, where EtOH concentrations in the Aldh2-KO mice were comparable to the EtOH concentrations in the WT mice. Furthermore, detection of EtOH and AcH in the blood and brain was found to be dose-dependent in both genotypes. PMID:26646001

  14. Altering blood flow does not reveal differences between nitrogen and helium kinetics in brain or in skeletal miracle in sheep.

    Science.gov (United States)

    Doolette, David J; Upton, Richard N; Grant, Cliff

    2015-03-01

    In underwater diving, decompression schedules are based on compartmental models of nitrogen and helium tissue kinetics. However, these models are not based on direct measurements of nitrogen and helium kinetics. In isoflurane-anesthetized sheep, nitrogen and helium kinetics in the hind limb (n = 5) and brain (n = 5) were determined during helium-oxygen breathing and after return to nitrogen-oxygen breathing. Nitrogen and helium concentrations in arterial, femoral vein, and sagittal sinus blood samples were determined using headspace gas chromatography, and venous blood flows were monitored continuously using ultrasonic Doppler. The experiment was repeated at different states of hind limb blood flow and cerebral blood flow. Using arterial blood gas concentrations and blood flows as input, parameters and model selection criteria of various compartmental models of hind limb and brain were estimated by fitting to the observed venous gas concentrations. In both the hind limb and brain, nitrogen and helium kinetics were best fit by models with multiexponential kinetics. In the brain, there were no differences in nitrogen and helium kinetics. Hind limb models fit separately to the two gases indicated that nitrogen kinetics were slightly faster than helium, but models with the same kinetics for both gases fit the data well. In the hind limb and brain, the blood:tissue exchange of nitrogen is similar to that of helium. On the basis of these results, it is inappropriate to assign substantially different time constants for nitrogen and helium in all compartments in decompression algorithms. PMID:25525213

  15. 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...

  16. 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.

  17. 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.

  18. 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

  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. 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.

  1. Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice.

    Science.gov (United States)

    Ku, Jacqueline M; Taher, Mohammadali; Chin, Kai Yee; Barsby, Tom; Austin, Victoria; Wong, Connie H Y; Andrews, Zane B; Spencer, Sarah J; Miller, Alyson A

    2016-09-01

    The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro- and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion (tMCAo). We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced blood-brain barrier (BBB) disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity and expression of 3-nitrotyrosine. Collectively, these results demonstrate that post-stroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischaemia/reperfusion-induced brain injury and swelling, and BBB disruption, by reducing oxidative and/or nitrosative damage. PMID:27303049

  2. Compartmentalized coculture of rat brain endothelial cells and astrocytes: a syngenic model to study the blood-brain barrier.

    Science.gov (United States)

    Demeuse, Ph; Kerkhofs, A; Struys-Ponsar, C; Knoops, B; Remacle, C; van den Bosch de Aguilar, Ph

    2002-11-15

    The specific structure of the blood-brain barrier (BBB) is based on the partnership of brain endothelial cells and astrocytes. In the last decade, cocultures of these two cell types have been developed as in vitro models. However, these studies did not allow close contacts between both cell types. We report here a syngenic coculture model using rat endothelial cells on one side of a polyethylene terephtalate filter and rat astrocytes on the other. Endothelial cells retain their typical morphology and are factor VIII and OX 26 positive. We optimized the diameter of the membrane pores to establish very close contacts between the cells through the membrane pores without mixing the two cell types. Transmission electron microscopy showed evidence of tight junction formation between the endothelial cells and few pinocytic vesicles. The cocultures reached high electrical resistances up to 1000 Omegacm(2) showing their ability to limit the passage of ions. A 15-fold increase in gamma-glutamyl transpeptidase activity was measured in the endothelial cells in coculture compared to endothelial cell monoculture. Our syngenic coculture represents a useful in vitro model of the rat BBB that may prove to be valuable for studying the passage of substances across the barrier as well as other aspects of the BBB function. PMID:12393158

  3. Melatonin promotes blood-brain barrier integrity in methamphetamine-induced inflammation in primary rat brain microvascular endothelial cells.

    Science.gov (United States)

    Jumnongprakhon, Pichaya; Govitrapong, Piyarat; Tocharus, Chainarong; Tocharus, Jiraporn

    2016-09-01

    Melatonin is a neurohormone and has high potent of antioxidant that is widely reported to be active against methamphetamine (METH)-induced toxicity to neuron, glial cells, and brain endothelial cells. However, the role of melatonin on the inflammatory responses which are mostly caused by blood-brain barrier (BBB) impairment by METH administration has not been investigated. This study used the primary rat brain microvascular endothelial cells (BMVECs) to determine the protective mechanism of melatonin on METH-induced inflammatory responses in the BBB via nuclear factor-ĸB (NF-κB) and nuclear factor erythroid 2-related factor-2 (Nrf2) signaling. Herein, we demonstrated that melatonin reduced the level of the inflammatory mediators, including intercellular adhesion molecules (ICAM)-1, vascular cell adhesion molecules (VCAM)-1, matrix metallopeptidase (MMP)-9, inducible nitric oxide synthase (iNOS), and nitric oxide (NO) caused by METH. These responses were related to the decrease of the expression and translocation of the NF-κB p65 subunit and the activity of NADPH oxidase (NOX)-2. In addition, melatonin promoted the antioxidant processes, modulated the expression and translocation of Nrf2, and also increased the level of heme oxygenase (HO)-1, NAD (P) H: quinone oxidoreductase (NQO)-1, γ-glutamylcysteine synthase (γ-GCLC), and the activity of superoxide dismutase (SOD) through NOX2 mechanism. In addition, we found that the protective role of melatonin in METH-induced inflammatory responses in the BBB was mediated through melatonin receptors (MT1/2). We concluded that the interaction of melatonin with its receptor prevented METH-induced inflammatory responses by suppressing the NF-κB signaling and promoting the Nrf2 signaling before BBB impairment. PMID:27268413

  4. 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.

  5. 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

  6. 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

  7. Blood oxygenation level-dependent MRI of the skeletal muscle during ischemia in patients with peripheral arterial occlusive disease

    Energy Technology Data Exchange (ETDEWEB)

    Potthast, Silke [Unispital Basel, Inst. fuer Radiologie (Switzerland); Schulte, A. [Univ. Hospital Ulm (Germany). Clinic for Radiation Therapy and Radiooncology; Kos, S.; Bilecen, D. [Unispital Basel, Interventional Radiology (Switzerland); Aschwanden, M. [Unispital Basel (Switzerland). Angiologie

    2009-12-15

    Purpose: to compare calf muscle Blood Oxygenation Level-Dependent (BOLD) response during ischemia in patients suffering from peripheral arterial occlusive disease (PAOD) and age-matched non-PAOD subjects. Materials and methods: PAOD patients with symptoms of intermittent calf claudication and an age-matched control group underwent T2*-weighted single-shot multi-echo planar imaging on a whole-body MR scanner at 1.5 T. The muscle BOLD signal in the calf was acquired during 60 sec of baseline and 240 sec of ischemia induced by cuff compression. T2* time courses in four calf muscles were evaluated. Results: significant differences in the mean T2* values were noted after 150 sec of measurement (p < 0.05). Patients with PAOD revealed a significantly reduced BOLD signal decrease compared to an age-matched control group. Conclusion: potential cause for this observation may be changes in the structure and/or the metabolic turnover of the muscle in PAOD patients. (orig.)

  8. 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

  9. 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.

  10. MicroRNA-155 negatively affects blood-brain barrier function during neuroinflammation.

    Science.gov (United States)

    Lopez-Ramirez, Miguel Alejandro; Wu, Dongsheng; Pryce, Gareth; Simpson, Julie E; Reijerkerk, Arie; King-Robson, Josh; Kay, Oliver; de Vries, Helga E; Hirst, Mark C; Sharrack, Basil; Baker, David; Male, David Kingsley; Michael, Gregory J; Romero, Ignacio Andres

    2014-06-01

    Blood-brain barrier (BBB) dysfunction is a hallmark of neurological conditions such as multiple sclerosis (MS) and stroke. However, the molecular mechanisms underlying neurovascular dysfunction during BBB breakdown remain elusive. MicroRNAs (miRNAs) have recently emerged as key regulators of pathogenic responses, although their role in central nervous system (CNS) microvascular disorders is largely unknown. We have identified miR-155 as a critical miRNA in neuroinflammation at the BBB. miR-155 is expressed at the neurovascular unit of individuals with MS and of mice with experimental autoimmune encephalomyelitis (EAE). In mice, loss of miR-155 reduced CNS extravasation of systemic tracers, both in EAE and in an acute systemic inflammation model induced by lipopolysaccharide. In cultured human brain endothelium, miR-155 was strongly and rapidly upregulated by inflammatory cytokines. miR-155 up-regulation mimicked cytokine-induced alterations in junctional organization and permeability, whereas inhibition of endogenous miR-155 partially prevented a cytokine-induced increase in permeability. Furthermore, miR-155 modulated brain endothelial barrier function by targeting not only cell-cell complex molecules such as annexin-2 and claudin-1, but also focal adhesion components such as DOCK-1 and syntenin-1. We propose that brain endothelial miR-155 is a negative regulator of BBB function that may constitute a novel therapeutic target for CNS neuroinflammatory disorders. PMID:24604078

  11. The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation

    Directory of Open Access Journals (Sweden)

    Sharanya M Kousik

    2012-06-01

    Full Text Available The blood brain barrier (BBB is a highly dynamic interface between the central nervous system and periphery. The BBB is comprised of a number of components and is part of the larger neuro(gliovascular unit. Current literature suggests that psychostimulant drugs of abuse alter the function of the BBB which likely contributes to the neurotoxicities associated with these drugs. In both preclinical and clinical studies, psychostimulants including methamphetamine, MDMA, cocaine, and nicotine, produce BBB dysfunction through alterations in tight junction protein expression and conformation, increased glial activation, increased enzyme activation related to BBB cytoskeleton remodeling, and induction of neuroinflammatory pathways. These detrimental changes lead to increased permeability of the BBB and subsequent vulnerability of the brain to peripheral toxins. In fact, abuse of these psychostimulants, notably methamphetamine and cocaine, has been shown to increase the invasion of peripheral bacteria and viruses into the brain. Much work in this field has focused on the co-morbidity of psychostimulant abuse and human immunodeficiency virus (HIV infection. As psychostimulants alter BBB permeability, it is likely that this BBB dysfunction results in increased penetration of the HIV virus into the brain thus increasing the risk of and severity of neuroAIDS. This review will provide an overview of the specific changes in components within the BBB associated with psychostimulant abuse as well as the implications of these changes in exacerbating the neuropathology associated with psychostimulant drugs and HIV co-morbidity.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Transplantation of human umbilical cord blood mesenchymal stem cells to treat a rat model of traumatic brain injury

    Institute of Scientific and Technical Information of China (English)

    Junjian Zhao; Hui Xue; Naiyao Chen; Na Shen; Hui Zhao; Dali Wang; Jun Shi; Yang Wang; Xiufeng Cui; Zhenyu Yan

    2012-01-01

    In the present study, human umbilical cord blood mesenchymal stem cells were injected into a rat model of traumatic brain injury via the tail vein. Results showed that 5-bromodeoxyuridine-labeled cells aggregated around the injury site, surviving up to 4 weeks post-transplantation. In addition, transplantation-related death did not occur, and neurological functions significantly improved. Histological detection revealed attenuated pathological injury in rat brain tissues following human umbilical cord blood mesenchymal stem cell transplantation. In addition, the number of apoptotic cells decreased. Immunohistochemistry and in situ hybridization showed increased expression of brain-derived neurotrophic factor, nerve growth factor, basic fibroblast growth factor, and vascular endothelial growth factor, along with increased microvessel density in surrounding areas of brain injury. Results demonstrated migration of transplanted human umbilical cord blood mesenchymal stem cells into the lesioned boundary zone of rats, as well as increased angiogenesis and expression of related neurotrophic factors in the lesioned boundary zone.

  2. 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...

  3. 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...... in migraine patients and normal volunteers also indicate a more general effect of sumatriptan on CNS indicating that the drug can cross the BBB in man. It has been discussed whether a defect in the BBB during migraine attacks could be responsible for a possible central effect of sumatriptan in migraine...

  4. 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.

  5. 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.

  6. 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.

  7. 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.)

  8. Experimental studies on local radiation injuries of the brain as a result of sup(99m)Tc penetration through the blood-brain barrier

    Energy Technology Data Exchange (ETDEWEB)

    Zolotov, V.A.; Lomanov, M.F.; Luk' yashin, V.E.; Shimchuk, G.G.; Minakova, E.I.; Lundkvist, Kh.; Rozander, Ch. (Gosudarstvennyj Komitet po Ispol' zovaniyu Atomnoj Ehnergii SSSR, Moscow. Inst. Teoreticheskoj i Ehksperimental' noj Fiziki; Akademiya Meditsinskikh Nauk SSSR, Moscow. Inst. Nevrologii)

    1982-07-01

    Studies on the blood-brain barrier have shown that disturbance of its permeability with reference to some dyes and radioactive tracers precedes histological changes found in the brain tissues. The paper is concerned with the techniques of detection of early changes in the blood-brain barrier during life-time after local irradiation of the brain with the proton beam, 5-7 mm in diameter. The use of sup(99m)Tc-pertechnate makes it possible to give a qualitative evaluation of the time course of radiation reactions in animals and to gain quite rapidly experimental data on the development of radiation injuries without killing large groups of experimental animals.

  9. 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 (pradiation exposure was found more effective on the male animals (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.

  10. Calibration of diffuse correlation spectroscopy blood flow index with venous-occlusion diffuse optical spectroscopy in skeletal muscle

    Science.gov (United States)

    Li, Zhe; Baker, Wesley B.; Parthasarathy, Ashwin B.; Ko, Tiffany S.; Wang, Detian; Schenkel, Steven; Durduran, Turgut; Li, Gang; Yodh, Arjun G.

    2015-12-01

    We investigate and assess the utility of a simple scheme for continuous absolute blood flow monitoring based on diffuse correlation spectroscopy (DCS). The scheme calibrates DCS using venous-occlusion diffuse optical spectroscopy (VO-DOS) measurements of arm muscle tissue at a single time-point. A calibration coefficient (γ) for the arm is determined, permitting conversion of DCS blood flow indices to absolute blood flow units, and a study of healthy adults (N=10) is carried out to ascertain the variability of γ. The average DCS calibration coefficient for the right (i.e., dominant) arm was γ=(1.24±0.15)×108 (mL·100 mL-1·min-1)/(cm2/s). However, variability can be significant and is apparent in our site-to-site and day-to-day repeated measurements. The peak hyperemic blood flow overshoot relative to baseline resting flow was also studied following arm-cuff ischemia; excellent agreement between VO-DOS and DCS was found (R2=0.95, slope=0.94±0.07, mean difference=-0.10±0.45). Finally, we show that incorporation of subject-specific absolute optical properties significantly improves blood flow calibration accuracy.

  11. The interaction of carbon nanotubes with an in vitro blood-brain barrier model and mouse brain in vivo

    OpenAIRE

    Kafa, Houmam; Wang, Julie Tzu-Wen; Rubio, Noelia; Venner, Kerrie; Anderson, Glenn; Pach, Elzbieta; Ballesteros, Belén; Preston, Jane E.; Abbott, N. Joan; Al-Jamal, Khuloud T.

    2015-01-01

    Carbon nanotubes (CNTs) are a novel nanocarriers with interesting physical and chemical properties. Here we investigate the ability of amino-functionalized multi-walled carbon nanotubes (MWNTs-NH3(+)) to cross the Blood-Brain Barrier (BBB) in vitro using a co-culture BBB model comprising primary porcine brain endothelial cells (PBEC) and primary rat astrocytes, and in vivo following a systemic administration of radiolabelled f-MWNTs. Transmission Electron microscopy (TEM) confirmed that MWNTs...

  12. Effect of Dietary Supplementation of Blood Meal and Additional Magnesium on Carnosine and Anserine Concentrations of Pig Muscles

    OpenAIRE

    Park, Se Won; Kim, Chan Ho; Kim, Jong Woong; Shin, Hye Seong; Paik, In Kee; Kil, Dong Yong

    2014-01-01

    The objective of this study was to investigate the effect of dietary supplementation of blood meal as a source of L-histidine, and the addition of magnesium (Mg) as a catalyst of carnosine synthetase for the carnosine and anserine concentrations of pig muscles (longissimus dorsi, LD and vastus intermedius, VI). A total of twenty-four pigs with an average body weight of 60.2±4.2 kg were randomly allotted to one of three dietary treatments (eight replicates), during 56 d of the feeding trial. D...

  13. Effect of feed withdrawal and handling intensity on longissimus muscle glycolytic potential and blood measurements in slaughter weight pigs.

    Science.gov (United States)

    Bertol, T M; Ellis, M; Ritter, M J; McKeith, F K

    2005-07-01

    This study was carried out to evaluate the effect of feed withdrawal and handling intensity on blood acid-base responses and muscle glycolytic potential in slaughter-weight pigs. Sixty crossbred pigs (BW = 107.7 +/- 0.56 kg; 44 barrows and 16 gilts) were used in a randomized complete block design with a 2 x 2 factorial arrangement of treatments: 1) feed withdrawal (0 vs. 24 h), and 2) handling intensity (low vs. high). The high-intensity handling treatment consisted of moving the pigs through a passage (12.2 m long x 0.91 m wide) for eight laps using an electric goad two times per lap. Pigs in the low-intensity handling treatment were moved at their own pace through the passage for eight laps using a livestock panel and paddle. Biopsy samples were collected from the LM at the beginning of feed withdrawal, at the end of the handling procedure, and 4 h after handling. Blood samples were collected 2 h before and immediately after the handling procedure. There were no interactions between feed withdrawal and handling intensity for any of the variables measured. Feed withdrawal decreased (P pressure of oxygen and partial pressure of carbon dioxide, and increased (P < 0.01) baseline and posthandling plasma free fatty acid concentrations. High-intensity handling produced higher (P < 0.01) posthandling lactate and glucose, and lower (P < 0.01) posthandling blood pH (7.33 vs. 7.18 +/- 0.02, respectively), bicarbonate, base excess, and total carbon dioxide than low-intensity handling. Longissimus muscle glycolytic potential of fasted pigs was lower (P < 0.01) than in fed pigs at the end of the handling procedure (177.2 vs. 137.0 micromol/g of wet tissue; SEM = 10.08, respectively). There was no effect of handling intensity on longissimus muscle glycolytic potential. Feed withdrawal did not attenuate the blood acid-base changes caused by handling; however, the combination of feed withdrawal and handling decreased muscle glycolytic potential. PMID:15956461

  14. A novel platform for engineering blood-brain barrier-crossing bispecific biologics.

    Science.gov (United States)

    Farrington, Graham K; Caram-Salas, Nadia; Haqqani, Arsalan S; Brunette, Eric; Eldredge, John; Pepinsky, Blake; Antognetti, Giovanna; Baumann, Ewa; Ding, Wen; Garber, Ellen; Jiang, Susan; Delaney, Christie; Boileau, Eve; Sisk, William P; Stanimirovic, Danica B

    2014-11-01

    The blood-brain barrier (BBB) prevents the access of therapeutic antibodies to central nervous system (CNS) targets. The engineering of bispecific antibodies in which a therapeutic "arm" is combined with a BBB-transcytosing arm can significantly enhance their brain delivery. The BBB-permeable single-domain antibody FC5 was previously isolated by phenotypic panning of a naive llama single-domain antibody phage display library. In this study, FC5 was engineered as a mono- and bivalent fusion with the human Fc domain to optimize it as a modular brain delivery platform. In vitro studies demonstrated that the bivalent fusion of FC5 with Fc increased the rate of transcytosis (Papp) across brain endothelial monolayer by 25% compared with monovalent fusion. Up to a 30-fold enhanced apparent brain exposure (derived from serum and cerebrospinal fluid pharmacokinetic profiles) of FC5- compared with control domain antibody-Fc fusions after systemic dosing in rats was observed. Systemic pharmacological potency was evaluated in the Hargreaves model of inflammatory pain using the BBB-impermeable neuropeptides dalargin and neuropeptide Y chemically conjugated with FC5-Fc fusion proteins. Improved serum pharmacokinetics of Fc-fused FC5 contributed to a 60-fold increase in pharmacological potency compared with the single-domain version of FC5; bivalent and monovalent FC5 fusions with Fc exhibited similar systemic pharmacological potency. The study demonstrates that modular incorporation of FC5 as the BBB-carrier arm in bispecific antibodies or antibody-drug conjugates offers an avenue to develop pharmacologically active biotherapeutics for CNS indications. PMID:25070367

  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. 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.)

  17. 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.

  18. Role of Microfluidics in Blood-Brain Barrier Permeability Cell Culture Modeling: Relevance to CNS Disorders.

    Science.gov (United States)

    Rusanov, Alexander L; Luzgina, Natalia G; Barreto, George E; Aliev, Gjumrakch

    2016-01-01

    In vitro modeling of the human blood-brain barrier (BBB) is critical for pre-clinical evaluation and predicting the permeability of newly developed potentially neurotoxic and neurotrophic drugs. Here we summarize the specific structural and functional features of endothelial cells as a key component of the BBB and compare analysis of different cell culture models in reflecting these features. Particular attention is paid to cellular models of the BBB in microfluidic devices capable of circulating nutrient media to simulate the blood flow of the brain. In these conditions, it is possible to reproduce a number of factors affecting endothelial cells under physiological conditions, including shear stress. In comparison with static cell models, concentration gradients, which determine the velocity of transport of substances, reproduce more accurately conditions of nutrient medium flow, since they eliminate the accumulation of substances near the basal membrane of cells, not typical for the situation in vivo. Co-cultivation of different types of cells forming the BBB, in separate cell chambers connected by microchannels, allows to evaluate the mutual influences of cells under normal conditions and when exposed to the test substance. New experimental possibilities that can be achieved through modeling of BBB in microfluidic devices determine the feasibility of their use in the practice for pre-clinical studies of novel drugs against neurodegenerative diseases. PMID:26831260

  19. 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...

  20. In the unloaded lower leg, vibration extrudes venous blood out of the calf muscles probably by direct acceleration and without arterial vasodilation

    OpenAIRE

    Zange, Jochen; Molitor, Sven; Illbruck, Agnes; Müller, Klaus; Schönau, Eckhard; Kohl-Bareis, Matthias; Rittweger, Jörn

    2014-01-01

    Purpose During vibration of the whole unloaded lower leg, effects on capillary blood content and blood oxygenation were measured in the calf muscle. The hypotheses predicted extrusion of venous blood by a tonic reflex contraction and that reactive hyperaemia could be observed after vibration. Methods Twelve male subjects sat in front of a vibration platform with their right foot affixed to the platform. In four intervals of 3-min duration vibration was applied with a peak-to-peak displacement...

  1. In the unloaded lower leg, vibration extrudes venous blood out of the calf muscles probably by direct acceleration and without arterial vasodilation

    OpenAIRE

    Zange, Jochen; Molitor, Sven; Illbruck, Agnes; Müller, Klaus; Schönau, Eckhard; Kohl-Bareis, Matthias; Rittweger, Jörn

    2014-01-01

    Purpose During vibration of the whole unloaded lower leg, effects on capillary blood content and blood oxygenation were measured in the calf muscle. The hypotheses predicted extrusion of venous blood by a tonic reflex contraction and that reactive hyperaemia could be observed after vibration. Methods T welve male subjects sat in front of a vibration platform with their right foot affixed to the platform. In four intervals of 3-min duration vibration was applied with ...

  2. 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.

  3. Development of brain damage as measured by brain impedance recordings, and changes in heart rate, and blood pressure induced by different stunning and killing methods.

    Science.gov (United States)

    Savenije, B; Lambooij, E; Gerritzen, M A; Korf, J

    2002-04-01

    Poultry are electrically stunned before slaughter to induce unconsciousness and to immobilize the chickens for easier killing. From a welfare point of view, electrical stunning should induce immediate and lasting unconsciousness in the chicken. As an alternative to electroencephalography, which measures brain electrical activity, this study used brain impedance recordings, which measure brain metabolic activity, to determine the onset and development of brain damage. Fifty-six chickens were surgically equipped with brain electrodes and a canula in the wing artery and were subjected to one of seven stunning and killing methods: whole body electrical stunning; head-only electrical stunning at 50, 100 or 150 V; or an i.v. injection with MgCl2. After 30 s, the chickens were exsanguinated. Brain impedance and blood pressure were measured. Extracellular volume was determined from the brain impedance data and heart rate from the blood pressure data. An immediate and progressive reduction in extracellular volume in all chickens was found only with whole body stunning at 150 V. This treatment also caused cardiac fibrillation or arrest in all chickens. With all other electrical stunning treatments, extracellular volume was immediately reduced in some but not all birds, and cardiac fibrillation or arrest was not often found. Ischemic conditions, caused by cessation of the circulation, stimulated this epileptic effect. A stunner setting of 150 V is therefore recommended to ensure immediate and lasting unconsciousness, which is a requirement for humane slaughter. PMID:11989758

  4. Mechanisms for exercise training-induced increases in skeletal muscle blood flow capacity: differences with interval sprint training versus aerobic endurance training.

    Science.gov (United States)

    Laughlin, M H; Roseguini, B

    2008-12-01

    Skeletal muscle blood flow capacity (BFC) is increased by exercise training due to structural vascular remodeling (in the form of angiogenesis of capillaries and remodeling of the arterial tree within skeletal muscle) and/or altered control of vascular resistance. Changes in control can be central or the result of changes in reactivity of arteries and arterioles (due to changes in vascular smooth muscle and/or endothelium). The purpose of this review is to evaluate the relative importance of these mechanisms for increased BFC following interval sprint training (IST) and endurance exercise training (ET). Based on the results discussed herein we conclude that the importance of each of these mechanisms varies throughout muscle tissue due to interactions of muscle fiber-type composition and muscle fiber recruitment patterns during exercise. The distribution of vascular adaptive changes varies with mode of training. For example, IST has been shown to produce the greatest relative increase in contractile activity in fast-twitch, white, skeletal muscle (i.e. white gastrocnemius muscle (Gw) and Gw muscle exhibits the largest increase in oxidative capacity, capillary density, BFC, and changes in vascular cells with IST. In contrast, ET has been shown to produce the greatest relative increase in contractile activity in red gastrocnemius muscle (Gr), and Gr muscle exhibits the largest increase in oxidative capacity, capillary density, and BFC after ET training. Results demonstrate that the increases in BFC are not mediated solely by structural adaptation. Rather, changes in vascular control predominate in Gr and soleus muscle, while increases in arteriolar and capillary density predominate following IST in Gw. Finally, evidence indicates that ET and IST induce non-uniform changes in smooth muscle and endothelium throughout skeletal muscle arteriolar networks.

  5. Interaction of Acupuncture and Electroacupuncture on the Pharmacokinetics of Aspirin and the Effect of Brain Blood Flow in Rats

    Directory of Open Access Journals (Sweden)

    Ming-Tsang Wu

    2013-01-01

    Full Text Available Acupuncture and electroacupuncture have been used to improve the brain and motor functions of poststroke patients, and aspirin is used for the prevention of stroke recurrence. Our hypothesis is that acupuncture and electroacupuncture treatments may interact with aspirin in terms of pharmacokinetics via affecting the brain blood flow. The aim of this study is to investigate the potential interactions of acupuncture and electroacupuncture on the pharmacokinetics of aspirin. The effects of acupuncture treatments on brain blood flow were measured by the laser Doppler blood flow imager. The parallel pharmacokinetic study design included three groups: control, acupuncture, and electroacupuncture groups. Two acupoints, namely, Quchi (LI 11 and Zusanli (ST 36, were needled and stimulated electronically in anaesthetized rats. The concentrations of aspirin and its metabolite, salicylic acid were determined by microdialysis and HPLC analysis after aspirin administration (30 mg/kg, i.v.. The brain blood flow responded to electroacupuncture treatments, but the pharmacokinetic parameters of aspirin and salicylic acid in blood and brain were not significantly changed by acupuncture and electroacupuncture treatments. This study may, in part, offer some evidence to support the contention that there is no significant interaction for the combination of aspirin with acupuncture or electroacupuncture.

  6. Interaction of acupuncture and electroacupuncture on the pharmacokinetics of aspirin and the effect of brain blood flow in rats.

    Science.gov (United States)

    Wu, Ming-Tsang; Shaw, Lee-Hsin; Wu, Yu-Tse; Tsai, Tung-Hu

    2013-01-01

    Acupuncture and electroacupuncture have been used to improve the brain and motor functions of poststroke patients, and aspirin is used for the prevention of stroke recurrence. Our hypothesis is that acupuncture and electroacupuncture treatments may interact with aspirin in terms of pharmacokinetics via affecting the brain blood flow. The aim of this study is to investigate the potential interactions of acupuncture and electroacupuncture on the pharmacokinetics of aspirin. The effects of acupuncture treatments on brain blood flow were measured by the laser Doppler blood flow imager. The parallel pharmacokinetic study design included three groups: control, acupuncture, and electroacupuncture groups. Two acupoints, namely, Quchi (LI 11) and Zusanli (ST 36), were needled and stimulated electronically in anaesthetized rats. The concentrations of aspirin and its metabolite, salicylic acid were determined by microdialysis and HPLC analysis after aspirin administration (30 mg/kg, i.v.). The brain blood flow responded to electroacupuncture treatments, but the pharmacokinetic parameters of aspirin and salicylic acid in blood and brain were not significantly changed by acupuncture and electroacupuncture treatments. This study may, in part, offer some evidence to support the contention that there is no significant interaction for the combination of aspirin with acupuncture or electroacupuncture. PMID:24371465

  7. 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.

  8. Agent based modeling of the effects of potential treatments over the blood-brain barrier in multiple sclerosis.

    Science.gov (United States)

    Pennisi, Marzio; Russo, Giulia; Motta, Santo; Pappalardo, Francesco

    2015-12-01

    Multiple sclerosis is a disease of the central nervous system that involves the destruction of the insulating sheath of axons, causing severe disabilities. Since the etiology of the disease is not yet fully understood, the use of novel techniques that may help to understand the disease, to suggest potential therapies and to test the effects of candidate treatments is highly advisable. To this end we developed an agent based model that demonstrated its ability to reproduce the typical oscillatory behavior observed in the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis. The model has then been used to test the potential beneficial effects of vitamin D over the disease. Many scientific studies underlined the importance of the blood-brain barrier and of the mechanisms that influence its permeability on the development of the disease. In the present paper we further extend our previously developed model with a mechanism that mimics the blood-brain barrier behavior. The goal of our work is to suggest the best strategies to follow for developing new potential treatments that intervene in the blood-brain barrier. Results suggest that the best treatments should potentially prevent the opening of the blood-brain barrier, as treatments that help in recovering the blood-brain barrier functionality could be less effective. PMID:26343337

  9. 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

  10. Blood-brain barrier properties in vitro depend on composition and assembly of endogenous extracellular matrices.

    Science.gov (United States)

    Zobel, Kathrin; Hansen, Uwe; Galla, Hans-Joachim

    2016-08-01

    Brain capillary endothelial cells, which constitute the blood-brain barrier (BBB), are enveloped by the extracellular matrix (ECM) produced by endothelial cells, pericytes and astrocytes. The contribution of matrix components secreted by the various cell types at the neurovascular unit, however, remains unclear with respect to their effect on endothelial barrier function. In this study, a new in vitro model was established by growing endothelial cells on an ECM produced by pericytes, astrocytes or a serial combination of both. The last-mentioned was found to be more in vivo-like. We investigated the role of the composition and morphology of ECM supra-structures in maintaining BBB function. The composition was analysed by protein analysis (enzyme-linked immunosorbent assay) and the ultrastructure of generated matrices was analysed by transmission electron microscopy including immunogold labelling. We could show by electric cell-substrate impedance sensing measurements that pericytes and combined matrices significantly improved the barrier tightness of porcine brain capillary endothelial cells (PBCEC). The increase of the resistance was verified by enhanced expression of tight junction proteins. Thus, for the first time, we have shown that barrier integrity is strictly controlled by the ECM, which is a product of all cells involved in the secretion of ECM components and their modification by corresponding cells. Moreover, we have demonstrated that complex matrices by the various cells of the BBB induce barrier marker enzymes in PBCEC, such as alkaline phosphatase. PMID:27053246

  11. Clinical trial of blood-brain barrier disruption by pulsed ultrasound.

    Science.gov (United States)

    Carpentier, Alexandre; Canney, Michael; Vignot, Alexandre; Reina, Vincent; Beccaria, Kevin; Horodyckid, Catherine; Karachi, Carine; Leclercq, Delphine; Lafon, Cyril; Chapelon, Jean-Yves; Capelle, Laurent; Cornu, Philippe; Sanson, Marc; Hoang-Xuan, Khê; Delattre, Jean-Yves; Idbaih, Ahmed

    2016-06-15

    The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain. PMID:27306666

  12. Blood-Brain Barrier Dysfunction as a Hallmark Pathology in Chronic Traumatic Encephalopathy.

    Science.gov (United States)

    Doherty, Colin P; O'Keefe, Eoin; Wallace, Eugene; Loftus, Teresa; Keaney, James; Kealy, John; Humphries, Marian M; Molloy, Michael G; Meaney, James F; Farrell, Michael; Campbell, Matthew

    2016-07-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE. PMID:27245243

  13. 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.

  14. 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.

  15. Study on permeability of the recombinant β-NGF through blood-brain barrier

    International Nuclear Information System (INIS)

    Objective: Study on the permeability of rhβ-nerve growth factors (NGF) through blood brain barrier (BBB) to provide scientific basis for research of β-NGF in clinical therapeutic application. Methods: to transfect the COS-7 cell line with recombination expressive vector, PcDNA3-β-NGF, by lipofectamine. The proteins, produced in the supernatant by the transfected cells, was isolated and purified by ion exchange chromatography on carboxymethyl cellulose. The biological activity of the purified protein was analyzed by the prospection of processes grow out from PC12 cell line; and the protein was labelled with 125I and injected i.v into rats, and then the radioactivity of rat brain tissue was analyzed by γ scintillometer. Results: The purified protein could stimulate the process growth of PC12 cell line and the results of γ scintigraphy analysis showed that the radioactivity achieved high level in rat brain tissue 30 min after the protein injection. Conclusion: Purified rhβ-NGF has good biological activity and it could partially penetrate the BBB

  16. Notch4 is activated in endothelial and smooth muscle cells in human brain arteriovenous malformations

    OpenAIRE

    ZhuGe, Qichuan; Wu, Zhebao; Huang, Lijie; Zhao, Bei; Zhong, Ming; Zheng, Weiming; GouRong, Chen; Mao, XiaoOu; XIE, Lin; Wang, Xiangdong; Jin, Kunlin

    2013-01-01

    Up-regulation of Notch4 was observed in the endothelial cells in the arteriovenous malformations (AVMs) in mice. However, whether Notch4 is also involved in brain AVMs in humans remains unclear. Here, we performed immunohistochemistry on normal brain vascular tissue and surgically resected brain AVMs and found that Notch4 was up-regulated in the subset of abnormal vessels of the brain AVM nidus, compared with control brain vascular tissue. Two-photon confocal images show that Notch4 was expre...

  17. 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.)

  18. 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.

  19. 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.

  20. 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

  1. In vivo field dependence of proton relaxation times in human brain, liver and skeletal muscle: a multicenter study

    DEFF Research Database (Denmark)

    Henriksen, O; de Certaines, J D; Spisni, A;

    1993-01-01

    and MRS, the in vivo field dispersion of T1 and T2 has been measured in order to evaluate whether ex vivo data are representative for the in vivo situation. Brain, skeletal muscle, and liver of healthy human volunteers were studied. Fifteen MR units with a field strength ranging from 0.08 T to 1.5 T took...... part in the trial, which comprised 218 volunteers. All the MR systems were tested for measurement accuracy using the Eurospin TO5 test object. The measured relaxation data were subsequently corrected according to the obtained calibration curves. The results showed a clear field dispersion of T1...

  2. 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.

  3. 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.

  4. 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.

  5. 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

  6. 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

  7. Differential effects of cocaine exposure on the abundance of phospholipid species in rat brain and blood*

    Science.gov (United States)

    Cummings, Brian S.; Pati, Sumitra; Sahin, Serap; Scholpa, Natalie E.; Monian, Prashant; Trinquero, Paul O.; Clark, Jason K.; Wagner, John J.

    2015-01-01

    Background Lipid profiles in the blood are altered in human cocaine users, suggesting that cocaine-exposure can induce lipid remodeling. Methods Cocaine-induced locomotor sensitization in rats was followed by shotgun lipidomics using electrospray ionization-mass spectrometry (ESI-MS) and determined changes in brain tissues. To determine if any lipidomic changes were also reflected in the blood, we performed principal component analysis (PCA) of lipidomic spectra isolated from cocaine-treated animals. Alterations in the abundance of phospholipid species were correlated with behavioral changes in the magnitude of either the initial response to drug or locomotor sensitization. Results Behavioral sensitization altered the relative abundance of several phospholipid species in the hippocampus and cerebellum, measured one week following the final exposure to cocaine. In contrast, relatively few effects on phospholipids in either the dorsal or the ventral striatum were observed. PCA analysis demonstrated that cocaine altered the relative abundance of several glycerophospholipid species as compared to saline-injected controls. Subsequent MS/MS analysis identified some of these lipids as phosphatidylethanolamines, phosphatidylserines and phosphatidylcholines. The relative abundance of some of these phospholipid species were well correlated (R2 of 0.7 or higher) with either the initial response to cocaine or locomotor sensitization. Conclusion Taken together, these data demonstrate that a cocaine-conditioning experience results in the remodeling of specific phospholipids in rat brain tissue in a region-specific manner and also alters the intensities and types of phospholipid species in rat blood. These results further suggest that such changes may serve as biomarkers to assess the neuroadaptations occurring following repeated exposure to cocaine. PMID:25960140

  8. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

    DEFF Research Database (Denmark)

    Matthews, V B; Åström, Maj-Brit; Chan, M H S;

    2009-01-01

    AIMS/HYPOTHESIS: Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. METHODS: We first examined whether exercise induced BDNF expression in humans. Next, C2......C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr(172)) and acetyl coenzyme A carboxylase beta (ACCbeta) (Ser......(79)) were analysed, as was fatty acid oxidation (FAO). Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. RESULTS: BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released...

  9. Metal levels in blood, muscle and liver of water snakes (Nerodia spp.) from New Jersey, Tennessee and South Carolina

    International Nuclear Information System (INIS)

    Reptiles, particularly snakes, could serve as bioindicators of contamination because some are comparatively long-lived, exhibit different trophic levels, and are at the top of their food chains. We test the null hypothesis that there are no differences in the concentrations of heavy metals in the blood, muscle and liver of water snakes (Nerodia spp.) from rivers in New Jersey, Tennessee and South Carolina. While the former site is in an urban/suburban area, the latter two sites are relatively rural and are located on Department of Energy sites. For the snakes from New Jersey, there were significant differences in metal concentrations among tissues for all metals, the highest levels for arsenic and selenium were in liver and kidney, for cadmium were in the liver, for chromium and lead were in skin, and for mercury and manganese were in the muscle. Body length was not correlated with metal levels, and there were more significant correlations for skin with internal tissues than for blood with other tissues. There were more significant correlations for mercury than for other metals. In comparing metal levels among states, levels were generally higher for snakes collected from South Carolina. These data indicate that, since water snakes accumulate contaminants differentially as a function of location, they can be useful bioindicators of environmental exposure to contaminants. Moreover, because of their wide geographical distribution and use of varying trophic compartments, this genus can be useful for cross-site comparisons

  10. Energy harvesting from arterial blood pressure for powering embedded brain sensors

    Science.gov (United States)

    Nanda, Aditya; Karami, M. Amin

    2016-04-01

    This paper investigates energy harvesting from arterial blood pressure via the piezoelectric effect by using a novel streaked cylinder geometry for the purpose of powering embedded micro-sensors in the brain. Initially, we look at the energy harvested by a piezoelectric cylinder placed inside an artery acted upon by blood pressure. Such an arrangement would be tantamount to constructing a stent out of piezoelectric materials. A stent is a cylinder placed in veins and arteries to prevent obstruction in blood flow. The governing equations of a conductor coated piezoelectric cylinder are obtained using Hamilton's principle. Pressure acting in arteries is radially directed and this is used to simplify the modal analysis and obtain the transfer function relating pressure to the induced voltage across the surface of the harvester. The power harvested by the cylindrical harvester is obtained for different shunt resistances. Radially directed pressure occurs elsewhere and we also look at harvesting energy from oil flow in pipelines. Although the energy harvested by the cylindrical energy harvester is significant at resonance, the natural frequency of the system is found to be very high. To decrease the natural frequency, we propose a novel streaked stent design by cutting it along the length, transforming it to a curved plate and decreasing the natural frequency. The governing equations corresponding to the new geometry are derived using Hamilton's principle and modal analysis is used to obtain the transfer function.

  11. Permeability analysis of neuroactive drugs through a dynamic microfluidic in vitro blood-brain barrier model.

    Science.gov (United States)

    Booth, R; Kim, H

    2014-12-01

    This paper presents the permeability analysis of neuroactive drugs and correlation with in vivo brain/plasma ratios in a dynamic microfluidic blood-brain barrier (BBB) model. Permeability of seven neuroactive drugs (Ethosuximide, Gabapentin, Sertraline, Sunitinib, Traxoprodil, Varenicline, PF-304014) and trans-endothelial electrical resistance (TEER) were quantified in both dynamic (microfluidic) and static (transwell) BBB models, either with brain endothelial cells (bEnd.3) in monoculture, or in co-culture with glial cells (C6). Dynamic cultures were exposed to 15 dyn/cm(2) shear stress to mimic the in vivo environment. Dynamic models resulted in significantly higher average TEER (respective 5.9-fold and 8.9-fold increase for co-culture and monoculture models) and lower drug permeabilities (average respective decrease of 0.050 and 0.052 log(cm/s) for co-culture and monoculture) than static models; and co-culture models demonstrated higher average TEER (respective 90 and 25% increase for static and dynamic models) and lower drug permeability (average respective decrease of 0.063 and 0.061 log(cm/s) for static and dynamic models) than monoculture models. Correlation of the resultant logP e values [ranging from -4.06 to -3.63 log(cm/s)] with in vivo brain/plasma ratios (ranging from 0.42 to 26.8) showed highly linear correlation (R (2) > 0.85) for all model conditions, indicating the feasibility of the dynamic microfluidic BBB model for prediction of BBB clearance of pharmaceuticals.

  12. Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Eric C Leuthardt

    Full Text Available Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery.Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption.In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks.The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced.ClinicalTrials.gov NCT01851733.

  13. Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound

    International Nuclear Information System (INIS)

    The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 0C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison(TM); 25-50 μl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 μm, scan time: 45-180 min) with gadolinium (Omniscan(TM); 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region

  14. 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

  15. 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.

  16. Blood-brain barrier transport kinetics of the neuromedin peptides NMU, NMN, NMB and NT.

    Science.gov (United States)

    Gevaert, Bert; Wynendaele, Evelien; Stalmans, Sofie; Bracke, Nathalie; D'Hondt, Matthias; Smolders, Ilse; van Eeckhaut, Ann; De Spiegeleer, Bart

    2016-08-01

    The neuromedin peptides are peripherally and centrally produced, but until now, it is generally believed that they only function as locally acting compounds without any quantitative knowledge about their blood-brain barrier (BBB) passage. Here, we characterize the transport kinetics of four neuromedins (NMU, NMN, NMB and NT) across the BBB, as well as their metabolization profile, and evaluate if they can act as endocrine hormones. Using the in vivo mouse model, multiple time regression (MTR), capillary depletion (CD) and brain efflux studies were performed. Data was fitted using linear (NMU, NT and NMB) or biphasic modeling (NMU and NMN). Three of the four investigated peptides, i.e. NMU, NT and NMN, showed a significant influx into the brain with unidirectional influx rate constants of 1.31 and 0.75 μL/(g × min) for NMU and NT respectively and initial influx constants (K1) of 72.14 and 7.55 μL/(g × min) and net influx constants (K) of 1.28 and 1.36 × 10(-16) μL/(g×min) for NMU and NMN respectively. The influx of NMB was negligible. Only NMN and NT showed a significant efflux out of the brain with an efflux constant (kout) of 0.042 min(-1) and 0.053 min(-1) respectively. Our results indicate that locally produced neuromedin peptides and/or fragments can be transported through the whole body, including passing the BBB, and taken up by different organs/tissues, supporting the idea that the neuromedins could have a much bigger role in the regulation of biological processes than currently assumed. PMID:27040796

  17. Identification of blood-brain barrier function following subarachnoid hemorrhage in rats at different stages

    Institute of Scientific and Technical Information of China (English)

    Zongyi Xie; Weiwei Shen; Ying Ma; Yuan Cheng

    2008-01-01

    BACKGROUND: Recent studies have indicated that blood-brain barrier (BBB) disruption following subarachnoid hemorrhage (SAH) significantly correlates with the development of brain injury and poor prognosis of patients subjected to SAH. OBJECTIVE: To investigate both functional and structural changes related to BBB in various phases after SAH in rats through quantitative and qualitative methods.DESIGN, TIME AND SETTING: This experiment, a completely randomized design and controlled experiment, was performed at the Department of Neurosurgery, the Second Affiliated Hospital of Chongqing University of Medical Sciences from June 2006 to March 2007.MATERIALS: A total of 128 female, healthy, Sprague-Dawley rats were selected for this study. Main reagents and instruments: Evans Blue dye (Sigma Company, USA), fluorescence spectrophotometer (Shimadzu Company, Japan), and transmission electron microscope (Olympus Company, Japan). MAIN OUTCOME MEASURES: Brain tissue water content was determined by the wet-dry method. BBB permeability in the cerebral cortex was determined by Evans Blue dye and fluorescent spectrophotometer. The ultrastructural changes in BBB were observed with transmission electron microscope.RESULTS: Compared with the sham-operated group, SAH induced a significant increase in brain water content between 24 and 60 hours (F = 888.32, P 0.05). Electron microscopy demonstrated only a mild perivascular edema at 24 hours after SAH. By 36 hours, a notable perivascular edema was associated with a collapse of the capillary. Astrocytic endfeet surrounding the capillary were prominently swollen in the edematous areas. The above-mentioned abnormal ultrastructural changes in the BBB were reversed by 72 hours after SAH. No obvious morphological changes in the BBB were detected in the sham-operated rats.CONCLUSION: These results directly suggest that SAH could induce rapid changes in BBB function and structure during the acute phases of BBB breakdown. Moreover, these dynamic

  18. Determination of endocrine disrupting compounds in fish liver, brain, and muscle using focused ultrasound solid-liquid extraction and dispersive solid phase extraction as clean-up strategy.

    Science.gov (United States)

    Ros, Oihana; Vallejo, Asier; Olivares, Maitane; Etxebarria, Nestor; Prieto, Ailette

    2016-08-01

    This study describes a new method for the simultaneous extraction of several endocrine disrupting compounds, including alkylphenols (APs), estrogen, bisphenol-A (BPA) and one phthalate metabolite (mono-2-ethylhexyl ester, MEHP) in fish liver, brain, and muscle. Parameters affecting the extraction (extraction solvent and temperature) and the clean-up (dispersive phase nature and amount) steps were evaluated. The extraction was performed by means of focused ultrasound solid-liquid extraction (FUSLE) using 10 mL of n-hexane:acetone (50:50, v/v) for 5 min at ~0 °C, and the clean-up was done by means of dispersive solid phase extraction (dSPE) using 100 mg of ENVI-CARB and 100 mg of MgSO4 for the cleaning of brain and muscle extracts together with 100 mg of PSA in the case of liver extracts. Good apparent recoveries were obtained in the case of liver (62-132 %), brain (66-120 %), and muscle (74-129 %), relative standard deviation (RSD%) was always below 26 %, and the method detection limits (MDLs) were at low ng/g level. The developed method was applied to fish captured in Urdaibai estuary (Bay of Biscay) in December 2015, and the concentrations obtained were in the range MDL-1115 ng/g in brain, MDL-962 ng/g in muscle, and MDL-672 ng/g in liver. In general, the highest concentrations were measured in liver, followed by brain and muscle. In addition, diethylstilbestrol was only detected in fish brain. Graphical Abstract MS method scheme for the/MS method scheme for the determination of EDCs in fish liver, brain and muscle. PMID:27342793

  19. Melatonin Preserves Blood-Brain Barrier Integrity and Permeability via Matrix Metalloproteinase-9 Inhibition.

    Directory of Open Access Journals (Sweden)

    Himakarnika Alluri

    Full Text Available Microvascular hyperpermeability that occurs at the level of the blood-brain barrier (BBB often leads to vasogenic brain edema and elevated intracranial pressure following traumatic brain injury (TBI. At a cellular level, tight junction proteins (TJPs between neighboring endothelial cells maintain the integrity of the BBB via TJ associated proteins particularly, zonula occludens-1 (ZO-1 that binds to the transmembrane TJPs and actin cytoskeleton intracellularly. The pro-inflammatory cytokine, interleukin-1β (IL-1β as well as the proteolytic enzymes, matrix metalloproteinase-9 (MMP-9 are key mediators of trauma-associated brain edema. Recent studies indicate that melatonin a pineal hormone directly binds to MMP-9 and also might act as its endogenous inhibitor. We hypothesized that melatonin treatment will provide protection against TBI-induced BBB hyperpermeability via MMP-9 inhibition. Rat brain microvascular endothelial cells grown as monolayers were used as an in vitro model of the BBB and a mouse model of TBI using a controlled cortical impactor was used for all in vivo studies. IL-1β (10 ng/mL; 2 hours-induced endothelial monolayer hyperpermeability was significantly attenuated by melatonin (10 μg/mL; 1 hour, GM6001 (broad spectrum MMP inhibitor; 10 μM; 1 hour, MMP-9 inhibitor-1 (MMP-9 specific inhibitor; 5 nM; 1 hour or MMP-9 siRNA transfection (48 hours in vitro. Melatonin and MMP-9 inhibitor-1 pretreatment attenuated IL-1β-induced MMP-9 activity, loss of ZO-1 junctional integrity and f-actin stress fiber formation. IL-1β treatment neither affected ZO-1 protein or mRNA expression or cell viability. Acute melatonin treatment attenuated BBB hyperpermeability in a mouse controlled cortical impact model of TBI in vivo. In conclusion, one of the protective effects of melatonin against BBB hyperpermeability occurs due to enhanced BBB integrity via MMP-9 inhibition. In addition, acute melatonin treatment provides protection against BBB

  20. Slowed muscle oxygen uptake kinetics with raised metabolism are not dependent on blood flow or recruitment dynamics.

    Science.gov (United States)

    Wüst, Rob C I; McDonald, James R; Sun, Yi; Ferguson, Brian S; Rogatzki, Matthew J; Spires, Jessica; Kowalchuk, John M; Gladden, L Bruce; Rossiter, Harry B

    2014-04-15

    Oxygen uptake kinetics (τVO2) are slowed when exercise is initiated from a raised metabolic rate. Whether this reflects the recruitment of muscle fibres differing in oxidative capacity, or slowed blood flow (Q) kinetics is unclear. This study determined τVO2 in canine muscle in situ, with experimental control over muscle activation and Q during contractions initiated from rest and a raised metabolic rate. The gastrocnemius complex of nine anaesthetised, ventilated dogs was isolated and attached to a force transducer. Isometric tetanic contractions (50 Hz; 200 ms duration) via supramaximal sciatic nerve stimulation were used to manipulate metabolic rate: 3 min stimulation at 0.33 Hz (S1), followed by 3 min at 0.67 Hz (S2). Circulation was initially intact (SPON), and subsequently isolated for pump-perfusion (PUMP) above the greatest value in SPON. Muscle VO2 was determined contraction-by-contraction using an ultrasonic flowmeter and venous oximeter, and normalised to tension-time integral (TTI). τVO2/TTI and τQ were less in S1SPON (mean ± s.d.: 13 ± 3 s and 12 ± 4 s, respectively) than in S2SPON (29 ± 19 s and 31 ± 13 s, respectively; P < 0.05). τVO2/TTI was unchanged by pump-perfusion (S1PUMP, 12 ± 4 s; S2PUMP, 24 ± 6 s; P < 0.001) despite increased O2 delivery; at S2 onset, venous O2 saturation was 21 ± 4% and 65 ± 5% in SPON and PUMP, respectively. VO2 kinetics remained slowed when contractions were initiated from a raised metabolic rate despite uniform muscle stimulation and increased O2 delivery. The intracellular mechanism may relate to a falling energy state, approaching saturating ADP concentration, and/or slowed mitochondrial activation; but further study is required. These data add to the evidence that muscle VO2 control is more complex than previously suggested. PMID:24469073

  1. Effect of X-irradiation on the pharmacokinetics of methotrexate in rats: alteration of the blood-brain barrier

    International Nuclear Information System (INIS)

    A study was designed to evaluate the effects of brain irradiation on the permeability of the blood-brain barrier for methotrexate (MTX). Female WAG/Rij rats were cranially irradiated with a single dose of 20 gy of 300 kV X-rays. At different times (1-15 days) after the exposure the rats were injected intravenously with MTX (25 mg/kg body wt). Irradiation had hardly any effect on the MTX concentrations in the plasma, heart and kidneys as determined by high-performance liquid chromatography. However, irradiation resulted in a significant increase of MTX (determined by 125I-radioimmunoassay) in brain tissue per gram wet weight (187.6 +- 17.9 pmol/g vs 46.4 +- 29.3 pmol/g in unirradiated brain). This change in permeability of the blood-brain barrier lasted for about 9 days. The MTX elimination from the irradiated brain was the same as that from the non-irradiated brain. This indicates that only the MTX uptake and not the elimination by the brain was affected by the irradiation treatment. (author)

  2. Expiratory muscle control during vomiting - Role of brain stem expiratory neurons

    Science.gov (United States)

    Miller, A. D.; Tan, L. K.

    1987-01-01

    The neural mechanisms controlling the muscles involved during vomiting were examined using decerebrated cats. In one experiment, the activity of the ventral respiratory group (VRG) expiratory (E) neurons was recorded during induced 'fictive vomiting' (i.e., a series of bursts of coactivation of abdominal and phrenic nerves that would be expected to produce expulsion in unparalyzed animals) and vomiting. In a second, abdominal muscle electromyographic and nerve activity were compared before and after sectioning the axons of descending VRG E neurons as they cross the midline between C1 and the obex (the procedure that is known to abolish expiratory modulation of internal intercostal muscle activity). The results of the study indicate that the abdominal muscles are controlled differently during respiration and vomiting.

  3. DISSEMINATED CYSTICERCOSIS WITH HUGE MUSCLE HYPERTROPHY

    OpenAIRE

    Bandyopadhyay Debabrata; Sen Sumit

    2009-01-01

    Cysticercosis is caused by cysticercus cellulose, which is the larva of Taenia solium , the pork tapeworm. The larvae are carried in the blood stream after penetrating the walls of the alimentary tract and they lodge in different tissues like the skin, skeletal muscles, brain, fundus and heart, to cause disseminated cysticercosis. Cases of disseminated cysticercosis have rarely been reported in the literature. They may inhabit the muscles and cause muscular hypertrophy, which, at times, may ...

  4. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, Hongseok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-Ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-08-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs.

  5. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier.

    Science.gov (United States)

    Biancardi, Vinicia Campana; Son, Sook Jin; Ahmadi, Sahra; Filosa, Jessica A; Stern, Javier E

    2014-03-01

    Angiotensin II-mediated vascular brain inflammation emerged as a novel pathophysiological mechanism in neurogenic hypertension. However, the precise underlying mechanisms and functional consequences in relation to blood-brain barrier (BBB) integrity and central angiotensin II actions mediating neurohumoral activation in hypertension are poorly understood. Here, we aimed to determine whether BBB permeability within critical hypothalamic and brain stem regions involved in neurohumoral regulation was altered during hypertension. Using digital imaging quantification after intravascularly injected fluorescent dyes and immunohistochemistry, we found increased BBB permeability, along with altered key BBB protein constituents, in spontaneously hypertensive rats within the hypothalamic paraventricular nucleus, the nucleus of the solitary tract, and the rostral ventrolateral medulla, all critical brain regions known to contribute to neurohumoral activation during hypertension. BBB disruption, including increased permeability and downregulation of constituent proteins, was prevented in spontaneously hypertensive rats treated with the AT1 receptor antagonist losartan, but not with hydralazine, a direct vasodilator. Importantly, we found circulating angiotensin II to extravasate into these brain regions, colocalizing with neurons and microglial cells. Taken together, our studies reveal a novel angiotensin II-mediated feed-forward mechanism during hypertension, by which circulating angiotensin II evokes increased BBB permeability, facilitating in turn its access to critical brain regions known to participate in blood pressure regulation.

  6. Localized Down-regulation of P-glycoprotein by Focused Ultrasound and Microbubbles induced Blood-Brain Barrier Disruption in Rat Brain

    Science.gov (United States)

    Cho, HongSeok; Lee, Hwa-Youn; Han, Mun; Choi, Jong-ryul; Ahn, Sanghyun; Lee, Taekwan; Chang, Yongmin; Park, Juyoung

    2016-01-01

    Multi-drug resistant efflux transporters found in Blood-Brain Barrier (BBB) acts as a functional barrier, by pumping out most of the drugs into the blood. Previous studies showed focused ultrasound (FUS) induced microbubble oscillation can disrupt the BBB by loosening the tight junctions in the brain endothelial cells; however, no study was performed to investigate its impact on the functional barrier of the BBB. In this study, the BBB in rat brains were disrupted using the MRI guided FUS and microbubbles. The immunofluorescence study evaluated the expression of the P-glycoprotein (P-gp), the most dominant multi-drug resistant protein found in the BBB. Intensity of the P-gp expression at the BBB disruption (BBBD) regions was significantly reduced (63.2 ± 18.4%) compared to the control area. The magnitude of the BBBD and the level of the P-gp down-regulation were significantly correlated. Both the immunofluorescence and histologic analysis at the BBBD regions revealed no apparent damage in the brain endothelial cells. The results demonstrate that the FUS and microbubbles can induce a localized down-regulation of P-gp expression in rat brain. The study suggests a clinically translation of this method to treat neural diseases through targeted delivery of the wide ranges of brain disorder related drugs. PMID:27510760

  7. STAT1 signaling modulates HIV-1–induced inflammatory responses and leukocyte transmigration across the blood-brain barrier

    OpenAIRE

    Chaudhuri, Anathbandhu; Yang, Bo; Gendelman, Howard E; Persidsky, Yuri; Kanmogne, Georgette D.

    2008-01-01

    The relationship among neuroinflammation, blood-brain barrier (BBB) dysfunction, and progressive HIV-1 infection as they affect the onset and development of neuroAIDS is incompletely understood. One possible link is signal transducers and activators of transcription (STATs) pathways. These respond to proinflammatory and regulatory factors and could affect neuroinflammatory responses induced from infected cells and disease-affected brain tissue. Our previous works demonstrated that HIV-1 activ...

  8. Impact of standing wave effects on transcranial focused ultrasound disruption of the blood-brain barrier in a rat model

    OpenAIRE

    O’Reilly, Meaghan A.; Huang, Yuexi; Hynynen, Kullervo

    2010-01-01

    Microbubble mediated disruption of the blood brain barrier (BBB) for targeted drug delivery using focused ultrasound shows great potential as a therapy for a wide range of brain disorders. This technique is currently at the pre-clinical stage and important work is being conducted in animal models. Measurements of standing waves in ex vivo rat skulls were conducted using an optical hydrophone and a geometry dependence was identified. Standing waves could not be eliminated through the use of sw...

  9. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    OpenAIRE

    Aryal, Muna; Arvanitis, Costas D.; Alexander, Phillip M.; McDannold, Nathan

    2014-01-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete t...

  10. Blood-brain barrier delivery of protein and non-viral gene therapeutics with molecular Trojan horses

    OpenAIRE

    Pardridge, William M

    2007-01-01

    The products of biotechnology, recombinant proteins, monoclonal antibodies, antisense, RNA interference, or non-viral gene transfer, cannot be developed as pharmaceuticals for the brain, unless these molecules are re-formulated to enable transport across the blood-brain barrier (BBB). Large molecule drugs, and plasmid DNA, can be delivered across the BBB with receptor-specific molecular Trojan horses. Trojan horse BBB delivery systems, coupled with one of 3 different technology platforms (fus...

  11. [Effect of cinnarizine on the brain mitochondrial oxidative system, antioxidant blood activity, and the rat behavior in hypoxia].

    Science.gov (United States)

    Belostotskaia, L I; Chaĭka, L A; Gomon, O N

    2003-01-01

    The effect of cinnarizine on the functional state of brain mitochondria, the activity of blood antioxidant system, and the behavior of rats was studied under model hypoxic hypoxia conditions. A four-day treatments with cinnarizine (50 mg/kg, twice per day via a gastric tube) prevents the hypoxic brain edema development, restores NAD+ dependent oxidation of a succinate substrate, normalizes emotional-exploratory activity, and causes hyperlocomotion of the experimental animals, while not influencing a high level of activity of the blood antioxidant system. PMID:14743704

  12. Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity

    OpenAIRE

    Mulac, Dennis; Hüwel, Sabine; Galla, Hans-Joachim; Humpf, Hans-Ulrich

    2011-01-01

    Scope Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. Methods and results In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-b...

  13. Seasonal variation in blood and muscle oxygen stores attributed to diving behavior, environmental temperature and pregnancy in a marine predator, the California sea lion.

    Science.gov (United States)

    Villegas-Amtmann, Stella; Atkinson, Shannon; Paras-Garcia, Alberto; Costa, Daniel P

    2012-08-01

    Survival depends on an animal's ability to find and acquire prey. In diving vertebrates, this ability is directly related to their physiological capability (e.g. oxygen stores). We studied the seasonal variation in oxygen stores, body temperature and body condition in California sea lions (Zalophus californianus) (CSL) as a function of seasonal variation in temperature, primary productivity, diving behavior and reproductive stage. During summer, blood oxygen stores were significantly greater and muscle oxygen stores were significantly lower than in winter. Total oxygen stores, body condition and body temperature did not change between seasons but variations in body temperature were greater during summer. Changes in oxygen stores are partly attributed to diving behavior, temperature and pregnancy that could increase oxygen consumption. Blood and muscle oxygen stores appear to be influenced by reproductive state. Blood oxygen stores are more likely influenced by diving behavior and temperature than muscle oxygen stores.

  14. Blood Thinners

    Science.gov (United States)

    If you have some kinds of heart or blood vessel disease, or if you have poor blood flow to your brain, your doctor may recommend that you take a blood thinner. Blood thinners reduce the risk of heart ...

  15. Effects of three days of dry immersion on muscle sympathetic nerve activity and arterial blood pressure in humans.

    Science.gov (United States)

    Iwase, S; Sugiyama, Y; Miwa, C; Kamiya, A; Mano, T; Ohira, Y; Shenkman, B; Egorov, A I; Kozlovskaya, I B

    2000-03-15

    The present study was performed to determine how sympathetic function is altered by simulated microgravity, dry immersion for 3 days, and to elucidate the mechanism of post-spaceflight orthostatic intolerance in humans. Six healthy men aged 21-36 years old participated in the study. Before and after the dry immersion, subjects performed head-up tilt (HUT) test to 30 degrees and 60 degrees (5 min each) with recordings of muscle sympathetic nerve activity (MSNA, by microneurography), electrocardiogram, and arterial blood pressure (Finapres). Resting MSNA was increased after dry immersion from 23.7+/-3.2 to 40.9+/-3.0 bursts/min (p<0.005) without significant changes in resting heart rate (HR). MSNA responsiveness to orthostasis showed no significant difference but HR response was significantly augmented after dry immersion (p<0. 005). A significant diastolic blood pressure fall at 5th min of 60 degrees HUT was observed in five orthostatic tolerant subjects despite enough MSNA discharge after dry immersion. A subject suffered from presyncope at 2 min after 60 degrees HUT. He showed gradual blood pressure fall 10 s after 60 degrees HUT with initially well-maintained MSNA response and then with a gradually attenuated MSNA, followed by a sudden MSNA withdrawal and abrupt blood pressure drop. In conclusion, dry immersion increased MSNA without changing MSNA response to orthostasis, and resting HR, while increasing the HR response to orthostasis. Analyses of MSNA and blood pressure changes in orthostatic tolerant subjects and a subject with presyncope suggested that not only insufficient vasoconstriction to sympathetic stimuli, but also a central mechanism to induce a sympathetic withdrawal might play a role in the development of orthostatic intolerance after microgravity exposure.

  16. Blood-Brain Barrier Permeability of Normal Appearing White Matter in Relapsing-Remitting Multiple Sclerosis

    DEFF Research Database (Denmark)

    Lund, Henrik; Krakauer, Martin; Skimminge, Arnold;

    2013-01-01

    Background: Multiple sclerosis (MS) affects the integrity of the blood-brain barrier (BBB). Contrast-enhanced T1 weighted magnetic resonance imaging (MRI) is widely used to characterize location and extent of BBB disruptions in focal MS lesions. We employed quantitative T1 measurements before...... and after the intravenous injection of a paramagnetic contrast agent to assess BBB permeability in the normal appearing white matter (NAWM) in patients with relapsing-remitting MS (RR-MS). Methodology/Principal Findings: Fifty-nine patients (38 females) with RR-MS undergoing immunomodulatory treatment...... and nine healthy controls (4 females) underwent quantitative T1 measurements at 3 tesla before and after injection of a paramagnetic contrast agent (0.2 mmol/kg Gd-DTPA). Mean T1 values were calculated for NAWM in patients and total cerebral white matter in healthy subjects for the T1 measurements before...

  17. Bicuculline methiodide in the blood-brain barrier-epileptogen model of epilepsy

    Energy Technology Data Exchange (ETDEWEB)

    Remler, M.P.; Marcussen, W.H.

    Focal epilepsy can be produced by a blood-brain barrier (BBB)-excluded systemic convulsant (penicillin, folic acid, etc.) in the presence of a focal BBB lesion. Bicuculline methiodide, a gamma-aminobutyric acid blocking epileptogen, crosses the normal BBB of rats poorly and produces no consistent abnormality behaviorally or on EEG at 36 mg/kg. When the BBB is opened in 0.25 ml of cortex by 6,000 rad of alpha particles, by a pin trauma lesion, or by a heat lesion, the rats are normal clinically and on EEG. When these lesioned rats are challenged with bicuculline methiodide, 36 mg/kg, an intense, highly localized epileptiform discharge results that begins approximately 20 min after injection and lasts 30-90 min. The plausibility and experimental utility of the BBB-epileptogen model of epilepsy are enhanced by these observations.

  18. Blood-brain barrier disruption by continuous-wave radio frequency radiation.

    Science.gov (United States)

    Sirav, Bahriye; Seyhan, Nesrin

    2009-01-01

    The increasing use of cellular phones and the increasing number of associated base stations are becoming a widespread source of non ionizing electromagnetic radiation. Some biological effects are likely to occur even at low-level EM fields. This study was designed to investigate the effects of 900 and 1,800 MHz Continuous Wave Radio Frequency Radiation (CW RFR) on the permeability of Blood Brain Barrier (BBB) of rats. Results have shown that 20 min RFR exposure of 900 and 1,800 MHz induces an effect and increases the permeability of BBB of male rats. There was no change in female rats. The scientific evidence on RFR safety or harm remains inconclusive. More studies are needed to demonstrate the effects of RFR on the permeability of BBB and the mechanisms of that breakdown. PMID:19811403

  19. Implications of MMP9 for Blood Brain Barrier Disruption And Hemorrhagic Transformation Following Ischemic Stroke

    Directory of Open Access Journals (Sweden)

    Renee Jade Turner

    2016-03-01

    Full Text Available Numerous studies have documented increases in matrix metalloproteinases (MMPs, specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB, increased risk of hemorrhagic complications and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke.

  20. Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke

    Science.gov (United States)

    Turner, Renée J.; Sharp, Frank R.

    2016-01-01

    Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke. PMID:26973468

  1. Influence of nutrient intake on antioxidant capacity, muscle damage and white blood cell count in female soccer players

    Directory of Open Access Journals (Sweden)

    Gravina Leyre

    2012-07-01

    Full Text Available Abstract Background Soccer is a form of exercise that induces inflammatory response, as well as an increase in free radicals potentially leading to muscle injury. Balanced nutritional intake provides important antioxidant vitamins, including vitamins A, C and E, which may assist in preventing exercise-related muscle damage. The purpose of the present study was to determine the effect of macro/micronutrient intake on markers of oxidative stress, muscle damage, inflammatory and immune response in female soccer players. Methods Twenty-eight female players belonging to two soccer teams of the same professional soccer club participated in this study after being informed about the aims and procedures and after delivering written consent. Each team completed an 8-day dietary record and played one competition match the same week. Participants were divided into two groups: the REC group (who complied with recommended intakes and the NO-REC group (who were not compliant. Laboratory blood tests were carried out to determine hematological, electrolytic and hormonal variables, as well as to monitor markers of cell damage and oxidative stress. Blood samples were obtained 24 h before, immediately after and 18 h after official soccer matches. Student t-test or Mann–Whitney U-test was used to compare both groups throughout the match. Results At rest, we observed that the REC group had higher levels of total antioxidant status (TAS, glutathione peroxidase (GPx, and lower levels of creatine kinase (CK and lactate dehydrogenase (LDH in comparison to the NO-REC group. Immediately after the match, levels of TAS, GPx, superoxide dismutase (SOD, LDH and % lymphocytes were higher and the % of neutrophils were lower in the REC group compared to the NO-REC group. These differences were also maintained 18 h post-match, only for TAS and GPx. Conclusions Our data reveal an association between nutritional intake and muscle damage, oxidative stress, immunity and inflammation

  2. Relations between blood supply of brain of students and condition of autonomic nervous system and risk factors

    OpenAIRE

    L. D. Korovina; T. M. Zaporozhets

    2015-01-01

    The purpose of our research was to estimate the brain blood supply level by rheoencephalography method in junior students of the Medical academy and to determine the blood supply links with the autonomic regulation state, behavioural and alimentary factors. Rheo-encephalographic study, research of the autonomic nervous system state, heart rate regulation and questioning of 17–29 year-old students have been conducted. Basic hemodynamic indices were normal in all surveyed students. Increase in ...

  3. Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system

    Science.gov (United States)

    McDannold, Nathan; Zhang, Yongzhi; Power, Chanikarn; Arvanitis, Costas D.; Vykhodtseva, Natalia; Livingstone, Margaret

    2015-05-01

    The physiology of the vasculature in the central nervous system (CNS), which includes the blood-brain barrier (BBB) and other factors, complicates the delivery of most drugs to the brain. Different methods have been used to bypass the BBB, but they have limitations such as being invasive, non-targeted or requiring the formulation of new drugs. Focused ultrasound (FUS), when combined with circulating microbubbles, is a noninvasive method to locally and transiently disrupt the BBB at discrete targets. The method presents new opportunities for the use of drugs and for the study of the brain.

  4. Learning from our failures in blood-brain permeability: what can be done for new drug discovery?

    Science.gov (United States)

    Martel, Sylvain

    2015-03-01

    Many existing pharmaceuticals are rendered ineffective in the treatment of cerebral diseases due to a permeability barrier well known as the blood-brain barrier (BBB). Such barrier between the blood within brain capillaries and the extracellular fluid in brain tissue has motivated several approaches aimed at delivering therapeutics to the brain. These approaches rely on strategies that can be classified as molecular modifications, the use of BBB bypassing pathways, and BBB disruptions. Although several of these approaches that have been investigated so far show promising results, none has addressed the optimization of the ratio of the dose of the drug molecules that contributes to the therapeutic effects. As such, the extensive research efforts, such as prioritizing the enhancement of the BBB permeability alone is likely to fail to provide the best therapeutic effects for a given dose if prior systemic circulation is not avoided while enhancing the spatial targeting only to regions of the brain that need treatment. Hence, new therapeutics for the brain could be synthesized to take advantage of recent technologies for non-systemic delivery and spatially targeted brain uptake.

  5. Effect of insulin in combination with selenium on blood glucose and GLUT4 expression in skeletal muscle of streptozotocin-induced diabetic rats

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Objective To evaluate the effect of low-dose insulin [1 U/(kg·d)] in combination with selenium [180 g/(kg·d)] on general physiological parameters and glucose transporter (GLUT4) level in skeletal muscle of streptozotocin (STZ)-induced diabetic rats. Methods Diabetic rats were treated with insulin,selenium,and insulin and selenium in combination for four weeks. The level of blood glucose was determined using One Touch SureStep Blood Glucose meter and the level of GLUT4 in skeletal muscle was examined by immu...

  6. Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability.

    Science.gov (United States)

    Laksitorini, Marlyn D; Kiptoo, Paul K; On, Ngoc H; Thliveris, James A; Miller, Donald W; Siahaan, Teruna J

    2015-03-01

    It is challenging to deliver molecules to the brain for diagnosis and treatment of brain diseases. This is primarily because of the presence of the blood-brain barrier (BBB), which restricts the entry of many molecules into the brain. In this study, cyclic-ADT peptides (ADTC1, ADTC5, and ADTC6) have been shown to modify the BBB to enhance the delivery of marker molecules [e.g., (14) C-mannitol, gadolinium-diethylenetriaminepentacetate (Gd-DTPA)] to the brain via the paracellular pathways of the BBB. The hypothesis is that these peptides modulate cadherin interactions in the adherens junctions of the vascular endothelial cells forming the BBB to increase paracellular drug permeation. In vitro studies indicated that ADTC5 had the best profile to inhibit adherens junction resealing in Madin-Darby canine kidney cell monolayers in a concentration-dependent manner (IC50 = 0.3 mM) with a maximal response at 0.4 mM. Under the current experimental conditions, ADTC5 improved the delivery of (14) C-mannitol to the brain about twofold compared with the negative control in the in situ rat brain perfusion model. Furthermore, ADTC5 peptide increased in vivo delivery of Gd-DTPA to the brain of Balb/c mice when administered intravenously. In conclusion, ADTC5 has the potential to improve delivery of diagnostic and therapeutic agents to the brain.

  7. Human umbilical cord blood cells restore brain damage induced changes in rat somatosensory cortex.

    Directory of Open Access Journals (Sweden)

    Maren Geissler

    Full Text Available Intraperitoneal transplantation of human umbilical cord blood (hUCB cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury.

  8. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Directory of Open Access Journals (Sweden)

    Sanberg Paul R

    2008-02-01

    Full Text Available Abstract Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

  9. Peripheral injection of human umbilical cord blood stimulates neurogenesis in the aged rat brain

    Science.gov (United States)

    Bachstetter, Adam D; Pabon, Mibel M; Cole, Michael J; Hudson, Charles E; Sanberg, Paul R; Willing, Alison E; Bickford, Paula C; Gemma, Carmelina

    2008-01-01

    Background Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation. Results We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis. Conclusion The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain. PMID:18275610

  10. Modelling Blood Flow and Metabolism in the Preclinical Neonatal Brain during and Following Hypoxic-Ischaemia.

    Directory of Open Access Journals (Sweden)

    Matthew Caldwell

    Full Text Available Hypoxia-ischaemia (HI is a major cause of neonatal brain injury, often leading to long-term damage or death. In order to improve understanding and test new treatments, piglets are used as preclinical models for human neonates. We have extended an earlier computational model of piglet cerebral physiology for application to multimodal experimental data recorded during episodes of induced HI. The data include monitoring with near-infrared spectroscopy (NIRS and magnetic resonance spectroscopy (MRS, and the model simulates the circulatory and metabolic processes that give rise to the measured signals. Model extensions include simulation of the carotid arterial occlusion used to induce HI, inclusion of cytoplasmic pH, and loss of metabolic function due to cell death. Model behaviour is compared to data from two piglets, one of which recovered following HI while the other did not. Behaviourally-important model parameters are identified via sensitivity analysis, and these are optimised to simulate the experimental data. For the non-recovering piglet, we investigate several state changes that might explain why some MRS and NIRS signals do not return to their baseline values following the HI insult. We discover that the model can explain this failure better when we include, among other factors such as mitochondrial uncoupling and poor cerebral blood flow restoration, the death of around 40% of the brain tissue.

  11. Computational Prediction of Blood-Brain Barrier Permeability Using Decision Tree Induction

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    Jörg Huwyler

    2012-08-01

    Full Text Available Predicting blood-brain barrier (BBB permeability is essential to drug development, as a molecule cannot exhibit pharmacological activity within the brain parenchyma without first transiting this barrier. Understanding the process of permeation, however, is complicated by a combination of both limited passive diffusion and active transport. Our aim here was to establish predictive models for BBB drug permeation that include both active and passive transport. A database of 153 compounds was compiled using in vivo surface permeability product (logPS values in rats as a quantitative parameter for BBB permeability. The open source Chemical Development Kit (CDK was used to calculate physico-chemical properties and descriptors. Predictive computational models were implemented by machine learning paradigms (decision tree induction on both descriptor sets. Models with a corrected classification rate (CCR of 90% were established. Mechanistic insight into BBB transport was provided by an Ant Colony Optimization (ACO-based binary classifier analysis to identify the most predictive chemical substructures. Decision trees revealed descriptors of lipophilicity (aLogP and charge (polar surface area, which were also previously described in models of passive diffusion. However, measures of molecular geometry and connectivity were found to be related to an active drug transport component.

  12. Biogenic amines, amino acids and regional blood flow in rat brain after prenatal irradiation

    International Nuclear Information System (INIS)

    Damage to nerve cells after prenatal irradiation could affect their later ability to function normally. The concentration of several biogenic amines and amino acids was therefore determined at different times after prenatal irradiation with 0.95 Gy on day 10, 12 or 15 of pregnancy. The offspring was sacrified 0.5, 1, 3 and 6 months after birth and the following structures were dissected: Cortex, hippocampus, striatum, thalamus, hypothalamus, cerebellum and medulla. Biogenic amines isolated by HPLC and detected electrochemically were: Dopamine, DOPA, DOPAC, epinephrine, norepinephrine, serotonin and hydroxyindolacetate. Amino acids converted to their dansyl derivatives and separated by HPLC were: Aspartate, glutamate, glutamine, gamma aminobutyrate and taurine. Many neurotransmitters were found increased in brain after prenatal irradiation, particularly on day 12 and 15 p.c. Marked changes were found for serotonin in several brain structures and for dopamin in striatum. An increase was also found in glutamate, glutamine and GABA. Studies on regional blood flow using injection of labelled 15 μ microspheres did not reveal significant alterations after prenatal irradiation. (orig.)

  13. Human Umbilical Cord Blood Cells Restore Brain Damage Induced Changes in Rat Somatosensory Cortex

    Science.gov (United States)

    Geißler, Maren; Dinse, Hubert R.; Neuhoff, Sandra; Kreikemeier, Klaus; Meier, Carola

    2011-01-01

    Intraperitoneal transplantation of human umbilical cord blood (hUCB) cells has been shown to reduce sensorimotor deficits after hypoxic ischemic brain injury in neonatal rats. However, the neuronal correlate of the functional recovery and how such a treatment enforces plastic remodelling at the level of neural processing remains elusive. Here we show by in-vivo recordings that hUCB cells have the capability of ameliorating the injury-related impairment of neural processing in primary somatosensory cortex. Intact cortical processing depends on a delicate balance of inhibitory and excitatory transmission, which is disturbed after injury. We found that the dimensions of cortical maps and receptive fields, which are significantly altered after injury, were largely restored. Additionally, the lesion induced hyperexcitability was no longer observed in hUCB treated animals as indicated by a paired-pulse behaviour resembling that observed in control animals. The beneficial effects on cortical processing were reflected in an almost complete recovery of sensorimotor behaviour. Our results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes. We propose that the intermediate level of cortical processing will become relevant as a new stage to investigate efficacy and mechanisms of cell therapy in the treatment of brain injury. PMID:21673795

  14. Oligodendrocyte precursor cells support blood-brain barrier integrity via TGF-β signaling.

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    Ji Hae Seo

    Full Text Available Trophic coupling between cerebral endothelium and their neighboring cells is required for the development and maintenance of blood-brain barrier (BBB function. Here we report that oligodendrocyte precursor cells (OPCs secrete soluble factor TGF-β1 to support BBB integrity. Firstly, we prepared conditioned media from OPC cultures and added them to cerebral endothelial cultures. Our pharmacological experiments showed that OPC-conditioned media increased expressions of tight-junction proteins and decreased in vitro BBB permeability by activating TGB-β-receptor-MEK/ERK signaling pathway. Secondly, our immuno-electron microscopic observation revealed that in neonatal mouse brains, OPCs attach to cerebral endothelial cells via basal lamina. And finally, we developed a novel transgenic mouse line that TGF-β1 is knocked down specifically in OPCs. Neonates of these OPC-specific TGF-β1 deficient mice (OPC-specific TGF-β1 partial KO mice: PdgfraCre/Tgfb1flox/wt mice or OPC-specific TGF-β1 total KO mice: PdgfraCre/Tgfb1flox/flox mice exhibited cerebral hemorrhage and loss of BBB function. Taken together, our current study demonstrates that OPCs increase BBB tightness by upregulating tight junction proteins via TGF-β signaling. Although astrocytes and pericytes are well-known regulators of BBB maturation and maintenance, these findings indicate that OPCs also play a pivotal role in promoting BBB integrity.

  15. Tight junction modulation of the blood brain barrier: CNS delivery of small molecules.

    Science.gov (United States)

    Greene, Chris; Campbell, Matthew

    2016-01-01

    The blood brain barrier (BBB) represents a major obstacle for targeted drug delivery to the brain for the treatment of central nervous system (CNS) disorders. Significant advances in barrier research over the past decade has led to the discovery of an increasing number of structural and regulatory proteins in tight junctions (TJ) and adherens junctions (AJ). These discoveries are providing the framework for the development of novel TJ modulators which can act specifically and temporarily to alter BBB function and regulate paracellular uptake of molecules. TJ modulators that have shown therapeutic potential in preclinical models include claudin-5 and occludin siRNAs, peptides derived from zonula occludens toxin as well as synthetic peptides targeting the extracellular loops of TJs. Adding to the array of modulating agents are novel mechanisms of BBB regulation such as focused ultrasound (FUS). This review will give a succinct overview of BBB biology and TJ modulation in general. Novel insights into BBB regulation in health and disease will also be summarized.

  16. Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models.

    Directory of Open Access Journals (Sweden)

    Iveta Novakova

    Full Text Available The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line for proper data comparison.

  17. Regional cerebral blood flow in various types of brain tumor. Effect of the space-occupying lesion on blood flow in brain tissue close to and remote from tumor site

    DEFF Research Database (Denmark)

    Kuroda, K; Skyhøj Olsen, T; Lassen, N A

    1982-01-01

    Regional cerebral blood flow (rCBF) was measured in 23 patients with brain tumors using the 133Xe intra-carotid injection method and a 254 channel gamma camera. The glioblastomas (4) and astrocytomas (4) all showed hyperemia in the tumor and tumor-near region. This was also seen in several...

  18. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking.

    Science.gov (United States)

    Maggioli, E; McArthur, S; Mauro, C; Kieswich, J; Kusters, D H M; Reutelingsperger, C P M; Yaqoob, M; Solito, E

    2016-01-01

    Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood-brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation. Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models. Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.

  19. In vitro blood-brain barrier permeability predictions for GABAA receptor modulating piperine analogs.

    Science.gov (United States)

    Eigenmann, Daniela Elisabeth; Dürig, Carmen; Jähne, Evelyn Andrea; Smieško, Martin; Culot, Maxime; Gosselet, Fabien; Cecchelli, Romeo; Helms, Hans Christian Cederberg; Brodin, Birger; Wimmer, Laurin; Mihovilovic, Marko D; Hamburger, Matthias; Oufir, Mouhssin

    2016-06-01

    The alkaloid piperine from black pepper (Piper nigrum L.) and several synthetic piperine analogs were recently identified as positive allosteric modulators of γ-aminobutyric acid type A (GABAA) receptors. In order to reach their target sites of action, these compounds need to enter the brain by crossing the blood-brain barrier (BBB). We here evaluated piperine and five selected analogs (SCT-66, SCT-64, SCT-29, LAU397, and LAU399) regarding their BBB permeability. Data were obtained in three in vitro BBB models, namely a recently established human model with immortalized hBMEC cells, a human brain-like endothelial cells (BLEC) model, and a primary animal (bovine endothelial/rat astrocytes co-culture) model. For each compound, quantitative UHPLC-MS/MS methods in the range of 5.00-500ng/mL in the corresponding matrix were developed, and permeability coefficients in the three BBB models were determined. In vitro predictions from the two human BBB models were in good agreement, while permeability data from the animal model differed to some extent, possibly due to protein binding of the screened compounds. In all three BBB models, piperine and SCT-64 displayed the highest BBB permeation potential. This was corroborated by data from in silico prediction. For the other piperine analogs (SCT-66, SCT-29, LAU397, and LAU399), BBB permeability was low to moderate in the two human BBB models, and moderate to high in the animal BBB model. Efflux ratios (ER) calculated from bidirectional permeability experiments indicated that the compounds were likely not substrates of active efflux transporters. PMID:27018328

  20. 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 (pmale animals (pfemale groups; dye contents in the whole brains were 0.14±0.01mg% in the control, 0.24±0.03mg% in 900MHz exposed and 0.14±0.02mg% in 1800MHz exposed animals. No statistical variance found between the control and 1800MHz exposed animals (p>0.01). 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. PMID:26723545

  1. Effect of low-dose methylprednisolone on peripheral blood endothelial progenitor cells and its significance in rats after brain injury

    Directory of Open Access Journals (Sweden)

    Bin ZHANG

    2011-05-01

    Full Text Available Objective To explore the effects of low-dose methylprednisolone(MP treatment after traumatic brain injury(TBI in rats on the number of peripheral blood endothelial progenitor cells(EPCs and injury area of the brain.Methods One hundred and fifty-four adult male Wistar rats were involved in the present study,and they were randomly divided into normal control group(n=18,TBI control group(n=38,MP control group(n=30,MP+TBI group(n=30 and TBI+MP group(n=38.The TBI model was reproduced by fluid percussion injury(FPI.MP(5mg/kg was intraperitoneally administered once a day for 4 days.Peripheral venous blood samples were taken on day 1,3,7 and 14,and the counts of EPCs were determined by flow cytometry.The rats were sacrificed on day 1 and 3,brain edema was estimated by dry-wet weight method,and the blood-brain barrier(BBB permeability was determined by Evans-blue extravasation.Results The counts of peripheral blood EPCs were significantly higher in MP control group,MP+TBI group and TBI+MP group on day 1,3 and 7 than that in normal control and TBI control group,and it returned to the level of normal control group on day 14.The BBB permeability was improved and brain edema alleviated in MP+TBI and TBI+MP group on day 3.Conclusion The administration of low-dose MP may increase the count of peripheral blood EPCs in rats,decrease BBB damage,and alleviate brain edema.

  2. Healthy Muscles Matter

    Science.gov (United States)

    ... body? These muscles help you move, lift things, pump blood through your body, and even help you breathe. ... is a specialized type of involuntary muscle. It pumps blood through your body, changing its speed to keep ...

  3. Correlation of acetylcholinesterase activity in the brain and blood of wistar rats acutely infected with Trypanosoma congolense

    Institute of Scientific and Technical Information of China (English)

    Habila N; Inuwa HM; Aimola IA; Lasisi OI; Chechet DG; Okafor IA

    2012-01-01

    Objective: To investigate the neurotransmitter enzyme Acetylcholinesterase (AChE) activity in the brain and blood of rats infected with Trypanosoma congolense (T. congo). Methods: Presence and degree of parasitemia was determined daily for each rat by the rapid matching method. AChE activity was determined by preparing a reaction mixture of brain homogenate and whole blood with 5, 5-dithiobisnitrobenzioc acid (DTNB or Ellman’s reagent) and Acetylthiocholine (ATC). The increase in absorbance was recorded at 436 nm over 10 min at 2 min intervals. Trypanosome species identification (before inoculation and on day 10 post infection) was done by Polymerase chain reaction using specific primers. Results: The AChE activity in the brain and blood decreased significantly as compared with the uninfected control. The AChE activity dropped to 0.32 from 2.20 μmol ACTC min-1mg protein-1 in the brain and 4.57 to 0.76 μmol ACTC min-1mg protein-1 in the blood. The animals treated with Diminaveto at 3.5 mg/kg/d were observed to have recovered significantly from parasitemia and were able to regain AChE activity in the blood but not in the brain as compared to the control groups. We also observed, that progressive parasitemia resulted to alterations in PCV, Hb, RBC, WBC, neurophils, total protein, lymphocytes, monocytes and eosinophil in acute infections of T. congo. Polymerase chain reaction (PCR) of infected blood before inoculation and on day 10 post infection revealed 600 bp on agarose gel electrophoresis. Conclusions: This finding suggest that decrease in AChE activity increases acetylcholine concentration in the synaptic cleft resulting to neurological failures in impulse transfer in T. congo infection rats.

  4. Anemia and Blood Transfusion in Patients with Isolated Traumatic Brain Injury

    Science.gov (United States)

    Al-Dorzi, Hasan M.; Al-Humaid, Waleed; Tamim, Hani M.; Haddad, Samir; Aljabbary, Ahmad; Arifi, Abdulaziz; Arabi, Yaseen M.

    2015-01-01

    Rationale. By reducing cerebral oxygen delivery, anemia may aggravate traumatic brain injury (TBI) secondary insult. This study evaluated the impact of anemia and blood transfusion on TBI outcomes. Methods. This was a retrospective cohort study of adult patients with isolated TBI at a tertiary-care intensive care unit from 1/1/2000 to 31/12/2011. Daily hemoglobin level and packed red blood cell (PRBC) transfusion were recorded. Patients with hemoglobin < 10 g/dL during ICU stay (anemic group) were compared with other patients. Results. Anemia was present on admission in two (2%) patients and developed in 48% during the first week with hemoglobin < 7 g/dL occurring in 3.0%. Anemic patients had higher admission Injury Severity Score and underwent more craniotomy (50% versus 13%, p < 0.001). Forty percent of them received PRBC transfusion (2.8 ± 1.5 units per patient, median pretransfusion hemoglobin = 8.8 g/dL). Higher hospital mortality was associated with anemia (25% versus 6% for nonanemic patients, p = 0.01) and PRBC transfusion (38% versus 9% for nontransfused patients, p = 0.003). On multivariate analysis, only PRBC transfusion independently predicted hospital mortality (odds ratio: 6.8; 95% confidence interval: 1.1–42.3). Conclusions. Anemia occurred frequently after isolated TBI, but only PRBC transfusion independently predicted mortality. PMID:26605080

  5. Caffeine blocks disruption of blood brain barrier in a rabbit model of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Ghribi Othman

    2008-04-01

    Full Text Available Abstract High levels of serum cholesterol and disruptions of the blood brain barrier (BBB have all been implicated as underlying mechanisms in the pathogenesis of Alzheimer's disease. Results from studies conducted in animals and humans suggest that caffeine might be protective against Alzheimer's disease but by poorly understood mechanisms. Using rabbits fed a cholesterol-enriched diet, we tested our hypothesis that chronic ingestion of caffeine protects against high cholesterol diet-induced disruptions of the BBB. New Zealand rabbits were fed a 2% cholesterol-enriched diet, and 3 mg caffeine was administered daily in drinking water for 12 weeks. Total cholesterol and caffeine concentrations from blood were measured. Olfactory bulbs (and for some studies hippocampus and cerebral cortex as well were evaluated for BBB leakage, BBB tight junction protein expression levels, activation of astrocytes, and microglia density using histological, immunostaining and immunoblotting techniques. We found that caffeine blocked high cholesterol diet-induced increases in extravasation of IgG and fibrinogen, increases in leakage of Evan's blue dye, decreases in levels of the tight junction proteins occludin and ZO-1, increases in astrocytes activation and microglia density where IgG extravasation was present. Chronic ingestion of caffeine protects against high cholesterol diet-induced increases in disruptions of the BBB, and caffeine and drugs similar to caffeine might be useful in the treatment of Alzheimer's disease.

  6. A Novel Dynamic Neonatal Blood-Brain Barrier on a Chip.

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    Sudhir P Deosarkar

    Full Text Available Studies of neonatal neural pathologies and development of appropriate therapeutics are hampered by a lack of relevant in vitro models of neonatal blood-brain barrier (BBB. To establish such a model, we have developed a novel blood-brain barrier on a chip (B3C that comprises a tissue compartment and vascular channels placed side-by-side mimicking the three-dimensional morphology, size and flow characteristics of microvessels in vivo. Rat brain endothelial cells (RBEC isolated from neonatal rats were seeded in the vascular channels of B3C and maintained under shear flow conditions, while neonatal rat astrocytes were cultured under static conditions in the tissue compartment of the B3C. RBEC formed continuous endothelial lining with a central lumen along the length of the vascular channels of B3C and exhibited tight junction formation, as measured by the expression of zonula occludens-1 (ZO-1. ZO-1 expression significantly increased with shear flow in the vascular channels and with the presence of astrocyte conditioned medium (ACM or astrocytes cultured in the tissue compartment. Consistent with in vivo BBB, B3C allowed endfeet-like astrocyte-endothelial cell interactions through a porous interface that separates the tissue compartment containing cultured astrocytes from the cultured RBEC in the vascular channels. The permeability of fluorescent 40 kDa dextran from vascular channel to the tissue compartment significantly decreased when RBEC were cultured in the presence of astrocytes or ACM (from 41.0 ± 0.9 x 10-6 cm/s to 2.9 ± 1.0 x 10-6 cm/s or 1.1±0.4 x 10-6 cm/s, respectively. Measurement of electrical resistance in B3C further supports that the addition of ACM significantly improves the barrier function in neonatal RBEC. Moreover, B3C exhibits significantly improved barrier characteristics compared to the transwell model and B3C permeability was not significantly different from the in vivo BBB permeability in neonatal rats. In summary, we

  7. Ruta 6 selectively induces cell death in brain cancer cells but proliferation in normal peripheral blood lymphocytes: A novel treatment for human brain cancer.

    Science.gov (United States)

    Pathak, Sen; Multani, Asha S; Banerji, Pratip; Banerji, Prasanta

    2003-10-01

    Although conventional chemotherapies are used to treat patients with malignancies, damage to normal cells is problematic. Blood-forming bone marrow cells are the most adversely affected. It is therefore necessary to find alternative agents that can kill cancer cells but have minimal effects on normal cells. We investigated the brain cancer cell-killing activity of a homeopathic medicine, Ruta, isolated from a plant, Ruta graveolens. We treated human brain cancer and HL-60 leukemia cells, normal B-lymphoid cells, and murine melanoma cells in vitro with different concentrations of Ruta in combination with Ca3(PO4)2. Fifteen patients diagnosed with intracranial tumors were treated with Ruta 6 and Ca3(PO4)2. Of these 15 patients, 6 of the 7 glioma patients showed complete regression of tumors. Normal human blood lymphocytes, B-lymphoid cells, and brain cancer cells treated with Ruta in vitro were examined for telomere dynamics, mitotic catastrophe, and apoptosis to understand the possible mechanism of cell-killing, using conventional and molecular cytogenetic techniques. Both in vivo and in vitro results showed induction of survival-signaling pathways in normal lymphocytes and induction of death-signaling pathways in brain cancer cells. Cancer cell death was initiated by telomere erosion and completed through mitotic catastrophe events. We propose that Ruta in combination with Ca3(PO4)2 could be used for effective treatment of brain cancers, particularly glioma.

  8. Capillary pericytes regulate cerebral blood flow in health and disease

    DEFF Research Database (Denmark)

    Hall, Catherine N; Reynell, Clare; Gesslein, Bodil;

    2014-01-01

    Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate...... blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain...

  9. Regional blood flow in brain and peripheral tissues during acute experimental arterial subdural bleeding.

    Science.gov (United States)

    Orlin, J R; Zwetnow, N N; Hall, C

    1993-01-01

    The effects of a large intracranial arterial subdural bleeding on regional blood flow in the brain (rCBF) and in other body organs were studied, using a porcine model. The bleeding was produced by leading blood through a catheter from the abdominal aorta via an electronic drop recorder into the subdural compartment (SDC) over the left cerebral hemisphere. Pressures in the right lateral cerebral ventricle and in the cisterna magna were recorded along with 15 other vital parameters. Measurements of rCBF were carried out using radioactive microspheres 1) before the start of bleeding, 2) during the early bleeding phase, and 3) during the late bleeding phase. When the bleeding was initiated, the intracranial pressures rose within one minute to a level approximately 40 mmHg below the systemic arterial pressure, whilst the latter usually decreased 30-40 mmHg. In the subsequent early bleeding phase the cerebral perfusion pressure and the bleeding pressure fluctuated at a level of approximately 40 mmHg for several minutes. In the late bleeding phase, the perfusion pressure decreased maximally, even when a Cushing reaction was activated. During the early bleeding phase the changes in rCBF varied between the cerebral regions. However, the mean flow remained largely constant in the presence of a decreasing cerebrovascular resistance, indicating that autoregulation of CBF was intact. Concomitantly, cardiac output and heart rate decreased, whilst regional blood flow in extracerebral organs tended to increase, possibly due to an intracranial effect on the autonomic nervous system. In the late bleeding phase, rCBF was critically reduced in all regions, in spite of a marked rise in systemic arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8372718

  10. Effect of insulin on human skeletal muscle protein synthesis is modulated by insulin-induced changes in muscle blood flow and amino acid availability

    OpenAIRE

    Fujita, Satoshi; Rasmussen, Blake B.; Cadenas, Jerson G.; Grady, James J.; Volpi, Elena

    2006-01-01

    Insulin promotes muscle anabolism, but it is still unclear whether it stimulates muscle protein synthesis in humans. We hypothesized that insulin can increase muscle protein synthesis only if it increases muscle amino acid availability. We measured muscle protein and amino acid metabolism using stable-isotope methodologies in 19 young healthy subjects at baseline and during insulin infusion in one leg at low (LD, 0.05), intermediate (ID, 0.15), or high (HD, 0.30 mU·min−1·100 ml−1) doses. Insu...

  11. Enhanced delivery of iodine for synchrotron stereotactic radiotherapy by means of intracarotid injection and blood-brain barrier disruption: Quantitative iodine biodistribution studies and associated dosimetry

    International Nuclear Information System (INIS)

    Purpose: Synchrotron stereotactic radiotherapy (SSR) is a binary cancer treatment modality that involves the selective accumulation of a high Z element, such as iodine, in tumors, followed by stereotactic irradiation with kilovoltage X-rays from a synchrotron source. The success of SSR is directly related to the absolute amount of iodine achievable in the tumor. The purposes of this preclinical study were to determine whether the delivery of iodine to brain tumor models in rats could be enhanced by the means of its intracarotid injection with or without a hyperosmotic solution and to evaluate corresponding absorbed X-ray doses. Methods and materials: Experiments were performed on four groups of F98 glioma-bearing rats, which received either intracarotid (IC) or intravenous (IV) infusions of a mixture (6 mL in 12 min) of an iodinated contrast agent associated or not with a transient blood-brain barrier opener (mannitol). The mixture volumetric proportions were 8/13 of Iomeron (C = 350 mg/mL) for 5/13 of mannitol or saline, respectively. Absolute iodine concentration kinetic was measured in vivo in the tumor, blood, contralateral and ipsilateral brain, and muscle by monochromatic computed tomography. Associated dosimetry was performed by computing the iodine dose enhancement factor (DEF) in each region and building dose distribution maps by analytical simulations. Results: Infusion of mannitol significantly enhanced iodine tumor uptake compared with the control values (p < 0.0001 and p = 0.0138, for IC and IV protocols, respectively). The mean iodine concentrations (C) reached 20.5 ± 0.98 mg/mL (DEF = 4.1) after administration of iodine and mannitol vs. 4.1 ± 1.2 mg/mL i.c. with serum (DEF = 1.6). The tumor iodine uptakes after jugular injection with mannitol (C = 4.4 ± 2.1 mg/mL, DEF = 1.7) were not significantly different from IC injection of iodine without mannitol (p = 0.8142). The IV injection of iodine with saline led to an iodine concentration in the tumor

  12. Non-invasive laser Doppler perfusion measurements of large tissue volumes and human skeletal muscle blood RMS velocity

    International Nuclear Information System (INIS)

    This study proposes the implementation of an algorithm allowing one to derive absolute blood root-mean-square (RMS) velocity values from laser Doppler perfusion meter (LDP) data. The algorithm is based on the quasi-elastic light scattering theory and holds for multiple scattering. While standard LDP measurements are normally applicable to a small region of interest (∼1 mm2), the present method allows the analysis of both small and large tissue volumes with small and large interoptode spacings (e.g., 1.5 cm). The applicability and the limits of the method are demonstrated with measurements on human skeletal muscle using a custom-built near-infrared LDP meter. Human brachioradialis muscle RMS velocity values of 9.99 ± 0.01 and 5.58 ± 0.03 mm s-1 at 1.5 cm and of 5.18 ± 0.01 and 2.54 ± 0.09 mm s-1 at 2 cm were found when the arm was (a) at rest and (b) occluded, respectively. At very large optode spacings or very high moving particle densities, the theory developed here would need to be amended to take into account second-order effects

  13. Smooth Muscle Cell Alignment and Phenotype Control by Melt Spun Polycaprolactone Fibers for Seeding of Tissue Engineered Blood Vessels

    Directory of Open Access Journals (Sweden)

    Animesh Agrawal

    2015-01-01

    Full Text Available A method has been developed to induce and retain a contractile phenotype for vascular smooth muscle cells, as the first step towards the development of a biomimetic blood vessel construct with minimal compliance mismatch. Melt spun PCL fibers were deposited on a mandrel to form aligned fibers of 10 μm in diameter. The fibers were bonded into aligned arrangement through dip coating in chitosan solution. This formed a surface of parallel grooves, 10 μm deep by 10 μm across, presenting a surface layer of chitosan to promote cell surface interactions. The aligned fiber surface was used to culture cells present in the vascular wall, in particular fibroblasts and smooth muscle cells. This topography induced “surface guidance” over the orientation of the cells, which adopted an elongated spindle-like morphology, whereas cells on the unpatterned control surface did not show such orientation, assuming more rhomboid shapes. The preservation of VSMC contractile phenotype on the aligned scaffold was demonstrated by the retention of α-SMA expression after several days of culture. The effect was assessed on a prototype vascular graft prosthesis fabricated from polylactide caprolactone; VSMCs aligned longitudinally along a fiberless tube, whereas, for the aligned fiber coated tubes, the VSMCs aligned in the required circumferential orientation.

  14. Smooth Muscle Cell Alignment and Phenotype Control by Melt Spun Polycaprolactone Fibers for Seeding of Tissue Engineered Blood Vessels.

    Science.gov (United States)

    Agrawal, Animesh; Lee, Bae Hoon; Irvine, Scott A; An, Jia; Bhuthalingam, Ramya; Singh, Vaishali; Low, Kok Yao; Chua, Chee Kai; Venkatraman, Subbu S

    2015-01-01

    A method has been developed to induce and retain a contractile phenotype for vascular smooth muscle cells, as the first step towards the development of a biomimetic blood vessel construct with minimal compliance mismatch. Melt spun PCL fibers were deposited on a mandrel to form aligned fibers of 10 μm in diameter. The fibers were bonded into aligned arrangement through dip coating in chitosan solution. This formed a surface of parallel grooves, 10 μm deep by 10 μm across, presenting a surface layer of chitosan to promote cell surface interactions. The aligned fiber surface was used to culture cells present in the vascular wall, in particular fibroblasts and smooth muscle cells. This topography induced "surface guidance" over the orientation of the cells, which adopted an elongated spindle-like morphology, whereas cells on the unpatterned control surface did not show such orientation, assuming more rhomboid shapes. The preservation of VSMC contractile phenotype on the aligned scaffold was demonstrated by the retention of α-SMA expression after several days of culture. The effect was assessed on a prototype vascular graft prosthesis fabricated from polylactide caprolactone; VSMCs aligned longitudinally along a fiberless tube, whereas, for the aligned fiber coated tubes, the VSMCs aligned in the required circumferential orientation. PMID:26413093

  15. Combined intermittent hypoxia and surface muscle electrostimulation as a method to increase peripheral blood progenitor cell concentration

    Directory of Open Access Journals (Sweden)

    Azqueta Carmen

    2009-10-01

    Full Text Available Abstract Background Our goal was to determine whether short-term intermittent hypoxia exposure, at a level well tolerated by healthy humans and previously shown by our group to increase EPO and erythropoiesis, could mobilize hematopoietic stem cells (HSC and increase their presence in peripheral circulation. Methods Four healthy male subjects were subjected to three different protocols: one with only a hypoxic stimulus (OH, another with a hypoxic stimulus plus muscle electrostimulation (HME and the third with only muscle electrostimulation (OME. Intermittent hypobaric hypoxia exposure consisted of only three sessions of three hours at barometric pressure 540 hPa (equivalent to an altitude of 5000 m for three consecutive days, whereas muscular electrostimulation was performed in two separate periods of 25 min in each session. Blood samples were obtained from an antecubital vein on three consecutive days immediately before the experiment and 24 h, 48 h, 4 days and 7 days after the last day of hypoxic exposure. Results There was a clear increase in the number of circulating CD34+ cells after combined hypobaric hypoxia and muscular electrostimulation. This response was not observed after the isolated application of the same stimuli. Conclusion Our results open a new application field for hypobaric systems as a way to increase efficiency in peripheral HSC collection.

  16. Commentary on “Alzheimer’s disease drug development and the problem of the blood-brain barrier”

    Science.gov (United States)

    Simpkins, James W.

    2016-01-01

    The perspective by Dr. William Pardridge entitled “Alzheimer’s Disease Drug Discovery and the Problem of the Blood-Brain Barrier” makes a strong case for the imbalance in resource distribution to the drug-discovery and brain drug delivery processes, where the latter received less than 1% of the investment of the former. My own calculations are consistent with this striking imbalance. Dr. Pardridge predicts that current trials of passive immunity against β-amyloid peptide will likely fail, whereas past trials of active immunization exhibited trial-ending side effects, in part because of disruption of the integrity of the blood-brain barrier. To bring an assessment of the physiology of the blood-brain barrier and the brain delivery of drugs to the fore, several changes are needed in the way we perceive the problem, train our young scientists, organize research efforts, and incentivize reaching our common goals of effective drug therapy for Alzheimer’s disease. PMID:19751923

  17. Blood-brain barrier transport and protein binding of flumazenil and iomazenil in the rat: implications for neuroreceptor studies

    DEFF Research Database (Denmark)

    Videbaek, C; Ott, P; Paulson, O B;

    1999-01-01

    The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements...

  18. Pig brain stereotaxic standard space: mapping of cerebral blood flow normative values and effect of MPTP-lesioning

    DEFF Research Database (Denmark)

    Andersen, F; Watanabe, Hideaki; Bjarkam, Carsten;

    2005-01-01

    of minipig brain, we calculated cerebral blood flow (CBF) maps from normal minipigs and from minipigs with a syndrome of parkisonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-poisoning. These maps were transformed from the native space into the common stereotaxic space. After global...

  19. Kinetic modeling of Fe-52/Mn-52m-citrate at the blood-brain barrier by positron emission tomography

    NARCIS (Netherlands)

    Calonder, C; Wurtenberger, PI; Maguire, RP; Pellikka, R; Leenders, KL

    1999-01-01

    The kinetics of iron at the blood-brain barrier of the monkey were studied in vivo using positron emission tomography (PET) and the tracer Fe-52/Mn-52m-citrate. Mn-52m is the beta(+)-emitting daughter nuclide of Fe-52 and therefore contributes to the observed signal and background in the PET images

  20. Localization of CGRP, CGRP receptor, PACAP and glutamate in trigeminal ganglion. Relation to the blood-brain barrier

    DEFF Research Database (Denmark)

    Eftekhari, Sajedeh; Salvatore, Christopher A; Johansson, Sara;

    2015-01-01

    ) and related this to the expression of CGRP and its receptor in rhesus trigeminal ganglion. Pituitary adenylate cyclase-activating polypeptide (PACAP) and glutamate were examined and related to the CGRP system. Furthermore, we examined if the trigeminal ganglion is protected by the blood-brain barrier...