WorldWideScience

Sample records for brain ischemia

  1. CSF transthyretin neuroprotection in a mouse model of brain ischemia

    DEFF Research Database (Denmark)

    Santos, Sofia Duque; Lambertsen, Kate Lykke; Clausen, Bettina Hjelm

    2010-01-01

    Brain injury caused by ischemia is a major cause of human mortality and physical/cognitive disability worldwide. Experimentally, brain ischemia can be induced surgically by permanent middle cerebral artery occlusion. Using this model, we studied the influence of transthyretin in ischemic stroke...... neuronal cell death, edema and inflammation, thereby influencing the survival of endangered neurons in cerebral ischemia....

  2. Hydrogen ion buffering during complete brain ischemia.

    Science.gov (United States)

    Kraig, R P; Pulsinelli, W A; Plum, F

    1985-09-09

    As a first step to quantify [H+] changes in brain during ischemia we used H+-selective microelectrodes and enzyme fluorometric techniques to describe the relationship between interstitial [H+] ([H+]o) and peak tissue lactate after cardiac arrest. We found a step function relationship between [H+]o and tissue lactate rather than the linear titration expected in a homogeneous protein solution. Within a blood glucose range from 3-7 mM, brain lactate rose from 8-13 mmol/kg along with a rise in [H+]o of 99 +/- 6 nM(0.44 +/- 0.02 pH). At higher blood glucose levels (17-80 mM), brain lactate accumulated to levels of 16-31 mmol/kg; concurrently [H+]o rose by 608 +/- 16 nM (1.07 +/- 0.02 pH). The unchanging level of [H+]o between 8-13 and 16-31 mmol/kg lactate implies that [H+]o is at a steady-state, but not equilibrium with respect to [H+] in other brain compartments. We propose that ion-transport characteristics of astroglia account for the observed relationship of [H+]o to tissue lactate during complete ischemia and suggest that brain infarction develops after plasma membranes in brain cells can no longer transport ions to regulate [H+].

  3. Hydrogen Ion Buffering During Complete Brain Ischemia

    OpenAIRE

    Kraig, Richard P.; PULSINELLI, WILLIAM A.; Plum, Fred

    1985-01-01

    As a first step to quantify [H+] changes in brain during ischemia we used H+-selective microelectrodes and enzyme fluorometric techniques to describe the relationship between interstitial [H+] ([H+]o) and peak tissue lactate after cardiac arrest. We found a step function relationship between [H+]o and tissue lactate rather than the linear titration expected in a homogeneous protein solution. Within a blood glucose range from 3–7 mM, brain lactate rose from 8–13 mmol/kg along with a rise in [H...

  4. Review on herbal medicine on brain ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Nahid Jivad; Zahra Rabiei

    2015-01-01

    Brain ischemia and reperfusion is the leading cause of serious and long-range disability in the world. Clinically significant changes in central nervous system function are observed following brain ischemia and reperfusion. Stroke patients exhibit behavioral, cognitive, emotional, affective and electrophysiological changes during recovery phase. Brain injury by transient complete global brain ischemia or by transient incomplete brain ischemia afflicts a very large number of patients in the world with death or permanent disability. In order to reduce this damage, we must sufficiently understand the mechanisms involved in brain ischemia and reperfusion and repair to design clinically effective therapy. Cerebral ischemia and reperfusion is known to induce the generation of reactive oxygen species that can lead to oxidative damage of proteins, membrane lipids and nucleic acids. A decrease in tissue antioxidant capacity, an increase in lipid peroxidation as well as an increase in lipid peroxidation inhibitors have been demonstrated in several models of brain ischemia. This paper reviews the number of commonly used types of herbal medicines effective for the treatment of stroke. The aim of this paper was to review evidences from controlled studies in order to discuss whether herbal medicine can be helpful in the treatment of brain ischemia and reperfusion.

  5. Review on herbal medicine on brain ischemia and reperfusion简

    Institute of Scientific and Technical Information of China (English)

    Nahid; Jivad; Zahra; Rabiei

    2015-01-01

    Brain ischemia and reperfusion is the leading cause of serious and long-range disability in the world. Clinically significant changes in central nervous system function are observed following brain ischemia and reperfusion. Stroke patients exhibit behavioral, cognitive,emotional, affective and electrophysiological changes during recovery phase. Brain injury by transient complete global brain ischemia or by transient incomplete brain ischemia afflicts a very large number of patients in the world with death or permanent disability. In order to reduce this damage, we must sufficiently understand the mechanisms involved in brain ischemia and reperfusion and repair to design clinically effective therapy.Cerebral ischemia and reperfusion is known to induce the generation of reactive oxygen species that can lead to oxidative damage of proteins, membrane lipids and nucleic acids.A decrease in tissue antioxidant capacity, an increase in lipid peroxidation as well as an increase in lipid peroxidation inhibitors have been demonstrated in several models of brain ischemia. This paper reviews the number of commonly used types of herbal medicines effective for the treatment of stroke. The aim of this paper was to review evidences from controlled studies in order to discuss whether herbal medicine can be helpful in the treatment of brain ischemia and reperfusion.

  6. [Neuroprotective mechanisms of cannabinoids in brain ischemia and neurodegenerative disorders].

    Science.gov (United States)

    Osuna-Zazuetal, Marcela Amparo; Ponce-Gómez, Juan Antonio; Pérez-Neri, Iván

    2015-06-01

    One of the most important causes of morbidity and mortality is neurologic dysfunction; its high incidence has led to an intense research of the mechanisms that protect the central nervous system from hypoxia and ischemia. The mayor challenge is to block the biochemical events leading to neuronal death. This may be achieved by neuroprotective mechanisms that avoid the metabolic and immunologic cascades that follow a neurological damage. When it occurs, several pathophysiological events develop including cytokine release, oxidative stress and excitotoxicity. Neuroprotective effects of cannabinoids to all those mechanisms have been reported in animal models of brain ischemia, excitotoxicity, brain trauma and neurodegenerative disorders. Some endocannabinoid analogs are being tested in clinical studies (I-III phase) for acute disorders involving neuronal death (brain trauma and ischemia). The study of the cannabinoid system may allow the discovery of effective neuroprotective drugs for the treatment of neurological disorders.

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

    Science.gov (United States)

    Dirnagl, U; Pulsinelli, W

    1990-05-01

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

  8. Selective glial vulnerability following transient global ischemia in rat brain.

    Science.gov (United States)

    Petito, C K; Olarte, J P; Roberts, B; Nowak, T S; Pulsinelli, W A

    1998-03-01

    Global cerebral ischemia selectively damages neurons, but its contribution to glial cell death is uncertain. Accordingly, adult male rats were sacrificed by perfusion fixation at 1, 2, 3, 5, and 14 days following 10 minutes of global ischemia. This insult produces CA1 hippocampal neuronal death at post-ischemic (PI) day 3, but minor or no damage to neurons in other regions. In situ end labeling (ISEL) and immunohistochemistry identified fragmented DNA of dead or dying glia and distinguished glial subtypes. Rare ISEL-positive oligodendroglia, astrocytes, and microglia were present in control brain. Apoptotic bodies and ISEL-positive glia significantly increased at PI day 1 in cortex and thalamus (p < 0.05), but were similar to controls in other regions and at other PI intervals. Most were oligodendroglia, although ISEL-positive microglia and astrocytes were also observed. These results show that oligodendroglia die rapidly after brief global ischemia and are more sensitive than neurons in certain brain regions. Their selective vulnerability to ischemia may be responsible for the delayed white matter damage following anoxia or CO poisoning or that associated with white matter arteriopathies. Glial apoptosis could contribute to the DNA ladders of apoptotic oligonucleosomes that have been found in post-ischemic brain.

  9. Regional protein synthesis in rat brain following acute hemispheric ischemia.

    Science.gov (United States)

    Dienel, G A; Pulsinelli, W A; Duffy, T E

    1980-11-01

    Regional protein synthesis was measured in rat brain at intervals up to 48 h following occlusion of the four major arteries to the brain for either 10 or 30 min. Four-vessel occlusions produces ischemia in the cerebral hemispheres and oligemia in the midbrain-diencephalon and brainstem. During the hour following 10 min of ischemia, protein synthesis, measured by incorporation of [14C]valine into protein, was inhibited in the cerebral cortex by 67%. Normal rates of protein synthesis were attained within 4 h of recirculation. In rats subjected to 30 min of ischemia, protein synthesis was inhibited by 83% during the first hour of recirculation in the cortex, caudate-putamen, and hippocampus. Recovery of protein synthesis in these regions was slow (25-48 h). The midbrain-diencephalon showed less inhibition, 67%, and faster recovery (by 12 h). Protein synthesis was unaffected in the brainstem. [14C]Autoradiography revealed that the pyramidal neurons of the hippocampus and areas of the caudate and cortex failed to recover normal rates of protein synthesis even after 48 h. The accumulation of TCA-soluble [14C]valine was enhanced (55-65%) in the cortex, caudate, and hippocampus after 30 min of ischemia; the increase persisted for 12 h. A smaller rise in [14C]valine content (30%) and more rapid normalization of valine accumulation (by 7 h) were observed in the midbrain-diencephalon; no changes were found in the brainstem. In the cortex, recovery was more rapid when the duration of ischemia was reduced. Thus, the degree of inhibition of protein synthesis, the accumulation of valine in the tissue, and the length of time required to reestablish normal values for these processes were dependent on both the severity and the duration of the ischemic insult. Restoration of normal rates of protein synthesis after ischemia was slow compared with the normalization of cerebral energy metabolites.

  10. Transient brain ischemia: NMDA receptor modulation and delayed neuronal death

    OpenAIRE

    Benquet, Pascal; Gee, Christine E.; Gerber, Urs

    2008-01-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiolo...

  11. Hydrogen ions kill brain at concentrations reached in ischemia.

    Science.gov (United States)

    Kraig, R P; Petito, C K; Plum, F; Pulsinelli, W A

    1987-08-01

    Elevation of brain glucose before the onset of nearly complete ischemia leads to increased lactic acid within brain. When excessive, such acidosis may be a necessary factor for converting selective neuronal loss to brain infarction from nearly complete ischemia. To examine the potential neurotoxicity of excessive lactic acid concentrations, we microinjected (0.5 microliter/min) 150 mM sodium lactate solutions (adjusted to 6.50-4.00 pH) for 20 min into parietal cortex of anesthetized rats. Interstitial pH (pH0) was monitored with hydrogen ion-selective microelectrodes. Animals were allowed to recover for 24 h before injection zones were examined with the light microscope. Injectants produced brain necrosis in a histological pattern resembling ischemic infarction only when pH0 was less than or equal to 5.30. Nonlethal injections showed only needle tract injuries. Abrupt deterioration of brain acid-base homeostatic mechanisms correlated with necrosis since pH0 returned to baseline more slowly after lethal tissue injections than after nonlethal ones. The slowed return of pH0 to baseline after the severely acidic injections may reflect altered function of plasma membrane antiport systems for pH regulation and loss of brain hydrogen ion buffers.

  12. N-Acetylaspartate distribution in rat brain striatum during acute brain ischemia

    DEFF Research Database (Denmark)

    Sager, T.N.; Laursen, H; Fink-Jensen, A

    1999-01-01

    Brain N-acetylaspartate (NAA) can be quantified by in vivo proton magnetic resonance spectroscopy (1H-MRS) and is used in clinical settings as a marker of neuronal density. It is, however, uncertain whether the change in brain NAA content in acute stroke is reliably measured by 1H-MRS and how NAA......]e increased linearly to 4 mmol/L after 3 hours and this level was maintained for the next 4 h. From the change in in vivo recovery of the interstitial space volume marker [14C]mannitol, the relative amount of NAA distributed in the interstitial space was calculated to be 0.2% of the total brain NAA during...... normal conditions and only 2 to 6% during ischemia. It was concluded that the majority of brain NAA is intracellularly located during ischemia despite large increases of interstitial [NAA]. Thus, MR quantification of NAA during acute ischemia reflects primarily changes in intracellular levels of NAA...

  13. Expression of neuropeptide Y in rat brain ischemia

    Directory of Open Access Journals (Sweden)

    Babović Siniša S.

    2013-01-01

    Full Text Available Introduction. The immunohistochemical method was used to follow the expression of neuropeptide Y in the course of pre ischemia of the rat brain. The aim of the study was to define all the areas of expression of this protein, show their localization, their map of distribution and histological types. Material and Methods. All the sections of telencephalon, diencephalon and midbrain were studied in resistant, and transitory ischemia, which enabled us to observe the reaction of neurons to an ischemic attack or to repeated attacks. The mapping was done for all three proteins by introducing our results into the maps of rat brain atlas, George Paxinos, Charles Watson. Photographing and protein expression was done using Analysis program. Results. The results of this research show that there is a differens in reaction between the resistant and transitory ischemia groups of rats, especially in the caudoputamen, gyrus dentatus, corpus amygdaloideum, particularly in the medial nucleus. The mapping shows the reaction in caudoputamen, gyrusdentatus, corpus amygdaloideum - especially in the central nucleus, then in the sensitive and secondary auditory cortex, mostly in the laminae V/VI, but less in neuron groups CA1, CA2, CA3 of hippocampus. Discussion. The phylogenetically older parts of the brain-rhinencephalon, also showed reaction, which lead us to conclude that both newer and older brain structures reacted immunohistochemically. Histological data have shown that small neurons are most commonly found while the second most common ones are big pyramidal cells of multipolar and bipolar type, with a different body shape. Conclusion. Our findings have confirmed the results obtained in some rare studies dealing with this issue, and offered a precise and detailed map of cells expressing neuropeptide Y in the rat brain following ischemic attack.

  14. Natural Defense Mechanisms of the Human Brain against Chronic Ischemia

    Directory of Open Access Journals (Sweden)

    A. V. Sergeev

    2015-01-01

    Full Text Available Objective: to study the structural bases of natural defense mechanisms of the human brain against chronic ischemia. Materials and methods. To accomplish this, histological, immunohistochemical (NSE, calbindin, NPY, p38 and morphometric examinations of intraoperative biopsy specimens were performed to determine the reorganization of excitatory and inhibitory neurons in the ischemic penumbra of the temporal cerebral cortex (CC. Morphometric analysis was made using the specially developed algorithms to verify neurons and their elements in the ImageJ 1.46 program. Results. The reduction in the total numerical density of neurons and synapses in chronic ischemia was ascertained to be accompanied by the compensatorily enhanced expression of NSE, calbindin, p38, and NPY in the remaining CC neurons. There were signs of hypertrophy of inhibitory CC interneurons and growth of their processes. In consequence, the impact of inhibitory CC interneurons on excitatory neurons was likely to enhance. Conclusion. In chronic ischemia, the human brain is anticipated to respond to damage to some cells via compensatory excitatory and inhibitory neuronal reorganization directed towards its natural defense against excitatory damage and towards better conditions for compensatory recovery of the structure and function of CC. 

  15. [Transient brain ischemia: NMDA receptor modulation and delayed neuronal death].

    Science.gov (United States)

    Benquet, Pascal; Gee, Christine E; Gerber, Urs

    2008-02-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

  16. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia.

    OpenAIRE

    Felicita Pedata; Anna Maria Pugliese; Elisabetta Coppi; Ilaria Dettori; Giovanna Maraula; Lucrezia Cellai; Alessia Melani

    2014-01-01

    The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes). Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by ...

  17. Pharmacological manipulation of brain glycogenolysis as a therapeutic approach to cerebral ischemia.

    Science.gov (United States)

    Xu, Li; Sun, Hongbin

    2010-10-01

    Brain ischemia resulting from multiple disease states including cardiac arrest, stroke and traumatic brain injury, is a leading cause of death and disability. Despite significant resources dedicated to developing pharmacological interventions, few effective therapeutic options are currently available. The basic consequence of cerebral ischemia, characterized by energy failure and subsequent brain metabolic abnormalities, enables the protective effects by pharmacological manipulation of brain metabolism. We present here the important roles of brain glycogen metabolism and propose inhibition of glycogenolysis as a therapeutic approach to cerebral ischemia.

  18. Nonlinear Dynamic Theory of Acute Cell Injuries and Brain Ischemia

    Science.gov (United States)

    Taha, Doaa; Anggraini, Fika; Degracia, Donald; Huang, Zhi-Feng

    2015-03-01

    Cerebral ischemia in the form of stroke and cardiac arrest brain damage affect over 1 million people per year in the USA alone. In spite of close to 200 clinical trials and decades of research, there are no treatments to stop post-ischemic neuron death. We have argued that a major weakness of current brain ischemia research is lack of a deductive theoretical framework of acute cell injury to guide empirical studies. A previously published autonomous model based on the concept of nonlinear dynamic network was shown to capture important facets of cell injury, linking the concept of therapeutic to bistable dynamics. Here we present an improved, non-autonomous formulation of the nonlinear dynamic model of cell injury that allows multiple acute injuries over time, thereby allowing simulations of both therapeutic treatment and preconditioning. Our results are connected to the experimental data of gene expression and proteomics of neuron cells. Importantly, this new model may be construed as a novel approach to pharmacodynamics of acute cell injury. The model makes explicit that any pro-survival therapy is always a form of sub-lethal injury. This insight is expected to widely influence treatment of acute injury conditions that have defied successful treatment to date. This work is supported by NIH NINDS (NS081347) and Wayne State University President's Research Enhancement Award.

  19. Compartmentation of acid-base balance in brain during complete ischemia.

    Science.gov (United States)

    Plum, F; Kraig, R P; Pulsinelli, W A

    1988-01-01

    During near complete hyperglycemic brain ischemia, brain lactate levels rise in excess of 16-18 mmol/K and are associated with severe brain infarction. Analyses of pHo, Pt(CO2), and total brain lactate under these circumstances suggest that H+, HCO3, and lactate become unequally distributed between cells and the interstitial space and, perhaps, even between different types of brain cells. In addition, to whatever physiological advantages it may generate, such compartmentalization may be a factor leading to cell death in brain ischemia.

  20. Brain ischemia changes the long term response to antidepressant drugs in mice.

    Science.gov (United States)

    Deplanque, Dominique; Venna, Venugopal Reddy; Bordet, Régis

    2011-06-01

    Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke.

  1. Expression of Bcl-2 and NF-κB in brain tissue after acute renal ischemia-reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Na Zhang; Gen-Yang Cheng; Xian-Zhi Liu; Feng-Jiang Zhang

    2014-01-01

    Objective:To investigate the effect of acute renal ischemia reperfusion on brain tissue. Methods:Fourty eight rats were randomly divided into four groups(n=12): sham operation group,30 min ischemia60 min reperfusion group,60 min ischemia60 min reperfusion group, and 120 min ischemia60 min reperfusion group.The brain tissues were taken after the experiment. TUNEL assay was used to detect the brain cell apoptosis, and western blot was used to detect the expression of apoptosis-related proteins and inflammatory factors.Results:Renal ischemia-reperfusion induced apoptosis of brain tissues, and the apoptosis increased with prolongation of ischemia time.The detection at the molecular level showed decreasedBcl-2 expression, increasedBax expression, upregulated expression ofNF-κB and its downstream factor COX-2/PGE2.Conclusions:Acute renal ischemia-reperfusion can cause brain tissue damage, manifested as induced brain tissues apoptosis and inflammation activation.

  2. MicroRNA responses to focal cerebral ischemia in male and female mouse brain

    Directory of Open Access Journals (Sweden)

    Theresa Ann Lusardi

    2014-02-01

    Full Text Available Stroke occurs with greater frequency in men than in women across diverse ethnic backgrounds and nationalities. Work from our lab and others have revealed a sex-specific sensitivity to cerebral ischemia whereby males exhibit a larger extent of brain damage resulting from an ischemic event compared to females. Previous studies revealed that microRNA (miRNA expression is regulated by cerebral ischemia in males; however, no studies to date have examined the effect of ischemia on miRNA responses in females. Thus, we examined miRNA responses in male and female brain in response to cerebral ischemia using miRNA arrays. These studies revealed that in male and female brains, ischemia leads to both a universal miRNA response as well as a sexually distinct response to challenge. Target prediction analysis of the miRNAs increased in male or female ischemic brain reveal sex-specific differences in gene targets and protein pathways. These data support that the mechanisms underlying sexually dimorphic responses to cerebral ischemia includes distinct changes in miRNAs in male and female brain, in addition to a miRNA signature response to ischemia that is common to both.

  3. Cerebral white matter injury and damage to myelin sheath following whole-brain ischemia.

    Science.gov (United States)

    Chen, Yingzhu; Yi, Qiong; Liu, Gang; Shen, Xue; Xuan, Lihui; Tian, Ye

    2013-02-01

    Myelin sheath, either in white matter or in other regions of brain, is vulnerable to ischemia. The specific events involved in the progression of ischemia in white matter have not yet been elucidated. The aim of this study was to determine histopathological alterations in cerebral white matter and levels of myelin basic protein (MBP) in ischemia-injured brain tissue during the acute and subacute phases of central nervous injury following whole-brain ischemia. The whole cerebral ischemia model (four-vessel occlusion (4-VO)) was established in adult Sprague-Dawley rats and MBP gene expression and protein levels in the brain tissue were measured using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at 2 days, 4 days, 7 days, 14 days, and 28 days following ischemia. Demyelination was determined by Luxol fast blue myelin staining, routine histopathological staining, and electron microscopy in injured brain tissue. Results showed that edema, vascular dilation, focal necrosis, demyelination, adjacent reactive gliosis and inflammation occurred 7 days after ischemia in HE staining and recovered to control levels at 28 days. The absence of Luxol fast blue staining and vacuolation was clearly visible at 7 days, 14 days, and 28 days. Semiquantitative analysis showed that the transparency of myelin had decreased significantly by 7 days, 14 days, and 28 days. Demyelination and ultrastructual changes were detected 7 days after ischemia. The relative levels of MBP mRNA decreased 2 days after ischemia and this trend continued throughout the remaining four points in time. The MBP levels measured using ELISA also decreased significantly at 2 days and 4 days, but they recovered by 7 days and returned to control levels by 14 days. These results suggest that the impact of ischemia on cerebral white matter is time-sensitive and that different effects may follow different courses over time.

  4. Regional energy balance in rat brain after transient forebrain ischemia.

    Science.gov (United States)

    Pulsinelli, W A; Duffy, T E

    1983-05-01

    Phosphocreatine, ATP, and glucose were severely depleted, and the lactate levels were increased in the paramedian neocortex, dorsal-lateral striatum, and CA1 zone of hippocampus of rats exposed to 30 min of forebrain ischemia. Upon recirculation of the brain, phosphocreatine, ATP, and lactate concentrations recovered to control values in the paramedian neocortex and CA1 zone of hippocampus and to near-control values in the striatum. The phosphocreatine and ATP concentrations then fell and the lactate levels rose in the striatum after 6-24 h, and in the CA1 zone of hippocampus after 24-72 h. The initial recovery and subsequent delayed changes in the phosphocreatine, ATP, and lactate concentrations in the striatum and hippocampus coincided with the onset and progression of morphological injury in these brain regions. The results suggest that cells in these regions regain normal or near-normal mitochondrial function and are viable, in terms of energy production, for many hours before unknown mechanisms cause irreversible neuronal before unknown mechanisms cause irreversible neuronal injury.

  5. Phosphorylation of tau protein over time in rats subjected to transient brain ischemia

    Institute of Scientific and Technical Information of China (English)

    Bo Song; Qiang Ao; Zhen Wang; Weiqiang Liu; Ying Niu; Qin Shen; Huancong Zuo; Xiufang Zhang; Yandao Gong

    2013-01-01

    Transient brain ischemia has been shown to induce hyperphosphorylation of the microtu-bule-associated protein tau. To further determine the mechanisms underlying these processes, we investigated the interaction between tau, glycogen synthase kinase (GSK)-3β and protein phos-phatase 2A. The results confirmed that tau protein was dephosphorylated during brain ischemia;in addition, the activity of GSK-3βwas increased and the activity of protein phosphatase 2A was de-creased. After reperfusion, tau protein was hyperphosphorylated, the activity of GSK-3β was de-creased and the activity of protein phosphatase 2A remained low. Importantly, the interaction of tau with GSK-3β and protein phosphatase 2A was altered during ischemia and reperfusion. Lithium chloride could affect tau phosphorylation by regulating the interaction of tau with GSK-3βand pro-tein phosphatase 2A, and improve learning and memory ability of rats after transient brain ischemia. The present study demonstrated that it was the interaction of tau with GSK-3β and protein phos-phatase 2A, rather than their individual activities, that dominates the phosphorylation of tau in tran-sient brain ischemia. Hyperphosphorylated tau protein may play an important role in the evolution of brain injury in ischemic stroke. The neuroprotective effects of lithium chloride partly depend on the inhibition of tau phosphorylation during transient brain ischemia.

  6. Ischemia

    Science.gov (United States)

    Byeon, Suk Ho; Kim, Min; Kwon, Oh Woong

    "Ischemia" implies a tissue damage derived from perfusion insufficiency, not just an inadequate blood supply. Mild thickening and increased reflectivity of inner retina and prominent inner part of synaptic portion of outer plexiform layer are "acute retinal ischemic changes" visible on OCT. Over time, retina becomes thinner, especially in the inner portion. Choroidal perfusion supplies the outer portion of retina; thus, choroidal ischemia causes predominant change in the corresponding tissue.

  7. Modulation of IκB kinase autophosphorylation and activity following brain ischemia

    Institute of Scientific and Technical Information of China (English)

    SHENWan-Hua; ZHANGHun-Yi; 等

    2003-01-01

    ATIM:To investigate the effects of different antagonists on the alteration of IκB kinase(IKK)activity in rat hipoocampus folluwing global brain ischemia,METHODS:Using 4-vessel occlusion(4-VO)as brain ischemia model,IKK protein expression was examined by immunoblotting and immunoprecipitation,and IKK activity was assayed by in vitro kinase assay.RESULTS:There was no alteration of IKK protein expression following ischemia or ischemia/reperfusion different time points,but IKK activity reached its peak level at ischemia 30min.Pretreatment with N-methyl-D-aspartate(NMDA)receptor antagonist ketamine,non-NMDA receptor antagonist DNQX,or NFκB inhibitor PDTC decreased the IKK activity following brain ischemia 30min.The increase in substrate myelin basic protein(MBP)phosphorylation by IKK is associated with an increase in autophosphorylation of IKK,which can also be antagonized by ketamine,DNQX,and PDTC,CONCLUSION:NMDA receptor and non-NMDA receptor mediate the increase of IKK activity following global brain ischemia in rat hippocampus,which contributes to the alterations of expression and activity of downstream factor NF-κB.

  8. Using laser confocal scanning microscope to study ischemia-hypoxia injury in rat brain slice

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The level of lipid peroxidation and cellular necrosis in rat living brain slices during brain ischemia-hypoxia injury have been observed using a laser confocal scanning microscope (LCSM) with double labeling of fluorescent probes D-399 (2,7-dichlorofluorescin diacetate) and propidium iodide (PI).The hypoxia and/or reoxygenation injury in rat brain slices is markedly decreased by pretreatment with L-NG-nitro-arginine (L-NNA) and N-acetylcysteine (NAC),showing that the nitric oxide (NO) and other free radicals play an important role in brain ischemia-hypoxia injury.

  9. Mild brain ischemia induces unique physiological properties in striatal astrocytes.

    Science.gov (United States)

    Wang, Li-Ping; Cheung, Giselle; Kronenberg, Golo; Gertz, Karen; Ji, Shengbo; Kempermann, Gerd; Endres, Matthias; Kettenmann, Helmut

    2008-07-01

    We studied the properties of GFAP-expressing cells in adult mouse striatum using acute brain slices from transgenic animals expressing EGFP under GFAP promoter. Under physiological conditions, two distinct populations of GFAP-EGFP cells could be identified: (1) brightly fluorescent cells had bushy processes, passive membrane properties, glutamate transporter activity, and high gap junction coupling rate typical for classical astrocytes; (2) weakly fluorescent cells were characterized by thin, clearly distinguishable processes, voltage-gated currents, complex responses to kainate, and low coupling rate reminiscent of an astrocyte subtype recently described in the hippocampus. Mild focal cerebral ischemia confers delayed neuronal cell death and astrogliosis in the striatum. Following middle cerebral artery occlusion and reperfusion, brightly fluorescent cells were the dominant GFAP-EGFP population observed within the ischemic lesion. Interestingly, the majority of these cells expressed voltage-gated channels, showed complex responses to kainate, and a high coupling rate exceeding that of brightly fluorescent control cells. A minority of cells had passive membrane properties and was coupled less compared with passive control cells. We conclude that, in the adult striatum, astrocytes undergo distinct pathophysiological changes after ischemic insults. The dominant population in the ischemic lesion constitutes a novel physiological phenotype unlike any normal astrocyte and generates a large syncytium which might be a neuroprotective response of reactive astrocytes.

  10. Caffeic acid ameliorates early and delayed brain injuries after focal cerebral ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Yu ZHOU; San-hua FANG; Yi-lu YE; Li-sheng CHU; Wei-ping ZHANG; Meng-ling WANG; Er-qing WEI

    2006-01-01

    Aim: To investigate the effects of caffeic acid on early and delayed injuries after focal cerebral ischemia in rats, and the possible relation to 5-lipoxygenase inhibition. Methods: Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in Sprague-Dawley rats. Caffeic acid (10 and 50 mg/kg) was ip injected for 5 d after ischemia. The brain injuries were observed, and the levels of cysteinyl leukotrienes and leukotriene B4 in the brain tissue were measured. Results: Caffeic acid (50 mg/kg) ameliorated neurological dysfunction and neuron loss, and decreased infarct volume 24 h after ischemia; it attenuated brain atrophy, infarct volume, and particularly astrocyte proliferation 14 d after ischemia. In addition, it reduced the production of leukotrienes (5-lipoxygenase metabolites) in the ischemic hemispheres 3 h and 7 d after ischemia. Conclusion: Caffeic acid has protective effect on both early and delayed injuries after focal cerebral ischemia in rats; and this effect may partly relate to 5-lipoxygenase inhibition.

  11. Rapamycin alleviates brain edema after focal cerebral ischemia reperfusion in rats.

    Science.gov (United States)

    Guo, Wei; Feng, Guoying; Miao, Yanying; Liu, Guixiang; Xu, Chunsheng

    2014-06-01

    Brain edema is a major consequence of cerebral ischemia reperfusion. However, few effective therapeutic options are available for retarding the brain edema progression after cerebral ischemia. Recently, rapamycin has been shown to produce neuroprotective effects in rats after cerebral ischemia reperfusion. Whether rapamycin could alleviate this brain edema injury is still unclear. In this study, the rat stroke model was induced by a 1-h left transient middle cerebral artery occlusion using an intraluminal filament, followed by 48 h of reperfusion. The effects of rapamycin (250 μg/kg body weight, intraperitoneal; i.p.) on brain edema progression were evaluated. The results showed that rapamycin treatment significantly reduced the infarct volume, the water content of the brain tissue and the Evans blue extravasation through the blood-brain barrier (BBB). Rapamycin treatment could improve histological appearance of the brain tissue, increased the capillary lumen space and maintain the integrity of BBB. Rapamycin also inhibited matrix metalloproteinase 9 (MMP9) and aquaporin 4 (AQP4) expression. These data imply that rapamycin could improve brain edema progression after reperfusion injury through maintaining BBB integrity and inhibiting MMP9 and AQP4 expression. The data of this study provide a new possible approach for improving brain edema after cerebral ischemia reperfusion by administration of rapamycin.

  12. Protein aggregation in association with delayed neuronal death in rat model of brain ischemia

    Institute of Scientific and Technical Information of China (English)

    Pengfei GE; Tianfei LUG; Shuanglin FU; Wenchen LI; Chonghao WANG; Chuibing ZHOU; Yinan LUO

    2008-01-01

    To investigate the relationship between protein aggregation and delayed neuronal death, we adopted rat models of 20 min ischemia. Brain ischemia was produced using the 2-vessel occlusion (2VO) model in rats Light microscopy, transmission electronic microscopy and Western blot analysis were performed for morphological analysis of neurons, and protein detection. The results showed delayed neuronal death took place at 72 h after ischemia-reperfusion, protein aggregates formed at 4 h after reperfusion and reached the peak at 24 h after reper-fusion, and Western blot analysis was consistent with transmission electronic microscopy. We conclude that protein aggregation is one of the important factors leading to delayed neuronal death.

  13. Protective effects of acupuncture on brain tissue following ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Mingshan Wang; Fuguo Ma; Huailong Chen

    2008-01-01

    BACKGROUND: In patients with cerebrovascular disease, by means of the neuroendocrine system, acupuncture supports the transformation of a local pathological status into a physiological status. Recently, great progress has been made in studying the protective effects of acupuncture on brain ischemia/reperfusion injury. OBJECTIVE: To summarize research advances in the protective effects of acupuncture on brain ischemia/reperfusion injury. RETRIEVAL STRATEGY: Using the terms "acupuncture, transcutaneous electrical acupoint stimulation, cerebral ischemia/reperfusion injury, and cerebral protection", we retrieved articles from the PubMed database published between January 1991 and June 1994. Meanwhile, we searched the China National Knowledge Infrastructure with the same terms. Altogether, 114 articles and their results were analyzed. Inclusive criteria: studies that were closely related to the protective effects of acupuncture on brain ischemia/reperfusion injury, or studies, whose contents were in the same study field and were published recently, or in the authorized journals. Exclusive criteria: repetitive studies. LITERATURE EVALUATION: Thirty articles that related to the protective effects of acupuncture on brain ischemia/reperfusion injury were included. Among them, 7 were clinical studies, and the remaining 23 articles were animal experimental studies. DATA SYNTHESIS: ① Animal experimental studies have demonstrated that acupuncture improves brain blood perfusion and brain electrical activity, influences pathomorphological and ultramicrostructural changes in ischemic brain tissue, is beneficial in maintaining the stability of intracellular and extracellular ions, resists free radical injury and lipid peroxidation, and influences cytokine, neurotransmitter, brain cell signal transduction, and apoptosis-regulating genes. ② Clinical studies have demonstrated that acupuncture not only promotes nutritional supply to local brain tissue in patients with cerebral

  14. A distinct boundary between the higher brain's susceptibility to ischemia and the lower brain's resistance.

    Directory of Open Access Journals (Sweden)

    C Devin Brisson

    Full Text Available Higher brain regions are more susceptible to global ischemia than the brainstem, but is there a gradual increase in vulnerability in the caudal-rostral direction or is there a discrete boundary? We examined the interface between `higher` thalamus and the hypothalamus the using live brain slices where variation in blood flow is not a factor. Whole-cell current clamp recording of 18 thalamic neurons in response to 10 min O2/glucose deprivation (OGD revealed a rapid anoxic depolarization (AD from which thalamic neurons do not recover. Newly acquired neurons could not be patched following AD, confirming significant regional thalamic injury. Coinciding with AD, light transmittance (LT imaging during whole-cell recording showed an elevated LT front that initiated in midline thalamus and that propagated into adjacent hypothalamus. However, hypothalamic neurons patched in paraventricular nucleus (PVN, n= 8 magnocellular and 12 parvocellular neurons and suprachiasmatic nucleus (SCN, n= 18 only slowly depolarized as AD passed through these regions. And with return to control aCSF, hypothalamic neurons repolarized and recovered their input resistance and action potential amplitude. Moreover, newly acquired hypothalamic neurons could be readily patched following exposure to OGD, with resting parameters similar to neurons not previously exposed to OGD. Thalamic susceptibility and hypothalamic resilience were also observed following ouabain exposure which blocks the Na(+/K(+ pump, evoking depolarization similar to OGD in all neuronal types tested. Finally, brief exposure to elevated [K(+]o caused spreading depression (SD, a milder, AD-like event only in thalamic neurons so SD generation is regionally correlated with strong AD. Therefore the thalamus-hypothalamus interface represents a discrete boundary where neuronal vulnerability to ischemia is high in thalamus (like more rostral neocortex, striatum, hippocampus. In contrast hypothalamic neurons are

  15. Alleviation of ischemia-induced brain edema by activation of the central histaminergic system in rats.

    Science.gov (United States)

    Irisawa, Yumi; Adachi, Naoto; Liu, Keyue; Arai, Tatsuru; Nagaro, Takumi

    2008-09-01

    We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of L-histidine, a precursor of histamine, and thioperamide, a histamine H(3)-receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of L-histidine (1000 mg/kg x 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg/kg, s.c.) with L-histidine (1000 mg/kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of L-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with L-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5 - 6 h after reperfusion. L-Histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.

  16. Effects of Moxibustion Pretreating on SOD and MDA in the Rat of Global Brain Ischemia

    Institute of Scientific and Technical Information of China (English)

    HUA Jin-shuang; LI Li-ping; ZHU Xian-min

    2008-01-01

    objective;To probe into the mechanism of moxibustion preconditioning in preventive brain-protecting effect.Methods;The global brain ischemia rat model was developed by blocking 4 artenes.Seventy-eight Wistarmale rats were randomly divided into 5 groups;a nomal control group,a sham-operation group,a brain ischemia group,a brain ischemia preconditioning group,a moxibustion pretreating group.The brains in the 5groups were taken at 24 h,48h,and 72h after operation respectively Superoxide dismulase(SOD)activity was determined with xanthine oxidase method and malondialdehyde(MDA)content with thiobarbituric acid method.Results;After the operation,in the moxibustion preconditioning group,SOD activity significantly increased,especially 24h after moxibustion preconditioning;and MDA content decreased,with a very significant difference as compared with that of the cerebral ischemia group(P<0.01).Conclusion;Moxibustion preconditioning protects the ischemic and anoxic brain tissue by increasing the activity of endogenous antioxidase.

  17. 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

  18. Role of morphine preconditioning and nitric oxide following brain ischemia reperfusion injury in mice

    Directory of Open Access Journals (Sweden)

    Maedeh Arabian

    2015-01-01

    Full Text Available Objective(s: Morphine dependence (MD potently protects heart against ischemia reperfusion (IR injury through specific signaling mechanisms, which are different from the pathways involved in acute morphine treatment or classical preconditioning. Since opioid receptor density changes post cerebral ischemia strongly correlated with brain histological damage, in the present study, we tried to elucidate the possible role of opioid receptors in IR injury among morphine-dependent mice. Materials and Methods: Accordingly, incremental doses (10 mg/kg/day to 30 mg/kg/day of morphine sulphate were subcutaneously administered for 5 days before global brain ischemia induction through bilateral common carotid artery occlusion. Animals were received naloxone (5 mg/kg or L-NAME (20 mg/kg 30 min after the last morphine dose. Twenty four hr after the ischemia induction, Retention trial of passive avoidance test and western blot analysis were done. histological analysis (TUNEL and NISSL staining performed 72 hr after ischemia. Results: MD improved post ischemia memory performance (P

  19. Carbonic acid buffer changes during complete brain ischemia.

    Science.gov (United States)

    Kraig, R P; Pulsinelli, W A; Plum, F

    1986-03-01

    Simultaneous measurements of tissue PCO2 (PtCO2), interstitial H+ concentration ([H+]o), and tissue lactate content were used to examine changes in interstitial HCO3- concentration ([HCO3-]o) during complete ischemia. In normoglycemic rats (blood glucose of 6-8 mM; neocortical ischemic-induced lactate content 8-12 mmol/kg) [H+]o increased from 7.22 +/- 0.02 to 6.79 +/- 0.02 pH (n = 3). By contrast, in hyperglycemic rats (blood glucose 18-75 mM; ischemic-induced lactate content 19-31 mmol/kg) [H+]o rose by a significantly larger amount to 6.19 +/- 0.02 pH (n = 7). Given that HCO3- is the predominant interstitial H+ buffer, changes in peak PtCO2 show why peak [H+]o were bimodally distributed compared with lactate content. Between 8 and 12 mmol/kg lactate, when peak PtCO2 rose from 99 to 186 Torr but [H+]o was constant at 6.79 pH, calculated [HCO3-]o increased from 11.9 to 21.9 mM. Then after transitional changes, peak PtCO2 and [H+]o remained constant at 389 +/- 9 Torr (n = 7) and 6.19 pH despite the fact that tissue lactate ranged from 19 to 31 mmol/kg lactate, respectively; [HCO3-]o must have remained constant at 12.3 +/- 0.7 mM (n = 7). Since ischemic brain continued to produce another 12 more mmol/kg of lactic acid above 19 mmol/kg lactate without further changes in PtCO2 or [H+]o, H+ and HCO3- must have been heterogeneously compartmented. The continued lactic acid production occurred in a compartment that occupied 36% of neocortical space. This compartment is likely to represent glial cells.

  20. Glutathione and ascorbate during ischemia and postischemic reperfusion in rat brain.

    Science.gov (United States)

    Cooper, A J; Pulsinelli, W A; Duffy, T E

    1980-11-01

    Thirty minutes of total cerebral ischemia (decapitation) decreased total glutathione (GSH + GSSG) by 7% but had no detectable effect on the concentration of oxidized glutathione (GSSG), reduced ascorbate, or total ascorbate, In a model of reversible, bilateral hemispheric ischemia (four-vessel occlusion) no changes in glutathione or ascorbate were detected after 30 min of ischemia. During 24 h of reperfusion following such an insult no detectable change in total ascorbate, reduced ascorbate, or oxidized glutathione was noted: however, total brain glutathione declined by 25%. The findings are discussed in relation to the hypothesis that the deleterious effects of ischemia are due to an increase in free radical production which in turn leads to increased lipid peroxidation.

  1. Synthesis of heat shock proteins in rat brain cortex after transient ischemia.

    Science.gov (United States)

    Dienel, G A; Kiessling, M; Jacewicz, M; Pulsinelli, W A

    1986-08-01

    Cell-free protein synthesis and two-dimensional gel autoradiography were used to characterize early postischemic protein synthesis in rat neocortex. Severe forebrain ischemia was induced for 30 min (four-vessel occlusion model) and followed by 3 h of recirculation. Polysomes were isolated from the cerebral cortex, translated in vitro in a reticulocyte system, and analyzed by two-dimensional gel electrophoresis. The translation products of postischemic polysomes included a major new protein family (70 kDa) with multiple isoelectric variants that was found to comigrate with the 68- to 70-kDa "heat shock" protein synthesized from polysomes of hyperthermic rats. Two other stress proteins (93 and 110 kDa) also appeared to be synthesized in increased amounts after ischemia. A complement of proteins that was indistinguishable from that of controls was also synthesized after ischemia, indicating that messenger ribonucleic acid coding for most brain proteins is preserved after ischemia and is bound to polysomes.

  2. A TIGAR-regulated metabolic pathway is critical for protection of brain ischemia.

    Science.gov (United States)

    Li, Mei; Sun, Meiling; Cao, Lijuan; Gu, Jin-hua; Ge, Jianbin; Chen, Jieyu; Han, Rong; Qin, Yuan-Yuan; Zhou, Zhi-Peng; Ding, Yuqiang; Qin, Zheng-Hong

    2014-05-28

    TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and increases the flow of pentose phosphate pathway (PPP), which generates NADPH and pentose. We hypothesized that TIGAR plays a neuroprotective role in brain ischemia as neurons do not rely on glycolysis but are vulnerable to oxidative stress. We found that TIGAR was highly expressed in brain neurons and was rapidly upregulated in response to ischemia/reperfusion insult in a TP53-independent manner. Overexpression of TIGAR in normal mice with lentivirus reduced ischemic neuronal injury, whereas lentivirus-mediated TIGAR knockdown aggravated it. In cultured primary neurons, increasing TIGAR expression reduced oxygen and glucose deprivation (OGD)/reoxygenation-induced injury, whereas decreasing its expression worsened the injury. The glucose 6-phosphate dehydrogenase was upregulated in mouse and cellular models of stroke, and its upregulation was further enhanced by overexpression of TIGAR. Supplementation of NADPH also reduced ischemia/reperfusion brain injury and alleviated TIGAR knockdown-induced aggravation of ischemic injury. In animal and cellular stroke models, ischemia/reperfusion increased mitochondrial localization of TIGAR. OGD/reoxygenation-induced elevation of ROS, reduction of GSH, dysfunction of mitochondria, and activation of caspase-3 were rescued by overexpression of TIGAR or supplementation of NADPH, while knockdown of TIGAR aggravated these changes. Together, our results show that TIGAR protects ischemic brain injury via enhancing PPP flux and preserving mitochondria function, and thus may be a valuable therapeutic target for ischemic brain injury.

  3. Deletion of TRAAK Potassium Channel Affects Brain Metabolism and Protects against Ischemia

    Science.gov (United States)

    Laigle, Christophe; Confort-Gouny, Sylviane; Le Fur, Yann; Cozzone, Patrick J.; Viola, Angèle

    2012-01-01

    Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K+ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K+ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak−/− mice using a combination of in vivo magnetic resonance imaging (MRI) techniques and multinuclear magnetic resonance spectroscopy (MRS) methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak−/− mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak+/+ mice. Upon ischemia, Traak−/− mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak+/+ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak−/− mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke. PMID:23285272

  4. Neuroprotective effects of nitric oxide donor NOC-18 against brain ischemia-induced mitochondrial damages: role of PKG and PKC.

    Science.gov (United States)

    Arandarcikaite, Odeta; Jokubka, Ramunas; Borutaite, Vilmante

    2015-01-23

    In this study we sought to determine whether NO donor NOC-18 can protect brain mitochondria against ischemia-induced dysfunction, particularly opening of mitochondrial permeability transition pore (MPTP), and cell death. We found that inhibition of respiration with NAD-dependent substrates, but not with succinate, was observed after 30 min ischemia indicating that complex I of the mitochondrial respiratory chain is the primary site affected by ischemia. There was no loss of mitochondrial cytochrome c during 30-120 min of brain ischemia. Prolonged, 90 min ischemia substantially decreased calcium retention capacity of brain mitochondria suggesting sensitization of mitochondria to Ca(2+)-induced MPTP opening, and this was prevented by NOC-18 infusion prior to ischemia. NOC-18 did not prevent ischemia-induced inhibition of mitochondrial respiration, however, it partially protected against ischemia-induced necrosis. Protective effects of NOC-18 were abolished in the presence of selective inhibitors of protein kinase G (PKG) and protein kinase C (PKC). These results indicate that pre-treatment with NOC-18 protected brain mitochondria against ischemia-induced MPTP opening by decreasing mitochondrial sensitivity to calcium and partly protected brain cells against necrotic death in PKG- and PKC-depending manner.

  5. Hyperlipidemia affects neuronal nitric oxide synthase expression in brains of focal cerebral ischemia rat model

    Institute of Scientific and Technical Information of China (English)

    Jianji Pei; Liqiang Liu; Jinping Pang; Xiaohong Tian

    2008-01-01

    BACKGROUND: Hyperlipidemia, a risk factor for ischemic cerebrovascular disease, may mediate production of neuronal nitric oxide synthase (nNOS) to induce increased nitric oxide levels, resulting in brain neuronal injury. OBJECTIVE: To investigate effects of hyperlipidemia on brain nNOS expression, and to verify changes in infarct volume and pathology during reperfusion, as well as neuronal injury following ischemia/reperfusion in a rat model of focal cerebral ischemia. DESIGN, TIME AND SETTING: Complete, randomized grouping experiment was performed at the Laboratory of Physiology, Shanxi Medical University from March 2005 to March 2006. MATERIALS: A total of 144 eight-week-old, male, Wistar rats, weighing 160-180 g, were selected. A rat model of middle cerebral artery occlusion was established by suture method after 4 weeks of formulated diet. Nitric oxide kit and rabbit anti-rat nNOS kit were respectively purchased from Nanjing Jiancheng Bioengineering Institute, China and Wuhan Boster Biological Technology, Ltd., China. METHODS: The rats were equally and randomly divided into high-fat diet and a normal diet groups. Rats in the high-fat diet group were fed a high-fat diet, consisting of 10% egg yolk powder, 5% pork fat, and 0.5% pig bile salt combined with standard chow to create hyperlipidemia. Rats in the normal diet group were fed a standard rat chow. A total of 72 rats in both groups were randomly divided into 6 subgroups: sham-operated, 4-hour ischemia, 4-hour ischemia/2-hour reperfusion, 4-hour ischemia/4-hour reperfusion, 4-hour ischemia/6-hour reperfusion, and 4-hour ischemia/12-hour reperfusion, with 12 rats in each subgroup. MAIN OUTCOME MEASURES: nNOS expression was measured by immunohistochemistry, and pathomorphology changes were detected by hematoxylin-eosin staining. Infarct volume and nitric oxide levels were respectively measured using 2, 3, 5-triphenyltetrazolium chloride (TTC) and immunohistochemistry. RESULTS: In the ischemic region, pathology

  6. The neuroprotective effects of preconditioning exercise on brain damage and neurotrophic factors after focal brain ischemia in rats.

    Science.gov (United States)

    Otsuka, Shotaro; Sakakima, Harutoshi; Sumizono, Megumi; Takada, Seiya; Terashi, Takuto; Yoshida, Yoshihiro

    2016-04-15

    Preconditioning exercise can exert neuroprotective effects after stroke. However, the mechanism underlying these neuroprotective effects by preconditioning exercise remains unclear. We investigated the neuroprotective effects of preconditioning exercise on brain damage and the expression levels of the midkine (MK) and brain-derived neurotrophic factor (BDNF) after brain ischemia. Animals were assigned to one of 4 groups: exercise and ischemia (Ex), no exercise and ischemia (No-Ex), exercise and no ischemia (Ex-only), and no exercise and intact (Control). Rats ran on a treadmill for 30 min once a day at a speed of 25 m/min for 5 days a week for 3 weeks. After the exercise program, stroke was induced by a 60 min left middle cerebral artery occlusion using an intraluminal filament. The infarct volume, motor function, neurological deficits, and the cellular expressions levels of MK, BDNF, GFAP, PECAM-1, caspase 3, and nitrotyrosine (NT) were evaluated 48 h after the induction of ischemia. The infarct volume, neurological deficits and motor function in the Ex group were significantly improved compared to that of the No-Ex group. The expression levels of MK, BDNF, GFAP, and PECAM-1 were enhanced in the Ex group compared to the expression levels in the No-Ex group after brain ischemia, while the expression levels of activated caspase 3 and NT were reduced in the area surrounding the necrotic lesion. Our findings suggest that preconditioning exercise reduced the infract volume and ameliorated motor function, enhanced expression levels of MK and BDNF, increased astrocyte proliferation, increased angiogenesis, and reduced neuronal apoptosis and oxidative stress.

  7. Neuroprotection of GST, an extract of traditional Chinese herb, against ischemic brain injury induced by transient brain ischemia and reperfusion in rat hippocampus.

    Science.gov (United States)

    Sun, Ya-Feng; Pei, Dong-Sheng; Zhang, Qing-Xiu; Zhang, Guang-Yi

    2008-06-01

    In this study, we investigated the effect of GST, an extract of Chinese traditional herb, on transient brain ischemia/reperfusion-induced neuronal cell death. Immunoblotting was used to detect the phosphorylation of MLK, JNK and c-jun. Transient (15 minutes) brain ischemia was induced by the four-vessel occlusion in Sprague-Dawley rats. GST was administrated to the SD rats 20 minutes before ischemia or 1 hour after ischemia. Our data showed that the pretreatment of GST could inhibit phosphorylation of MLK, JNK and c-jun. Moreover, GST showed potent neuroprotective effects on ischemic brain damage in vivo and administration of it 1 hour after ischemia also achieved the protective effects. These results indicate that GST has a prominent neuroprotection action against brain ischemic damage and provides a promising therapeutic approach for ischemic brain injury.

  8. L-DEPRENYL REDUCES BRAIN-DAMAGE IN RATS EXPOSED TO TRANSIENT HYPOXIA-ISCHEMIA

    NARCIS (Netherlands)

    KNOLLEMA, S; AUKEMA, W; HOM, H; KORF, J; TERHORST, GJ

    1995-01-01

    Background and Purpose L-Deprenyl (Selegiline) protects animal brains against toxic substances such as 1-methyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine. Experiments were conducted to test whether L-deprenyl prevents or reduces cerebral damage in a transient hypoxia/ischemia rat model. Metho

  9. Uptake of radiolabeled ions in normal and ischemia-damaged brain.

    Science.gov (United States)

    Dienel, G A; Pulsinelli, W A

    1986-05-01

    The regional concentrations of nine radiochemicals were measured in rat brain after induction of cerebral ischemia to identify tracers concentrated by brain undergoing selective neuronal necrosis. Transient (30 minute) forebrain ischemia was produced in the rat; 24 hours after cerebral recirculation the radiochemicals were injected intravenously and allowed to circulate for 5 hours. The brain concentrations of the radiochemicals in dissected regions were determined by scintillation counting. Forebrain ischemia of this nature will produce extensive injury to striatal neurons but will spare the great majority of neocortical neurons at 24 hours. The regional concentrations of these radiochemicals varied considerably in both control and ischemic animals. In postischemic animals, 4 radionuclides (63Ni, 99TcO4, 22Na, and [3H]tetracycline) were concentrated in the irreversibly damaged striatum in amounts ranging from 1.4 to 2.4 times greater than in normal tissue. The concentrations of 65Zn, 59Fe, 32PO4, and 147Pm in postischemic brain were similar to or less than those in normal brain. The concentration of [14C]EDTA was increased in injured and uninjured brain of postischemic rats. Autoradiographic analysis of the distribution patterns of some of these ions in normal animals showed that 99TcO4, 22Na, 65Zn, and 59Fe were distributed more uniformly throughout the brain than were 32PO4, 63Ni, and 147Pm. At 24 or 48 hours after ischemia, 63Ni, 99TcO4, and 22Na were preferentially concentrated in the damaged striatum and hippocampus, whereas 65Zn, 59Fe, 32PO4, and 147Pm did not accumulate in irreversibly injured tissue. Of the radiochemicals tested to date, Ni, TcO4, and tetracycline may be useful for diagnosing ischemic brain injury in humans, using positron emission tomography.

  10. Neuroprotection by complement (C1) inhibitor in mouse transient brain ischemia.

    Science.gov (United States)

    De Simoni, M G; Storini, C; Barba, M; Catapano, L; Arabia, A M; Rossi, E; Bergamaschini, L

    2003-02-01

    The authors investigated the effect of the C1 inhibitor (C1-INH), the only known inhibitor of complement C1, in a murine model of transient focal ischemia. Ischemia was induced by intraluminal occlusion of the middle cerebral artery. After 2 hours, reperfusion was produced by removing the nylon monofilament occluding the artery. The effect of 15 U C1-INH (intravenously) was evaluated in terms of general and focal neurologic deficits, ischemic volume, neutral red staining (to identify the brain areas subject to ischemic damage), and glial fibrillary acidic protein immunoreactivity (to show astrocytic response). Forty-eight hours after ischemia, C1-INH significantly improved general and focal deficits by 36% and 54%, respectively, and significantly reduced infarct volume (CI-INH, 6.69% +/- 2.93%; saline, 24.24% +/- 8.24%) of total brain. Neutral red staining further showed the strong protective effect of C1-INH in cortex, hippocampus, and striatum. Astrocyte activation induced by ischemia was not affected by C1-INH. These findings show that C1-INH displayed a potent neuroprotective action by effectively reducing ischemia-reperfusion injury.

  11. Adenosine A2A Receptors Modulate Acute Injury and Neuroinflammation in Brain Ischemia

    Directory of Open Access Journals (Sweden)

    Felicita Pedata

    2014-01-01

    Full Text Available The extracellular concentration of adenosine in the brain increases dramatically during ischemia. Adenosine A2A receptor is expressed in neurons and glial cells and in inflammatory cells (lymphocytes and granulocytes. Recently, adenosine A2A receptor emerged as a potential therapeutic attractive target in ischemia. Ischemia is a multifactorial pathology characterized by different events evolving in the time. After ischemia the early massive increase of extracellular glutamate is followed by activation of resident immune cells, that is, microglia, and production or activation of inflammation mediators. Proinflammatory cytokines, which upregulate cell adhesion molecules, exert an important role in promoting recruitment of leukocytes that in turn promote expansion of the inflammatory response in ischemic tissue. Protracted neuroinflammation is now recognized as the predominant mechanism of secondary brain injury progression. A2A receptors present on central cells and on blood cells account for important effects depending on the time-related evolution of the pathological condition. Evidence suggests that A2A receptor antagonists provide early protection via centrally mediated control of excessive excitotoxicity, while A2A receptor agonists provide protracted protection by controlling massive blood cell infiltration in the hours and days after ischemia. Focus on inflammatory responses provides for adenosine A2A receptor agonists a wide therapeutic time-window of hours and even days after stroke.

  12. 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

  13. Ischemia/reperfusion mediated oxygen free radical production in rat brain endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Grammas, P.; Wood, K. (Univ. of Oklahoma, Oklahoma City (United States)); Liu, G.J.; Floyd, R.A. (Oklahoma Medical Research Foundation, Oklahoma City (United States)); Wood, K. (Univ. of Oklahoma Health Sciences Center, Oklahoma City (United States) Oklahoma Medical Research Foundation, Oklahoma City (United States))

    1991-03-11

    Oxygen free radicals have been increasingly implicated in ischemia/reperfusion mediated injury to tissue. Recent methods of assessing tissue oxygen free radical flux including spin trapping, salicylate hydroxylation, protein oxidation and specific enzymatic activity loss have clearly shown that ischemia/reperfusion mediates oxidative damage in brain. Vascular endothelia cells are increasingly implicated in inactivating oxidative damage. The authors have used salicylate to assess hydroxyl free radical flux during an anoxia-reoxygenation insult in isolated brain microvessels. Brain microvessels that were subjected to a 20 min anoxia period and then reoxygenated for 20 min hydroxylated salicylate to form tissue localized 2,3-dihydroxybenzoic acid (2,3-DHBA) whereas microvessels that remained oxygenated throughout contained very little 2,3-DHBA. The data suggest that anoxia/reoxygenation of microvessels produces tissue localized hydroxyl free radical flux.

  14. Intranasal pyrrolidine dithiocarbamate decreases brain inflammatory mediators and provides neuroprotection after brain hypoxia-ischemia in neonatal rats.

    Science.gov (United States)

    Wang, Zhi; Zhao, Huijuan; Peng, Shuling; Zuo, Zhiyi

    2013-11-01

    Brain injury due to birth asphyxia is the major cause of death and long-term disabilities in newborns. We determined whether intranasal pyrrolidine dithiocarbamate (PDTC) could provide neuroprotection in neonatal rats after brain hypoxia-ischemia (HI). Seven-day old male and female Sprague-Dawley rats were subjected to brain HI. They were then treated with intranasal PDTC. Neurological outcomes were evaluated 7 or 30 days after the brain HI. Brain tissues were harvested 6 or 24 h after the brain HI for biochemical analysis. Here, PDTC dose-dependently reduced brain HI-induced brain tissue loss with an effective dose (ED)50 at 27 mg/kg. PDTC needed to be applied within 45 min after the brain HI for this neuroprotection. This treatment reduced brain tissue loss and improved neurological and cognitive functions assessed 30 days after the HI. PDTC attenuated brain HI-induced lipid oxidative stress, nuclear translocation of nuclear factor κ-light-chain-enhancer of activated B cells, and various inflammatory mediators in the brain tissues. Inhibition of inducible nitric oxide synthase after brain HI reduced brain tissue loss. Our results suggest that intranasal PDTC provides neuroprotection possibly via reducing inflammation and oxidative stress. Intranasal PDTC may have a potential to provide neuroprotection to human neonates after birth asphyxia.

  15. Carbonic acid buffer changes during complete brain ischemia

    OpenAIRE

    Kraig, Richard P.; PULSINELLI, WILLIAM A.; Plum, Fred

    1986-01-01

    Simultaneous measurements of tissue PCO2 (PtCO2), interstitial H+ concentration ([H+]o), and tissue lactate content were used to examine changes in interstitial HCO3− concentration ( [HCO3−]o) during complete ischemia. In normoglycemic rats (blood glucose of 6–8 mM; neocortical ischemic-induced lactate content 8–12 mmol/kg) [H+]o increased from 7.22 ± 0.02 to 6.79 ± 0.02 pH (n = 3). By contrast, in hyperglycemic rats (blood glucose 18–75 mM; ischemic-induced lactate content 19–31 mmol/...

  16. Deletion of TRAAK potassium channel affects brain metabolism and protects against ischemia.

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    Christophe Laigle

    Full Text Available Cerebral stroke is a worldwide leading cause of disability. The two-pore domain K⁺ channels identified as background channels are involved in many functions in brain under physiological and pathological conditions. We addressed the hypothesis that TRAAK, a mechano-gated and lipid-sensitive two-pore domain K⁺ channel, is involved in the pathophysiology of brain ischemia. We studied the effects of TRAAK deletion on brain morphology and metabolism under physiological conditions, and during temporary focal cerebral ischemia in Traak⁻/⁻ mice using a combination of in vivo magnetic resonance imaging (MRI techniques and multinuclear magnetic resonance spectroscopy (MRS methods. We provide the first in vivo evidence establishing a link between TRAAK and neurometabolism. Under physiological conditions, Traak⁻/⁻ mice showed a particular metabolic phenotype characterized by higher levels of taurine and myo-inositol than Traak⁺/⁺ mice. Upon ischemia, Traak⁻/⁻ mice had a smaller infarcted volume, with lower contribution of cellular edema than Traak⁺/⁺ mice. Moreover, brain microcirculation was less damaged, and brain metabolism and pH were preserved. Our results show that expression of TRAAK strongly influences tissue levels of organic osmolytes. Traak⁻/⁻ mice resilience to cellular edema under ischemia appears related to their physiologically high levels of myo-inositol and of taurine, an aminoacid involved in the modulation of mitochondrial activity and cell death. The beneficial effects of TRAAK deletion designate this channel as a promising pharmacological target for the treatment against stroke.

  17. Does closure of acid-sensing ion channels reduce ischemia/reperfusion injury in the rat brain?

    Institute of Scientific and Technical Information of China (English)

    Jie Wang; Yinghui Xu; Zhigang Lian; Jian Zhang; Tingzhun Zhu; Mengkao Li; Yi Wei; Bin Dong

    2013-01-01

    Acidosis is a common characteristic of brain damage. Because studies have shown that permeable Ca2+-acid-sensing ion channels can mediate the toxic effects of calcium ions, they have become new targets against pain and various intracranial diseases. However, the mechanism associated with expression of these channels remains unclear. This study sought to observe the expression characteristics of permeable Ca2+-acid-sensing ion channels during different reperfusion inflows in rats after cerebral ischemia. The rat models were randomly divided into three groups: adaptive ischemia/reperfusion group, one-time ischemia/reperfusion group, and severe cerebral ischemic injury group. Western blot assays and immunofluorescence staining results exhibited that when compared with the one-time ischemia/reperfusion group, acid-sensing ion channel 3 and Bcl-x/l expression decreased in the adaptive ischemia/reperfusion group. Calmodulin expression was lowest in the adaptive ischemia/reperfusion group. Following adaptive reperfusion, common carotid artery flow was close to normal, and the pH value improved. Results verified that adaptive reperfusion following cerebral ischemia can suppress acid-sensing ion channel 3 expression, significantly reduce Ca2+ influx, inhibit calcium overload, and diminish Ca2+ toxicity. The effects of adaptive ischemia/reperfusion on suppressing cell apoptosis and relieving brain damage were better than that of one-time ischemia/reperfusion.

  18. Increased expression of receptor for advanced glycation end-products worsens focal brain ischemia in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    Ying Xing; Jinting He; Weidong Yu; Lingling Hou; Jiajun Chen

    2012-01-01

    A rat model of diabetes mellitus was induced by a high fat diet, followed by focal brain ischemia induced using the thread method after 0.5 month. Immunohistochemistry showed that expression of receptor for advanced glycation end-products was higher in the ischemic cortex of diabetic rats compared with non-diabetic rats with brain ischemia. Western blot assay revealed increased phosphorylated c-Jun N-terminal kinase expression, and unchanged phosphorylated extracellular signal-regulated protein kinase protein expression in the ischemic cortex of diabetic rats compared with non-diabetic rats with brain ischemia. Additionally, phosphorylated p38 mitogen-activated protein kinase protein was not detected in any rats in the two groups. Severity of limb hemiplegia was worse in diabetic rats with brain ischemia compared with ischemia alone rats. The results suggest that increased expression of receptor for advanced glycation end-products can further activate the c-Jun N-terminal kinase pathway in mitogen-activated protein kinase, thereby worsening brain injury associated with focal brain ischemia in diabetic rats.

  19. Recruitment of neutrophils across the blood-brain barrier: the role of posttraumatic hepatic ischemia

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    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.

  20. Moringa Oleifera Lam Mitigates Oxidative Damage and Brain Infarct Volume in Focal Cerebral Ischemia

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    Woranan Kirisattayakul

    2012-01-01

    Full Text Available Problem statement: At present, the therapeutic outcome of cerebral ischemia is still not in the satisfaction level. Therefore, the preventive strategy is considered. Based on the protective effect against oxidative damage of Moringa oleifera Lam. Leaves extract, we hypothesized that this plant extract might protect against cerebral ischemia, one of the challenge problems nowadays. In order to test this hypothesis, we aimed to determine the protective effect of M.oleifera leaves extract in animal model of focal cerebral ischemia induced by permanent occlusion of right middle cerebral artery. Approach: Male Wistar rats, weighing 300-350 g, were orally given the extract once daily at doses of 100, 200 and 400 mg kg-1 BW at a period of 2 weeks, then, they were permanently occluded the right Middle Cerebral Artery (MCAO. The animals were assessed the cerebral infarction volume and oxidative damage markers including MDA level and the activities of SOD, CAT and GSHPx enzymes at 24 h after occlusion. Results: Rats subjected to M.oleifera extract at all doses used in this study significantly decreased brain infarct volume both at cortical and subcortical structures in accompany with the elevation of SOD activity in both hippocampus and striatum while only the rats exposed to the extract at doses of 100 and 400 mg kg-1 BW showed the increased GSHPx activity in hippocampus. No the changes were observed. Therefore, our results demonstrates the potential benefit of M.oleifera leaves to decrease oxidative stress damage and brain infarct volume. Conclusion: This study is the first study to demonstrate the neuroprotective effect against focal cerebral ischemia of M.oleifera leaves. It suggests that M.oleifera may be served as natural resource for developing neuroprotectant against focal cerebral ischemia. However, the precise underlying mechanism and possible active ingredient are still required further study.

  1. Cortisol in plasma and cerebrospinal fluid of patients with brain ischemia

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    Selaković Vesna M.

    2004-01-01

    Full Text Available Introduction One of the reactions to ischemia is increased release of glucocorticoid hormones, included in regulation of effects of numerous mediators/modulators that could be released in the acute phase of brain ischemia. The aim of our investigation was to define temporal dynamics of cortisol concentrations in plasma and cerebrospinal fluid of patients with different types of ischemic brain disease. Material and methods The study included 263 patients of both sexes, aged 55-68 years. History, clinical examination and cerebral computerized tomography were performed to establish the diagnosis. 97 patients had brain infarction, 66 had a reversible ischemic attack, 66 had a transient ischemic attack, and 34 patients had chronic encephalopathy. The control group included 22 age- and sex- matched patients, subjected to diagnostic lumbar radiculography, without disturbances in the cerebrospinal fluid passage. Cortisol concentrations were measured by direct radioimmunoassay. Results and discussion Results obtained in this research showed that in acute brain ischemic period there was a significant increase of cortisol concentration in plasma and cerebrospinal fluid. The increase was highest in patients with brain infarction, somewhat lower in reversible ischemic attack, and the lowest in transient ischemic attack compared to controls (331.7±92.8 pmol/ml of plasma and 2.5±1.1 pmol/ml of cerebrospinal fluid. Maximum concentrations were found during the first two days after insult. The main potentially protective effects of increased cortisol concentrations in patients with acute stroke could be the decrease of effects of deleterious reactions induced by ischemia. This mechanism might be an attempt of organism to compensate for disturbed homeostasis. Conclusion Measurement of cortisol in plasma and cerebrospinal fluid in patients with acute stroke is significant for monitoring the intensity of response of an organism to acute brain damage.

  2. Identification of the boundary between normal brain tissue and ischemia region using two-photon excitation fluorescence microscopy

    Science.gov (United States)

    Du, Huiping; Wang, Shu; Wang, Xingfu; Zhu, Xiaoqin; Zhuo, Shuangmu; Chen, Jianxin

    2016-10-01

    Ischemic stroke is one of the common neurological diseases, and it is becoming the leading causes of death and permanent disability around the world. Early and accurate identification of the potentially salvageable boundary region of ischemia brain tissues may enable selection of the most appropriate candidates for early stroke therapies. In this work, TPEF microscopy was used to image the microstructures of normal brain tissues, ischemia regions and the boundary region between normal and ischemia brain tissues. The ischemia brain tissues from Sprague-Dawley (SD) rats were subjected to 6 hours of middle cerebral artery occlusion (MCAO). Our study demonstrates that TPEF microscopy has the ability to not only reveal the morphological changes of the neurons but also identify the boundary between normal brain tissue and ischemia region, which correspond well to the hematoxylin and eosin (H and E) stained images. With the development of miniaturized TPEF microscope imaging devices, TPEF microscopy can be developed into an effectively diagnostic and monitoring tool for cerebral ischemia.

  3. Uptake of radiolabeled ions in normal and ischemia-damaged brain

    Energy Technology Data Exchange (ETDEWEB)

    Dienel, G.A.; Pulsinelli, W.A.

    1986-05-01

    The regional concentrations of nine radiochemicals were measured in rat brain after induction of cerebral ischemia to identify tracers concentrated by brain undergoing selective neuronal necrosis. Transient (30 minute) forebrain ischemia was produced in the rat; 24 hours after cerebral recirculation the radiochemicals were injected intravenously and allowed to circulate for 5 hours. The brain concentrations of the radiochemicals in dissected regions were determined by scintillation counting. Forebrain ischemia of this nature will produce extensive injury to striatal neurons but will spare the great majority of neocortical neurons at 24 hours. The regional concentrations of these radiochemicals varied considerably in both control and ischemic animals. In postischemic animals, 4 radionuclides (/sup 63/Ni, /sup 99/TcO/sub 4/, /sup 22/Na, and (/sup 3/H)tetracycline) were concentrated in the irreversibly damaged striatum in amounts ranging from 1.4 to 2.4 times greater than in normal tissue. The concentrations of /sup 65/Zn, /sup 59/Fe, /sup 32/PO/sub 4/, and /sup 147/Pm in postischemic brain were similar to or less than those in normal brain. The concentration of (14C)EDTA was increased in injured and uninjured brain of postischemic rats. Autoradiographic analysis of the distribution patterns of some of these ions in normal animals showed that /sup 99/TcO/sub 4/, /sup 22/Na, /sup 65/Zn, and /sup 59/Fe were distributed more uniformly throughout the brain than were /sup 32/PO/sub 4/, /sup 63/Ni, and /sup 147/Pm. At 24 or 48 hours after ischemia, /sup 63/Ni, /sup 99/TcO/sub 4/, and /sup 22/Na were preferentially concentrated in the damaged striatum and hippocampus, whereas /sup 65/Zn, /sup 59/Fe, /sup 32/PO/sub 4/, and /sup 147/Pm did not accumulate in irreversibly injured tissue. Of the radiochemicals tested to date, Ni, TcO/sub 4/, and tetracycline may be useful for diagnosing ischemic brain injury in humans, using positron emission tomography.

  4. Protective effects of Guizhi-Fuling-Capsules on rat brain ischemia/reperfusion injury.

    Science.gov (United States)

    Li, Tie-Jun; Qiu, Yan; Mao, Jun-Qin; Yang, Peng-Yuan; Rui, Yao-Cheng; Chen, Wan-Sheng

    2007-09-01

    Previous studies revealed that Guizhi-Fuling-Capsules (GZFLC), a traditional Chinese medical (Kampo) formulation composed of five kinds of medicinal plants, Cinnamomum cassia BLUME (Cinnamomi Cortex), Paeonia lactiflora PALL. (Peonies Radix), Paeonia suffruticosa ANDREWS (Moutan Cortex), Prunus persica BATSCH (Persicae Semen), and Poria cocos WOLF (Hoelen), exerts a protective effect against vascular injury and has a protective effect against glutamate- or nitro oxide-mediated neuronal damage. In the present study, the effect of GZFLC in a rat in vivo model of focal cerebral ischemia and reperfusion was investigated. Administration of GZFLC (0.3 and 0.9 g/kg, p.o.) after focal cerebral ischemia significantly decreased brain infarction and water contents in rats subjected to 2-h ischemia followed by 24-h reperfusion from 31.72 +/- 2.49%, 84.76 +/- 1.63% in the model group to 17.31 +/- 3.66%, 82.51 +/- 1.36% and 8.30 +/- 3.73%, 81.35 +/- 1.73%, respectively. Furthermore, analysis of inflammatory cytokines in ischemic brain showed that GZFLC treatment significantly down-regulated expressions of pro-inflammatory cytokines including interleukin (IL)-1beta and tissue necrosis factor-alpha and markedly up-regulated expressions of anti-inflammatory cytokines IL-10 and IL-10R both in mRNA and protein levels. The serum levels of these inflammatory cytokines were also regulated the same way. These results suggested that GZFLC may be beneficial for the treatment of brain ischemia-reperfusion injury partly due to its anti-inflammatory properties.

  5. MLKL inhibition attenuates hypoxia-ischemia induced neuronal damage in developing brain.

    Science.gov (United States)

    Qu, Yi; Shi, Jing; Tang, Ying; Zhao, Fengyan; Li, Shiping; Meng, Junjie; Tang, Jun; Lin, Xuemei; Peng, Xiaodong; Mu, Dezhi

    2016-05-01

    Mixed lineage kinase domain-like protein (MLKL) is a critical molecule mediating cell necroptosis. However, its role in brain injury remains obscure. We first investigated the functions and mechanisms of MLKL in mediating neuronal damage in developing brain after hypoxia-ischemia. Neuronal necroptosis was induced by oxygen-glucose deprivation (OGD) plus caspase inhibitor zVAD treatment (OGD/zVAD). We found that two important necroptosis related proteins, receptor-interacting protein 1 and 3 (RIP1, RIP3) were upregulated. Furthermore, the interaction of RIP1-RIP3 with MLKL increased. Inhibition of MLKL through siRNA diminished RIP1-RIP3-MLKL interaction and attenuated neuronal death induced by OGD/zVAD. The translocation of oligomerized MLKL to the neuronal membrane leading to the injury of cellular membrane is the possible new mechanism of neuronal necroptosis. Animal experiment with neonatal rats further proved that MLKL inhibition attenuated brain damage induced by hypoxia-ischemia. These findings suggest that MLKL is a target to attenuate brain damage in developing brain.

  6. Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models.

    Science.gov (United States)

    Buendia, Izaskun; Gómez-Rangel, Vanessa; González-Lafuente, Laura; Parada, Esther; León, Rafael; Gameiro, Isabel; Michalska, Patrycja; Laudon, Moshe; Egea, Javier; López, Manuela G

    2015-12-01

    Stopping the ischemic cascade by targeting its components is a potential strategy for acute ischemic stroke treatment. During ischemia and especially over reperfusion, oxidative stress plays a major role in causing neuronal cell death. Melatonin has been previously reported to provide neuroprotective effects in in vivo models of stroke by a mechanism that implicates melatonin receptors. In this context, this study was planned to test the potential neuroprotective effects of the novel melatonin MT1/MT2 receptor agonist, Neu-P11, against brain ischemia in in vitro and in vivo models, and to elucidate its underlying mechanism of action. Neu-P11 proved to be a good antioxidant, to protect against glutamate-induced excitotoxicity and oxygen and glucose deprivation in hippocampal slices, and to reduce infarct volume in an in vivo stroke model. Regarding its mechanism of action, the protective effect of Neu-P11 was reverted by luzindole (melatonin receptor antagonist), AG490 (JAK2 inhibitor), LY294002 (PI3/AKT inhibitor) and PD98059 (MEK/ERK1/2 inhibitor). In conclusion, Neu-P11 affords neuroprotection against brain ischemia in in vitro and in vivo models by activating a pro-survival signaling pathway that involves melatonin receptors, JAK/STAT, PI3K/Akt and MEK/ERK1/2.

  7. Pretreatment with Danhong injection protects the brain against ischemia-reperfusion injury.

    Science.gov (United States)

    Wang, Shaoxia; Guo, Hong; Wang, Xumei; Chai, Lijuan; Hu, Limin; Zhao, Tao; Zhao, Buchang; Tan, Xiaoxu; Jia, Feifei

    2014-08-01

    Danhong injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii, is widely used in China for treating acute ischemic stroke. In the present study, we explored the neuroprotective efficacy of DHI in a rat model of temporary middle cerebral artery occlusion, and evaluated the potential mechanisms underlying its effects. Pretreatment with DHI (0.9 and 1.8 mL/kg) resulted in a significantly smaller infarct volume and better neurological scores than pretreatment with saline. Furthermore, DHI significantly reduced the permeability of the blood-brain barrier, increased occludin protein expression and decreased neutrophil infiltration, as well as profoundly suppressing the upregulation of matrix metallopeptidase-9 expression seen in rats that had received vehicle. Matrix metallopeptidase-2 expression was not affected by ischemia or DHI. Moreover, DHI (1.8 mL/kg) administered 3 hours after the onset of ischemia also improved neurological scores and reduced infarct size. Our results indicate that the neuroprotective efficacy of DHI in a rat model of cerebral ischemia-reperfusion injury is mediated by a protective effect on the blood-brain barrier and the reversal of neutrophil infiltration.

  8. Increased expression of neurotrophin 4 following focal cerebral ischemia in adult rat brain with treadmill exercise.

    Directory of Open Access Journals (Sweden)

    Jin-Young Chung

    Full Text Available Neurotrophin 4 (NT-4 belongs to the family of neurotrophic factors, and it interacts with the tyrosine kinase B (trkB receptor. NT-4 has neuroprotective effects following cerebral ischemia. Its role might be similar to brain-derived neurotrophic factor (BDNF, because both interact with trkB. Exercise also improves neural function by increasing neurotrophic factors. However, expression profiles of NT-4 in the brain during exercise are unknown. Here, we assessed the expressions of NT-4 and its receptor, trkB, following cerebral ischemia and hypothesized that exercise changes the expressions of NT-4 and trkB. Results showed that in a permanent middle cerebral artery occlusion rat model, ischemia decreased NT-4 and trkB expression. Immunohistochemistry showed their immunoreactivities around the region of the ischemic area. Treadmill exercise changed the expression of NT-4, which increased in the contralateral hemisphere in rats with ischemic injury. TrkB also showed similar patterns to its neurotophins. The change in NT-4 suggested that exercise might have primed NT4 production so that further injury causes slightly greater increases in NT4 compared with non-exercise controls.

  9. Altered mitochondrial respiration in selectively vulnerable brain subregions following transient forebrain ischemia in the rat.

    Science.gov (United States)

    Sims, N R; Pulsinelli, W A

    1987-11-01

    Mitochondrial respiratory function, assessed from the rate of oxygen uptake by homogenates of rat brain subregions, was examined after 30 min of forebrain ischemia and at recirculation periods of up to 48 h. Ischemia-sensitive regions which develop extensive neuronal loss during the recirculation period (dorsal-lateral striatum, CA1 hippocampus) were compared with ischemia-resistant areas (paramedian neocortex, CA3 plus CA4 hippocampus). All areas showed reductions (to 53-69% of control) during ischemia for oxygen uptake rates determined in the presence of ADP or an uncoupling agent, which then recovered within 1 h of cerebral recirculation. In the ischemia-resistant regions, oxygen uptake rates remained similar to control values for at least 48 h of recirculation. After 3 h of recirculation, a significant decrease in respiratory activity (measured in the presence of ADP or uncoupling agent) was observed in the dorsal-lateral striatum which progressed to reductions of greater than 65% of the initial activity by 24 h. In the CA1 hippocampus, oxygen uptake rates were unchanged for 24 h, but were significantly reduced (by 30% in the presence of uncoupling agent) at 48 h. These alterations parallel the development of histological evidence of ischemic cell change determined previously and apparently precede the appearance of differential changes between sensitive and resistant regions in the content of high-energy phosphate compounds. These results suggest that alterations of mitochondrial activity are a relatively early change in the development of ischemic cell death and provide a sensitive biochemical marker for this process.

  10. [Recurrence plot analysis of HRV for brain ischemia and asphyxia].

    Science.gov (United States)

    Chen, Xiaoming; Qiu, Yihong; Zhu, Yisheng

    2008-02-01

    Heart rate variability (HRV) is the tiny variability existing in the cycles of the heart beats, which reflects the corresponding balance between sympathetic and vagus nerves. Since the nonlinear characteristic of HRV is confirmed, the Recurrence Plot method, a nonlinear dynamic analysis method based on the complexity, could be used to analyze HRV. The results showed the recurrence plot structures and some quantitative indices (L-Mean, L-Entr) during asphyxia insult vary significantly as compared to those in normal conditions, which offer a new method to monitor brain asphyxia injury.

  11. IMPACT OF SEVOFLURANE AND ACETYLCYSTEINE ON ISCHEMIA-REPERFUSION INJURY OF THE LIVER FROM BRAIN-DEAD DONOR

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    A. E. Shcherba

    2013-01-01

    Full Text Available Aim. The purpose of our work was to estimate the impact of preconditioning with acetylcysteine and sevoflurane on ischemia-reperfusion injury of cadaveric donor liver with marginal features. Methods and results. In this prospective randomized controlled trial we recruited 21 heart beating donors with brain death. We assigned 11 donors to the study group, and 10 donors to the control group. Morphological characteristics of ischemia- reperfusion injury in both groups were analyzed. Conclusion. Use of pharmacological preconditioning with acetylcysteine and sevoflurane resulted in necrosis and hepatocyte apoptosis reduction as compared to the control group, thereby had a protective effect against ischemia-reperfusion injury. 

  12. Advanced neuroprotection for brain ischemia: an alternative approach to minimize stroke damage.

    Science.gov (United States)

    Ayuso, Maria Irene; Montaner, Joan

    2015-01-01

    Despite decades of research on neuroprotectants in the fight against ischemic stroke, no successful results have been obtained and new alternative approaches are urgently needed. Translation of effective candidate drugs in experimental studies to patients has systematically failed. However, some of those treatments or neuroprotectant diets which demonstrated only beneficial effects if given before (but not after) ischemia induction and discarded for conventional neuroprotection, could be rescued in order to apply an 'advanced neuroprotection strategy' (ADNES). Herein, the authors discuss how re-profiling those neuroprotective candidate drugs and diets with the best potential, some of which are mentioned in this article as an ADNES, may be a good approach for developing successful treatments that protect the brain against ischemic damage. This novel approach would try to protect the brain of patients who are at high risk of suffering a stroke, before damage occurs, in order to minimize brain injury by having the neuroprotectant drug or diet 'on board' if unfortunately stroke occurs.

  13. Developmental changes of glutamate acid decarboxylase 67 in mouse brain after hypoxia ischemia

    Institute of Scientific and Technical Information of China (English)

    Fa-Lin XU; Chang-Lian ZHU; Xiao-Yang WANG

    2006-01-01

    Objective To study the developmental changes of glutamic acid decarboxylase-67 ( GAD-67, a GABA synthetic enzyme) in normal and hypoxic ischemic (HI) brain. Methods C57/BL6 mice on postnatal day (P) 5, 9, 21and 60, corresponding developmentally to premature, term, juvenile and adult human brain were investigated by using both Western blot and immunohistochemistry methods either in normal condition or after hypoxic ischemic insult. Results The immunoreactivity of GAD67 was up regulated with brain development and significant difference was seen between mature (P21, P60) and immature (P5, P9) brain. GAD67 immunoreactivity decreased in the ipsilateral hemisphere in all the ages after hypoxia ischemia (HI) insult, but, significant decrease was only seen in the immature brain. Double labeling of GAD67 and cell death marker, TUNEL, in the cortex at 8h post-HI in the P9 mice showed that (15.6 ±7.0)%TUNEL positive cells were GAD67 positive which was higher than that of P60 mice. Conclusion These data suggest that GABAergic neurons in immature brain were more vulnerable to HI insult than that of mature brain.

  14. CD38 exacerbates focal cytokine production, postischemic inflammation and brain injury after focal cerebral ischemia.

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    Chi-un Choe

    Full Text Available BACKGROUND: Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose, which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. METHODOLOGY/PRINCIPAL FINDINGS: We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8(+ cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO model. CONCLUSION/SIGNIFICANCE: CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke.

  15. Porcine Brain Extract Attenuates Memory Impairments Induced by Focal Cerebral Ischemia

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    Jinatta Jittiwat

    2009-01-01

    Full Text Available Problem statement: Stroke or cerebral ischemia has been recognized as one important problem worldwide. To date, the effectiveness of protective and therapeutic strategies against stroke is still very limited. Therefore, the development of novel strategy is required. Porcine brain is traditional believed to improve brain functions. Recent studies showed that the extract of porcine brain could protect against brain damage related to the oxidative stress, therefore, we hypothesized that it could protect against brain damage in stroke. Approach: To test the potential of porcine brain extract as the novel protective supplement against stroke, various doses of porcine brain extract at doses of 0.5 and 2.5 mg kg-1 b.w. were orally given to male Wistar rats, weighing 300-350 g, at the period of 14 days before and 21 days after the occlusion of right middle cerebral artery. Then, all rats were determined the neurological score, motor performance, cognitive function and brain infarct volume. Moreover, the possible neuroprotective mechanisms of the extract were also determined via the alteration of Malondialdehyde (MDA or lipid peroxidation product and via the activities of scavenger enzymes including Superoxide Dismutase (SOD, Catalase (CAT and Glutathione Peroxides (GPx. Results: The results showed that the low dose of porcine extract decreased the infarct volume and improved brain functions including neurological score, motor performance and memory deficit. In addition, it also decreased MDA but increased the activities of SOD, CAT and GPx. Conclusion: Our results suggested the potential role of porcine brain extract as neuroprotectant. The possible underlying mechanism appeared to be related to the enhanced activities of SOD, CAT and GPx which in turn resulted in the decrease MDA. Moreover, our findings may shed light on the pharmacologic basis for the clinical application of traditional Chinese medicine to protect against stroke.

  16. Antimicrobial peptides and complement in neonatal hypoxia-ischemia induced brain damage

    Directory of Open Access Journals (Sweden)

    Eridan eRocha-Ferreira

    2015-02-01

    Full Text Available Hypoxic-ischemic encephalopathy (HIE is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5 per 1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy and cognitive disabilities. Even though the brain is considered an immune-privileged site, it has innate and adaptive immune response and can produce complement (C components and antimicrobial peptides (AMPs. Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain.Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS, including neonatal hypoxia-ischemia (HI, resident microglia and astroglia are the main cells providing immune defence to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI-injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins which can chemoattract and promote maturation of dendritic cells, and can also limit inflammation by controlling the viability of these same dendritic cells. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI-injury and the effect of that balance on the

  17. The protective effect of erdosteine on short-term global brain ischemia/reperfusion injury in rats.

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    Ozerol, Elif; Bilgic, Sedat; Iraz, Mustafa; Cigli, Ahmet; Ilhan, Atilla; Akyol, Omer

    2009-02-01

    Experimental studies have demonstrated that free radicals play a major role on neuronal injury during ischemia/reperfusion (I/R) in rats. Erdosteine is a thioderivative endowed with mucokinetic, mucolytic and free-radical-scavenging properties. The aim of the present study was to investigate the effect of erdosteine treatment against short-term global brain ischemia/reperfusion injury in rats. The study was carried out on Wistar rats divided into four groups. (i) Control group, (ii) ischemia/reperfusion group, (iii) ischemia/reperfusion+erdosteine group, and (iv) erdosteine group. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities as well as thiobarbituric acid reactive substances (TBARSs) and nitric oxide (NO) levels were analysed in erythrocyte and plasma of rats. Plasma NO levels were significantly higher in the ischemia/reperfusion group than the other groups. The activities of SOD and GSH-Px were decreased, while TBARS levels increased in the ischemia/reperfusion group compared to other groups in both plasma and erythrocyte. The erythrocyte CAT activity was higher in erdosteine group and there was a statistically significant increase, when compared with the erdosteine plus ischemia/reperfusion group. By treating the rats with erdosteine, the depletion of endogenous antioxidant enzymes (SOD, CAT, GSH-Px) and increase of TBARS and NO levels were prevented. This study, therefore, suggests that erdosteine reduces parameters of oxidative stress is well supported by the data.

  18. Brain edema and tumor necrosis factor-like weak inducer of apoptosis in rats with cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Renlan Zhou; Peng Xie

    2008-01-01

    BACKGROUND: Recent studies have demonstrated that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in brain edema. However, it is unclear whether blood-brain barrier (BBB) disruption is associated with TWEAK during the process of brain edema OBJECTIVE: To investigate the effects of TWEAK on BBB permeability in brain edema.DESIGN, TIME AND SETTING: An immunohistochemical observation, randomized, controlled animal experiment was pertbrmed at the Laboratory of Neurosurgical Anatomy, Xiangya Medical College, Central South University & Central Laboratory, Third Xiangya Hospital, Central South University between January 2006 and December 2007.MATERIALS: A total of 48 adult Wistar rats were randomly divided into three groups: normal control (n =8), sham-operated (n = 8), and ischemia/reperfusion (n = 32). Rats from the ischemia/reperfusion group were randomly assigned to four subgroups according to different time points, i.e., 2 hours of ischemia followed by 6 hours (n = 8), 12 hours {n = 8), 1 day (n = 8), or 12 days (n = 8) of reperfusion.METHODS: Focal cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion (MCAO) using the suture method in rats from the ischemia/reperfusion group. Thread was introduced at a depth of 17-19 mm. Rats in the sham-operated group were subjected to experimental procedures similar to the ischemia/reperfusion group; however, the introducing depth of thread was 10 mm. The normal control group was not given any intervention.MAIN OUTCOME MEASURES: TWEAK expression was examined by immunohistochemistry; brain water content on the ischemic side was calculated as the ratio of dry to wet tissue weight; BBB permeability was measured by Evans blue extravasation.RESULTS: A total of eight rats died prior to and after surgery and an additional eight rats were randomly entered into the study. Thus 48 rats were included in the final analysis. In the ischemia/reperfusion group,TWEAK-positive cells were

  19. Direct cortical stimulation but not transcranial electrical stimulation motor evoked potentials detect brain ischemia during brain tumor resection.

    Science.gov (United States)

    Li, Fenghua; Deshaies, Eric M; Allott, Geoffrey; Canute, Gregory; Gorji, Reza

    2011-09-01

    Motor evoked potentials (MEPs) elicited by both direct cortical stimulation (DCS) and transcranial electrical stimulation are used during brain tumor resection. Parallel use of direct cortical stimulation motor evoked potentials (DCS-MEPs) and transcranial electrical stimulation motor evoked potentials (TCeMEPs) has been practiced during brain tumor resection. We report that DCS-MEPs elicited by direct subdural grid stimulation, but not TCeMEPs, detected brain ischemia during brain tumor resection. Following resection of a brainstem high-grade glioma in a 21-year-old, the threshold of cortical motor-evoked-potentials (cMEPs) increased from 13 mA to 20 mA while amplitudes decreased. No changes were noted in transcranial motor evoked potentials (TCMEPs), somatosensory evoked potentials (SSEPs), auditory evoked potentials (AEPs), anesthetics, or hemodynamic parameters. Our case showed the loss of cMEPs and SSEPs, but not TCeMEPs. Permanent loss of DCS-MEPs and SSEPs was correlated with permanent left hemiplegia in our patient even when appropriate action was taken. Parallel use of DCS- and TCeMEPs with SSEPs improves sensitivity of intraoperative detection of motor impairment. DCS may be superior to TCeMEPs during brain tumor resection.

  20. [Effect of salvianolic acid B on neural cells damage and neurogenesis after brain ischemia-reperfusion in rats].

    Science.gov (United States)

    Zhong, Jing; Tang, Min-ke; Zhang, Yan; Xu, Qiu-ping; Zhang, Jun-tian

    2007-07-01

    This study is to observe the effect of salvianolic acid B (Sal B) on neural cells damage and neurogenesis in sub-granular zone (SGZ) and sub-ventricular zone (SVZ) after brain ischemia-reperfusion (I/R) in rats. A modified middle cerebral artery occlusion (MCAO) model of focal cerebral ischemia-reperfusion was used. The rats were divided into four groups: sham control group, ischemia-reperfusion group, Sal B 1 and 10 mg x kg(-1) groups. Sal B was consecutively administrated once a day by ip injection after MCAO. The neurogenesis in SGZ and SVZ was investigated by BrdU method 7 days after MCAO. The Nissl staining for neurons in the hippocampal CA1 and cerebral cortex was performed 14 days after MCAO. A beam-walking test was used to monitor the motor function recovery. We found that brain ischemia resulted in an increase of BrdU positive cells both in ipsilateral SGZ and SVZ at 7th day after MCAO. Sal B (10 mg x kg(-1)) significantly increased further the number of BrdU positive cells both in SGZ and SVZ (P loss and improved motor function recovery after brain ischemia in rats.

  1. Sildenafil Improves Brain Injury Recovery following Term Neonatal Hypoxia-Ischemia in Male Rat Pups.

    Science.gov (United States)

    Yazdani, Armin; Khoja, Zehra; Johnstone, Aaron; Dale, Laura; Rampakakis, Emmanouil; Wintermark, Pia

    2016-01-01

    Term asphyxiated newborns remain at risk of developing brain injury despite available neuropreventive therapies such as hypothermia. Neurorestorative treatments may be an alternative. This study investigated the effect of sildenafil on brain injury induced by neonatal hypoxia-ischemia (HI) at term-equivalent age. Neonatal HI was induced in male Long-Evans rat pups at postnatal day 10 (P10) by left common carotid ligation followed by a 2-hour exposure to 8% oxygen; sham-operated rat pups served as the control. Both groups were randomized to oral sildenafil or vehicle twice daily for 7 consecutive days. Gait analysis was performed on P27. At P30, the rats were sacrificed, and their brains were extracted. The surfaces of both hemispheres were measured on hematoxylin and eosin-stained brain sections. Mature neurons and endothelial cells were quantified near the infarct boundary zone using immunohistochemistry. HI caused significant gait impairment and a reduction in the size of the left hemisphere. Treatment with sildenafil led to an improvement in the neurological deficits as measured by gait analysis, as well as an improvement in the size of the left hemisphere. Sildenafil, especially at higher doses, also caused a significant increase in the number of neurons near the infarct boundary zone. In conclusion, sildenafil administered after neonatal HI may improve brain injury recovery by promoting neuronal populations.

  2. Correlation of aquaporin-4 expression to blood-brain barrier permeability in rats with focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Pengcheng Xu; Haorong Feng; Jinbu Xu; Yongping Wu

    2008-01-01

    BACKGROUND: Ischemic cerebrovascular disease causes injury to the blood-brain barrier. The occurrence of brain edema is associated with aquaporin expression following cerebral ischemia/reperfusion. OBJECTIVE: To analyze the correlation of aquaporin-4 expression to brain edema and blood-brain barrier permeability in brain tissues of rat models of ischemia/reperfusion. DESIGN, TIME AND SETTING: The randomized control experiment was performed at the Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, China from December 2006 to October 2007. MATERIALS: A total of 112 adult, male, Sprague-Dawley rats, weighing 220-250 g, were used to establish rat models of middle cerebral artery occlusion and reperfusion by the suture method. Rabbit anti-aquaporin-4 (Santa Cruz, USA) and Evans blue (Sigma, USA) were used to analyze the tissue. METHODS: The rats were randomized into sham-operated (n = 16) and ischemia/reperfusion (n = 96) groups. There were 6 time points in the ischemia/reperfusion group, comprising 4, 6, 12, 24, 48, and 72 hours after reperfusion, with 16 rats for each time point. Rat models in the sham-operated group at 4 hours after surgery and rat models in the ischemia/reperfusion group at different time points were equally and randomly assigned into 4 different subgroups. MAIN OUTCOME MEASURES: Brain water content on the ischemic side and the control side was measured using the dry-wet weight method. Blood-brain barrier function was determined by Evans Blue. Aquaporin-4 expression surrounding the ischemic focus, as well as the correlation of aquaporin-4 expression with brain water content and Evans blue staining, were measured using immunohistochemistry and Western blot analysis. RESULTS: Brain water content on the ischemic side significantly increased at 12 hours after reperfusion, reached a peak at 48 hours, and was still high at 72 hours. Brain water content was greater on the ischemic hemispheres, compared with the control hemispheres

  3. Microglial involvement in neuroplastic changes following focal brain ischemia in rats.

    Directory of Open Access Journals (Sweden)

    Alexandre Madinier

    Full Text Available The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p. was used to inhibit the poly(ADP-ribose polymerase-1 (PARP-1. Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis and GAP-43 (marker of neuritogenesis as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted

  4. Reduced brain edema and infarct volume in aquaporin-4 deficient mice after transient focal cerebral ischemia.

    Science.gov (United States)

    Yao, Xiaoming; Derugin, Nikita; Manley, Geoffrey T; Verkman, A S

    2015-01-01

    Aquaporin-4 (AQP4) is a water channel expressed in astrocyte end-feet lining the blood-brain barrier. AQP4 deletion in mice is associated with improved outcomes in global cerebral ischemia produced by transient carotid artery occlusion, and focal cerebral ischemia produced by permanent middle cerebral artery occlusion (MCAO). Here, we investigated the consequences of 1-h transient MCAO produced by intraluminal suture blockade followed by 23 h of reperfusion. In nine AQP4(+/+) and nine AQP4(-/-) mice, infarct volume was significantly reduced by an average of 39 ± 4% at 24h in AQP4(-/-) mice, cerebral hemispheric edema was reduced by 23 ± 3%, and Evans Blue extravasation was reduced by 31 ± 2% (mean ± SEM). Diffusion-weighted magnetic resonance imaging showed greatest reduction in apparent diffusion coefficient around the occlusion site after reperfusion, with remarkably lesser reduction in AQP4(-/-) mice. The reduced infarct volume in AQP4(-/-) mice following transient MCAO supports the potential utility of therapeutic AQP4 inhibition in stroke.

  5. Preventive administration of cromakalim reduces aquaporin-4 expression and blood-brain barrier permeability in a rat model of cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Shilei Wang; Yanting Wang; Yan Jiang; Qingxian Chang; Peng Wang; Shiduan Wang

    2011-01-01

    Cromakalim, an adenosine triphosphate-sensitive potassium channel opener, exhibits protective effects on cerebral ischemia/reperfusion injury. However, there is controversy as to whether this effect is associated with aquaporin-4 and blood-brain barrier permeability. Immunohistochemistry results show that preventive administration of cromakalim decreased aquaporin-4 and IgG protein expression in rats with ischemia/reperfusion injury; it also reduced blood-brain barrier permeability, and alleviated brain edema, ultimately providing neuroprotection.

  6. Middle cerebral artery remodeling following transient brain ischemia is linked to early postischemic hyperemia: a target of uric acid treatment.

    Science.gov (United States)

    Onetti, Yara; Dantas, Ana P; Pérez, Belén; Cugota, Roger; Chamorro, Angel; Planas, Anna M; Vila, Elisabet; Jiménez-Altayó, Francesc

    2015-04-15

    Ischemia impairs blood supply to the brain, and reperfusion is important to restore cerebral blood flow (CBF) and rescue neurons from cell death. However, reperfusion can induce CBF values exceeding the basal values before ischemia. This hyperemic effect has been associated with a worse ischemic brain damage, albeit the mechanisms that contribute to infarct expansion are not clear. In this study, we investigated the influence of early postischemic hyperemia on brain damage and middle cerebral artery (MCA) properties and the effect of treatment with the endogenous antioxidant uric acid (UA). The MCA was occluded for 90 min followed by 24 h reperfusion in adult male Sprague-Dawley rats. Cortical CBF increases at reperfusion beyond 20% of basal values were taken as indicative of hyperemia. UA (16 mg/kg) or vehicle (Locke's buffer) was administered intravenously 135 min after MCA occlusion. Hyperemic compared with nonhyperemic rats showed MCA wall thickening (sham: 22.4 ± 0.8 μm; nonhyperemic: 23.1 ± 1.2 μm; hyperemic: 27.8 ± 0.9 at 60 mmHg; P < 0.001, hyperemic vs. sham) involving adventitial cell proliferation, increased oxidative stress, and interleukin-18, and more severe brain damage. Thus MCA remodeling after ischemia-reperfusion takes place under vascular oxidative and inflammatory stress conditions linked to hyperemia. UA administration attenuated MCA wall thickening, induced passive lumen expansion, and reduced brain damage in hyperemic rats, although it did not increase brain UA concentration. We conclude that hyperemia at reperfusion following brain ischemia induces vascular damage that can be attenuated by administration of the endogenous antioxidant UA.

  7. How does the motor relearning program improve neurological function of brain ischemia monkeys?

    Institute of Scientific and Technical Information of China (English)

    Yong Yin; Zhongtang Feng; Zhen Gu; Lei Pan; Lu Gan; Dongdong Qin; Bo Yang; Jin Guo; Xintian Hu; Tinghua Wang

    2013-01-01

    The motor relearning program can significantly improve various functional disturbance induced by ischemic cerebrovascular diseases. However, its mechanism of action remains poorly understood. In injured brain tissues, glial fibrillary acidic protein and neurofilament protein changes can reflect the condition of injured neurons and astrocytes, while vascular endothelial growth factor and basic fibroblast growth factor changes can indicate angiogenesis. In the present study, we induced ischemic brain injury in the rhesus macaque by electrocoagulation of the M1 segment of the right middle cerebral artery. The motor relearning program was conducted for 60 days from the third day after model establishment. Immunohistochemistry and single-photon emission CT showed that the numbers of glial fibrillary acidic protein-, neurofilament protein-, vascular endothelial growth factorand basic fibroblast growth factor-positive cells were significantly increased in the infarcted side compared with the contralateral hemisphere following the motor relearning program. Moreover, cerebral blood flow in the infarcted side was significantly improved. The clinical rating scale for stroke was used to assess neurological function changes in the rhesus macaque following the motor relearning program. Results showed that motor function was improved, and problems with consciousness, self-care ability and balance function were significantly ameliorated. These findings indicate that the motor relearning program significantly promoted neuronal regeneration, repair and angiogenesis in the surroundings of the infarcted hemisphere, and improve neurological function in the rhesus macaque following brain ischemia.

  8. Brain immune cell composition and functional outcome after cerebral ischemia: Comparison of two mouse strains

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    Hyun Ah eKim

    2014-11-01

    Full Text Available Inflammatory cells may contribute to secondary brain injury following cerebral ischemia. The C57Bl/6 mouse strain is known to exhibit a T helper 1-prone, pro-inflammatory type response to injury, whereas the FVB strain is relatively T helper 2-prone, or anti-inflammatory, in its immune response. We tested whether stroke outcome is more severe in C57Bl/6 than FVB mice. Male mice of each strain underwent sham surgery or 1 h occlusion of the middle cerebral artery followed by 23 h of reperfusion. Despite no difference in infarct size, C57Bl/6 mice displayed markedly greater functional deficits than FVB mice after stroke, as assessed by neurological scoring and hanging wire test. Total numbers of CD45+ leukocytes tended to be larger in the brains of C57Bl/6 than FVB mice after stroke, but there were marked differences in leukocyte composition between the two mouse strains. The inflammatory response in C57Bl/6 mice primarily involved T and B lymphocytes, whereas neutrophils, monocytes and macrophages were more prominent in FVB mice. Our data are consistent with the concept that functional outcome after stroke is dependent on the immune cell composition which develops following ischemic brain injury.

  9. Mechanisms of oxidative stress in brain ischemia injury%氧化应激在脑缺血损伤中的作用机制

    Institute of Scientific and Technical Information of China (English)

    赵丹洋; 吴伟康

    2004-01-01

    Oxidative stress has been implicated in brain injury after ischemia, which is a complex cascade. These oxidants produced by oxidative stress are directly involved in oxidative damage with cellular macromolecules such as lipids, proteins and nucleic acids, which lead to cell death. Oxidants are also mediators in signaling involving mitochondria pathway, DNA repair enzymes, and transcription factor that may lead to apoptosis after cerebral ischemia. Antioxidangt enzymes (such as superoxide dismutase,etc) provide useful tools in dissecting the events involving oxidative stress in signaling and damage in ischemic brain injury. This review focuses on the mechanisms of oxidative stress during brain ischemia.

  10. Whole brain CT perfusion in acute anterior circulation ischemia: coverage size matters

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    Emmer, B.J. [Erasmus Medical Centre, Department of Radiology, Postbus 2040, Rotterdam (Netherlands); Rijkee, M.; Walderveen, M.A.A. van [Leiden University Medical Centre, Department of Radiology, Leiden (Netherlands); Niesten, J.M.; Velthuis, B.K. [University Medical Centre Utrecht, Department of Radiology, Utrecht (Netherlands); Wermer, M.J.H. [Leiden University Medical Centre, Department of Neurology, Leiden (Netherlands)

    2014-12-15

    Our aim was to compare infarct core volume on whole brain CT perfusion (CTP) with several limited coverage sizes (i.e., 3, 4, 6, and 8 cm), as currently used in routine clinical practice. In total, 40 acute ischemic stroke patients with non-contrast CT (NCCT) and CTP imaging of anterior circulation ischemia were included. Imaging was performed using a 320-multislice CT. Average volumes of infarct core of all simulated partial coverage sizes were calculated. Infarct core volume of each partial brain coverage was compared with infarct core volume of whole brain coverage and expressed using a percentage. To determine the optimal starting position for each simulated CTP coverage, the percentage of infarct coverage was calculated for every possible starting position of the simulated partial coverage in relation to Alberta Stroke Program Early CT Score in Acute Stroke Triage (ASPECTS 1) level. Whole brain CTP coverage further increased the percentage of infarct core volume depicted by 10 % as compared to the 8-cm coverage when the bottom slice was positioned at the ASPECTS 1 level. Optimization of the position of the region of interest (ROI) in 3 cm, 4 cm, and 8 cm improved the percentage of infarct depicted by 4 % for the 8-cm, 7 % for the 4-cm, and 13 % for the 3-cm coverage size. This study shows that whole brain CTP is the optimal coverage for CTP with a substantial improvement in accuracy in quantifying infarct core size. In addition, our results suggest that the optimal position of the ROI in limited coverage depends on the size of the coverage. (orig.)

  11. The GluN3A Subunit Exerts a Neuroprotective Effect in Brain Ischemia and the Hypoxia Process

    Directory of Open Access Journals (Sweden)

    Hui Wang

    2013-07-01

    Full Text Available NMDARs (N-methyl-d-aspartate receptors mediate the predominantly excitatory neurotransmission in the CNS (central nervous system. Excessive release of glutamate and overactivation of NMDARs during brain ischemia and the hypoxia process are causally linked to excitotoxicity and neuronal damage. GluN3 subunits, the third member of the NMDAR family with two isoforms, GluN3A and GluN3B, have been confirmed to display an inhibitory effect on NMDAR activity. However, the effect of GluN3 subunits in brain ischemia and hypoxia is not clearly understood. In the present study, the influence of ischemia and hypoxia on GluN3 subunit expression was observed by using the 2VO (two-vessel occlusion rat brain ischemia model and cell OGD (oxygen and glucose deprivation hypoxia model. It was found that GluN3A protein expression in rat hippocampus and the prefrontal cortex was increased quickly after brain ischemia and remained at a high level for at least 24 h. However, the expression of the GluN3B subunit was not remarkably changed in both the animal and cell models. After OGD exposure, rat hippocampal neurons with GluN3A subunit overexpression displayed more viability than the wild-type neurons. NG108-15 cells overexpressing GluN3A presented pronounced resistance to glutamate insult. Blocking the increase of intracellular Ca2+ concentration may underlie the neuroprotective mechanism of up-regulated GluN3A subunit. Suppressing the generation of hydroxyl radicals and NO (nitric oxide is probably also involved in the neuroprotection.

  12. Effect of PAMd on proteins expression of Bax and Bcl-2 of nerve cells in the brain tissue of ischemia-reperfusion mice

    Institute of Scientific and Technical Information of China (English)

    GUOLianjun; LVQing; QULing

    2004-01-01

    AIM : To study the effects of PAMd ( Phenolic alkaloids from Menispermum dauricum on Brain ischemia and ischemic reperfusion injury in mice. METHODS : Bilateral carotid arteries of mice were ligated and 0. 3ml blood was letted from post-eyeball venous jungle, one hour later the carotid arteries were loosed. After cerebral ischemia-reperfusion, mice

  13. Anesthesia-Induced Hypothermia Attenuates Early-Phase Blood-Brain Barrier Disruption but Not Infarct Volume following Cerebral Ischemia.

    Science.gov (United States)

    Liu, Yu-Cheng; Lee, Yu-Da; Wang, Hwai-Lee; Liao, Kate Hsiurong; Chen, Kuen-Bao; Poon, Kin-Shing; Pan, Yu-Ling; Lai, Ted Weita

    2017-01-01

    Blood-brain barrier (BBB) disruption is thought to facilitate the development of cerebral infarction after a stroke. In a typical stroke model (such as the one used in this study), the early phase of BBB disruption reaches a peak 6 h post-ischemia and largely recovers after 8-24 h, whereas the late phase of BBB disruption begins 48-58 h post-ischemia. Because cerebral infarct develops within 24 h after the onset of ischemia, and several therapeutic agents have been shown to reduce the infarct volume when administered at 6 h post-ischemia, we hypothesized that attenuating BBB disruption at its peak (6 h post-ischemia) can also decrease the infarct volume measured at 24 h. We used a mouse stroke model obtained by combining 120 min of distal middle cerebral arterial occlusion (dMCAo) with ipsilateral common carotid arterial occlusion (CCAo). This model produced the most reliable BBB disruption and cerebral infarction compared to other models characterized by a shorter duration of ischemia or obtained with dMCAO or CCAo alone. The BBB permeability was measured by quantifying Evans blue dye (EBD) extravasation, as this tracer has been shown to be more sensitive for the detection of early-phase BBB disruption compared to other intravascular tracers that are more appropriate for detecting late-phase BBB disruption. We showed that a 1 h-long treatment with isoflurane-anesthesia induced marked hypothermia and attenuated the peak of BBB disruption when administered 6 h after the onset of dMCAo/CCAo-induced ischemia. We also demonstrated that the inhibitory effect of isoflurane was hypothermia-dependent because the same treatment had no effect on ischemic BBB disruption when the mouse body temperature was maintained at 37°C. Importantly, inhibiting the peak of BBB disruption by hypothermia had no effect on the volume of brain infarct 24 h post-ischemia. In conclusion, inhibiting the peak of BBB disruption is not an effective neuroprotective strategy, especially in comparison

  14. The protective effect of HET0016 on brain edema and blood-brain barrier dysfunction after cerebral ischemia/reperfusion.

    Science.gov (United States)

    Liu, Yu; Wang, Di; Wang, Huan; Qu, Youyang; Xiao, Xingjun; Zhu, Yulan

    2014-01-28

    N-hydroxy-N-(4-butyl-2-methylphenyl) formamidine (HET0016) is a specific 20-hydroxyeicosatetraenoic acid (20-HETE) inhibitor which was first synthesized in 2001. It has been demonstrated that HET0016 reduces cerebral infarction volume in rat middle cerebral artery occlusion (MCAO) models. However, little is known about the role of HET0016 in the blood-brain barrier (BBB) dysfunction after cerebral ischemia/reperfusion (I/R) injury. The present study was designed to examine the effect of HET0016 in a MCAO and reperfusion rat model to determine whether it protects against brain edema and BBB disruption. Rats were subjected to 90 min MCAO, followed by 4, 24, 48, and 72 h reperfusion. Brain edema was measured according to the wet and dry weight method. BBB permeability based on the extravasation of Evans blue and sodium fluorescein was detected. BBB ultrastructure alterations were presented through transmission electron microscope. Superoxide production in ischemic tissue was also measured by dihydroethidium fluorescent probe. Western blot was used to analyze the expression of Claudin-5, ZO-1, MMP-9, and JNK pathway. At 24h after reperfusion, HET0016 reduced brain edema and BBB leakage. Ultrastructural damage of BBB and the increase of superoxide production were attenuated by HET0016 treatment. Western blot showed that HET0016 suppressed the activation of MMP-9 and JNK pathway but restored the expression of Claudin-5 and ZO-1. In conclusion, these results suggest that HET0016 protects BBB dysfunction after I/R by regulating the expression of MMP-9 and tight junction proteins. Furthermore, inhibition of oxidative stress and JNK pathway may be involved in this protecting effect.

  15. Early upregulation of matrix metalloproteinases following reperfusion triggers neuroinflammatory mediators in brain ischemia in rat.

    Science.gov (United States)

    Amantea, Diana; Russo, Rossella; Gliozzi, Micaela; Fratto, Vincenza; Berliocchi, Laura; Bagetta, G; Bernardi, G; Corasaniti, M Tiziana

    2007-01-01

    Abnormal expression of matrix metalloproteinases (MMPs) has been implicated in the pathophysiology of neuroinflammatory processes that accompany most central nervous system disease. In particular, early upregulation of the gelatinases MMP-2 and MMP-9 has been shown to contribute to disruption of the blood-brain barrier and to death of neurons in ischemic stroke. In situ zymography reveals a significant increase in gelatinolytic MMPs activity in the ischemic brain hemisphere after 2-h middle cerebral artery occlusion (MCAo) followed by 2-h reperfusion in rat. Accordingly, gel zymography demonstrates that expression and activity of MMP-2 and MMP-9 are enhanced in cortex and striatum ipsilateral to the ischemic insult. The latter effect appears to be instrumental for development of delayed brain damage since administration of a broad spectrum, highly specific MMPs inhibitor, GM6001, but not by its negative control, results in a significant (50%) reduction in ischemic brain volume. Increased gelatinase activity in the ischemic cortex coincides with elevation (166% vs sham) of mature interleukin-1beta (IL-1beta) after 2-h reperfusion and this does not appear to implicate a caspase-1-dependent processing of pro(31kDa)-IL-1beta to yield mature (17kDa) IL-1beta. More importantly, when administered at a neuroprotective dose GM6001 abolishes the early IL-1beta increase in the ischemic cortex and reduces the cleavage of the cytokine proform supporting the deduction that MMPs may initiate IL-1beta processing. In conclusion, development of tissue damage that follows transient ischemia implicates a crucial interplay between MMPs and mediators of neuroinflammation (e.g., IL-1beta), and this further underscores the therapeutic potential of MMPs inhibitors in the treatment of stroke.

  16. Pentoxifylline attenuates TNF-α protein levels and brain edema following temporary focal cerebral ischemia in rats.

    Science.gov (United States)

    Vakili, Abedin; Mojarrad, Somye; Akhavan, Maziar Mohammad; Rashidy-Pour, Ali

    2011-03-04

    Cerebral edema is the most common cause of neurological deterioration and mortality during acute ischemic stroke. Despite the clinical importance of cerebral ischemia, the underlying mechanisms remain poorly understood. Recent studies suggest a role for TNF-α in the brain edema formation. To further investigate whether TNF-α would play a role in brain edema formation, we examined the effects of pentoxifylline (PTX, an inhibitor of TNF-α synthesis) on the brain edema and TNF-α levels in a model of transient focal cerebral ischemia. The right middle cerebral artery (MCA) of rats was occluded for 60 min using the intraluminal filament method. The animals received PTX (60 mg/kg) immediately, 1, 3, or 6h post-ischemic induction. Twenty-four hours after induction of ischemic injury, permeability of the blood-brain barrier (BBB) and brain edema were determined by in situ brain perfusion of Evans Blue (EB) and wet-to-dry weight ratio, respectively. TNF-α protein levels in ischemic cortex were also measured at 1, 4, and 24h after the beginning of an ischemic stroke by using an enzyme-linked immunosorbent assay method. The administration of PTX up to 6h after occlusion of the MCA significantly reduced the brain edema. Moreover, PTX significantly reduced the concentration of TNF-α in ischemic brain cortex up to 4h post-transient focal stroke (Pedema in a model of transient focal cerebral ischemia. The beneficial effects of PTX may be mediated, at least in part, through a decline in TNF-α production and BBB breakdown.

  17. Total Flavone of Hawthorn Leaf inhibits neuronal apoptosis in brain tissue of rat models of chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Tan Rong-fang; Xia Ai-hua; Wu Xiao-guang; Cao Na-na; Li Meng-meng; Zhang Tian-ge; Wang Yi-ru; Yue Zhi-ling

    2014-01-01

    BACKGROUND: Cerebrovascular disease often causes dysfunction of the brain nerve, and nerve cel apoptosis is the important factor of cerebral nerve dysfunction. The excessive expression of c-fos can block the transduction of intracelular signal so that producing some apoptosis-promoting factors, which involve in nerve cel apoptosis process after ischemia injury of brain. Bcl-2 is an inhibited factor. It might to be the key to treat ischemic cerebrovascular disease by inhibiting or reducing the apoptosis of nerve cels after ischemia injury. OBJECTIVE: To investigate the therapeutic effect and mechanism of the Total Flavone of Hawthorn Leaf on chronic cerebral ischemia rats. METHODS: A total of 72 healthy male Sprague-Dawley rats were randomly divided into sham surgery group, model group, Total Flavone of Hawthorn Leaf group and ginkgo leaf group. Permanent bilateral carotid artery ligation was used to prepare chronic cerebral ischemia model in the model group, Total Flavone of Hawthorn Leaf group and ginkgo leaf group. Total Flavone of Hawthorn Leaf group and ginkgo leaf group respectively received 140 mg/kg Total Flavone of Hawthorn Leaf and 12.3 mg/kg ginkgo leaf intragastricaly for 36 days from 36 days after model induction. Model group and sham surgery group received 3.5 mL/kg physiological saline intragastricaly. RESULTS AND CONCLUSION: Compared with the model group, the expression of c-fos protein significantly deceased in the Total Flavone of Hawthorn Leaf group (P 0.05). These data indicated that the protective effect of Total Flavone of Hawthorn Leaf on chronic cerebral ischemia was associated with its inhibition of neuronal apoptosis. Its mechanism of anti-apoptosis might be associated with up-regulating expression of Bcl-2, down-regulating expression of c-fos and decreasing Ca2+ content in brain.

  18. Changes in cerebral blood flow and psychometric indicators in veterans with early forms of chronic brain ischemia

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    Vasilenko Т.М.

    2015-09-01

    Full Text Available The goal is to study the cerebral blood flow and psychometric characteristics in veterans of Afghanistan with early forms of chronic brain ischemia. Material and Methods. The study included 74 veterans of the Afghan war aged from 45 to 55 years: group 1, 28 people with NPNKM; Group 2-28 patients with circulatory encephalopathy stage 1; group 3-18 healthy persons. Doppler examination of cerebral vessels was carried out on the unit «Smart-lite». Reactive and personal anxiety of patients was assessed using the scale of Spielberger, evaluation of the quality of life through the test SAN. Determining the level of neuroticism and psychoticism was conducted by the scale of neuroticism and psy-choticism. Results: The study of cerebral blood flow in the Afghan war veterans showed signs of insolvency of carotid and carotid-basilar anastomoses, hypoperfusion phenomenon with the depletion of autoregulation, violation of the outflow of venous blood at the level of the microvasculature, accompanied by cerebral arteries spasm. More than 40% of patients with early forms of chronic brain ischemia had high personal anxiety, low levels of well-being and activity, with maximum expression of dyscirculatory hypoxia. Conclusion. Readaptation of veterans of Afghanistan is accompanied by the changes in psychometric performance and the formation of the earliest forms of brain chronic ischemia associated with inadequate hemodynamics providing increased functional activity of the brain and the inefficiency of compensatory-adaptive reactions.

  19. Minocycline inhibits 5-lipoxygenase activation and brain inflammation after focal cerebral ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Li-sheng CHU; San-hua FANG; Yu ZHOU; Guo-hang YU; Meng-ling WANG; Wei-ping ZHANG; Er-qing WEI

    2007-01-01

    Aim: To determine whether the anti-inflanunatory effect of minocycline on postis-chemic brain injury is mediated by the inhibition of 5-lipoxygenase (5-LOX) expression and enzymatic activation in rats.Methods: Focal cerebral ischemia was induced for 30 min with middle cerebral artery occlusion, followed by reperfusion. The ischemic injuries, endogenous IgG exudation, the accumulation of neutrophils and macrophage/microglia, and 5-LOX mRNA expression were determined 72 h after reperfusion. 5-LOX metabolites (leukotriene B4 and cysteinyl leukotrienes) were measured 3 h after reperfusion.Results: Minocycline (22.5 and 45 mg/kg, ip, for 3 d) attenuated ischemic injuries, IgG exudation, and the accumulation of neutrophils and macrophage/microglia 72 h after reperfusion. It also inhibited 5-LOX expression 72 h after reperfusion and the production of leukotrienes 3 h after reperfusion.Conclusion: Minocycline inhibited postis-chemic brain inflammation, which might be partly mediated by the inhibition of 5-LOX expression and enzymatic activation.

  20. Placental ischemia-induced increases in brain water content and cerebrovascular permeability: role of TNF-α.

    Science.gov (United States)

    Warrington, Junie P; Drummond, Heather A; Granger, Joey P; Ryan, Michael J

    2015-12-01

    Cerebrovascular complications and increased risk of encephalopathies are characteristic of preeclampsia and contribute to 40% of preeclampsia/eclampsia-related deaths. Circulating tumor necrosis factor-α (TNF-α) is elevated in preeclamptic women, and infusion of TNF-α into pregnant rats mimics characteristics of preeclampsia. While this suggests that TNF-α has a mechanistic role to promote preeclampsia, the impact of TNF-α on the cerebral vasculature during pregnancy remains unclear. We tested the hypothesis that TNF-α contributes to cerebrovascular abnormalities during placental ischemia by first infusing TNF-α in pregnant rats (200 ng/day ip, from gestational day 14 to 19) at levels to mimic those reported in preeclamptic women. TNF-α increased mean arterial pressure (MAP, P blood-brain barrier (BBB) permeability in the anterior cerebrum or posterior cerebrum. We then assessed the role of endogenous TNF-α in mediating these abnormalities in a model of placental ischemia induced by reducing uterine perfusion pressure followed by treatment with the soluble TNF-α receptor (etanercept, 0.8 mg/kg sc) on gestational day 18. Etanercept reduced placental ischemia-mediated increases in MAP, anterior brain water content (P permeability (202 ± 44% in placental ischemic rats to 101 ± 28% of normal pregnant rats). Our results indicate that TNF-α mechanistically contributes to cerebral edema by increasing BBB permeability and is an underlying factor in the development of cerebrovascular abnormalities associated with preeclampsia complicated by placental ischemia.

  1. Phenolic Alkaloids from Menispermum dauricum Rhizome Protect against Brain Ischemia Injury via Regulation of GLT-1, EAAC1 and ROS Generation

    OpenAIRE

    Lian-Jun Guo; Jie Ding; Jin-Jin Zhan; Mei Zhou; Xi Sun; Yang Chen; Bo Zhao

    2012-01-01

    Menispermum dauricum rhizome has been widely used in China to treat various cardiovascular and thrombosis disorders. Some studies have reported that the phenolic alkaloids of Menispermum dauricum rhizome (PAM) have protective effects against brain ischemia injury, but the mechanism of this action remains to be clarified. In the present study, we investigated the possible mechanisms of action of PAM on experimental brain ischemia injury. Oxygen and glucose deprivation (OGD) in rat primary cort...

  2. Puerarin protects brain tissue against cerebral ischemia/reperfusion injur y by inhibiting the inlfammator y response

    Institute of Scientific and Technical Information of China (English)

    Feng Zhou; Liang Wang; Panpan Liu; Weiwei Hu; Xiangdong Zhu; Hong Shen; Yuanyuan Yao

    2014-01-01

    Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral isch-emia/reperfusion injury, but its mechanism is unknown. Here, we established rat models of middle cerebral artery ischemia/reperfusion injury using the suture method. Puerarin (100 mg/kg) was administered intraperitoneally 30 minutes before middle cerebral artery occlusion and 8 hours after reperfusion. Twenty-four hours after reperfusion, we found that puerarin signiifcantly im-proved neurological deifcit, reduced infarct size and brain water content, and notably diminished the expression of Toll-like receptor-4, myeloid differentiation factor 88, nuclear factor kappa B and tumor necrosis factor-αin the ischemic region. These data indicate that puerarin exerts an anti-inlfammatory protective effect on brain tissue with ischemia/reperfusion damage by down-regulating the expression of multiple inlfammatory factors.

  3. Withania coagulans Extract Attenuates Histopathological Alteration and Apoptosis in Rat Brain Cortex Following Ischemia/Reperfusion Injury

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    Sarbishegi

    2016-01-01

    Full Text Available Background Cerebral ischemia and reperfusion (I/R is a pathological condition that arises by reduction or cessation in cerebral blood flow and return of oxygen and metabolites to brain cells, which cause oxidative damage. Objectives The aim of this study was to investigate the neuroprotective effects of Withania coagulans (WC extract on brain cortex in a rat model of I/R. Materials and Methods Thirty-two adult male Wistar rats weighing 280 - 300 g were used in this study. Animals were randomly divided to four groups (n = 8 as follow: sham operated group (I, I/R group (II, WCE500 + I/R (III and WCE1000 + I/R groups (IV. Pretreatment with WC extract (500, 1000 mg/kg was done by oral gavage for 30 days and global brain ischemia was induced by the common carotid occlusion for 30 minutes. After 72 hours, the animals were perfused transcardially and then the brains were prepared for histological study (H & E and TUNEL staining. Results The I/R group showed a significant increase in pycnotic (dying neurons and pretreatment with WC at doses of 500 mg/kg and 1000 mg/kg significantly reduced pycnotic and TUNEL positive neurons, in a dose dependent manner in ischemic brain cortex. Conclusions Our findings indicated that WC has neuroprotective effects and is able to reduce histopathological alterations and apoptosis in brain cortex I/R in rats.

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

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    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.

  5. Naoxintong dose effects on inflammatory factor expression in the rat brain following focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Xiangjian Zhang; Li Xü; Zuoran Chen; Shuchao Hu; Liying Zhang; Haiyan Li; Ruichun Liu

    2008-01-01

    BACKGROUND: Certain components of tetramethylpyrazine, a traditional Chinese medicine, exhibit protective effects against brain injury.OBJECTIVE: To investigate the effects of different Naoxintong doses on expression of nuclear factor-kappa B (κ B), interleukin-6, tumor necrosis factor-α, and complement 3 in rats following focal cerebral ischemia.DESIGN, TIME AND SETTING: The randomized experiment was performed at the Laboratory of Neurology, Second Hospital of Hebei Medical University from June 2004 to June 2006. MATERIAIS: A total of 150 adult, healthy, male, Sprague Dawley rats, weighing 280-320 g, were selected. Naoxintong powder (mainly comprising szechwan lovage rhizome, milkvetch root, danshen root, and radix angelicae sinensis) was obtained from Buchang Pharmacy Co., Ltd. in Xianyang City of Shanxi Province of China, lot number 040608.METHODS: The rats were randomly assigned into sham operation, saline, high-dose Naoxintong, moderate-dose Naoxintong, and low-dose Naoxintong groups, with 30 rats in each group. Rat models of middle cerebral artery occlusion were established using the suture method, with the exception of the sham operation group. Rats in the high-dose, moderate-dose and low-dose Naoxintong groups received 4, 2, and 1 glkg Naoxintong respectively, by gavage. Rats in the saline group were treated with 1 mL saline by gavage. All rats were administered by garage at 5 and 23 hours following surgery, and subsequently, once per day.MAIN OUTCOME MEASURES: At 6, 24, 48, 72 hours, and 7 days following model establishment, brain water content was measured. Histopathological changes in brain tissues were detected using hematoxylin-eosin staining. Expression of nuclear factor- κB, interleukin-6, tumor necrosis factor-α, and complement 3 was examined by immunohistochemistry.RESULTS: A total of 150 rats were included in the final analysis with no loss. Brain water content was significantly increased in the ischemic hemisphere of rats from the saline, as

  6. Ophthalmoplegic migraine with reversible thalamic ischemia by Tc-99m ethylcysteinate dimer brain SPECT

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    Kim, Jong Ho; Shin, Dong Jin; Kang, Sung Soo [Gachon Medical School, Gil Medical Center, Inchon (Korea, Republic of)

    1999-07-01

    Two patients presented with ophthalmoplegic migraine (OM) underwent EEG, Brain-MRI, cerebral angiography, and Tc-99m ECD SPECT during an attack. Follow-up SPECT was performed after neurologic symptoms resolved. In both cases, SPECT during an attack of ophthalmoplegia and headache demonstrated a significantly decreased regional cerebral blood flow in the thalamus to the side of ophthalmoplegia, which was normalized on the follow-up SPECT during a symptom free recovery phase (Lesion to Non-lesion thalamic ratio=1.19 to 0.96 and 1.16 to 0.98, respectively). The other roentgenographic and laboratory findings were normal. These findings are suggestive the ischemia in the perforators of PCA results in third nerve palsy because the portion of oculomotor nerve behind the cavernous sinus derives its blood supply from small perforating branches of the basilar and PCA. Matched ictal hypoperfusion of the thalamus to the site of ophthalmoplegic migraine is suggestive of the ischemic neuropathy as an etiology of OM.

  7. Effects of ketamine, midazolam, thiopental, and propofol on brain ischemia injury in rat cerebral cortical slices

    Institute of Scientific and Technical Information of China (English)

    Qing-shengXUE; Bu-weiYU; Ze-jianWANG; Hong-zhuanCHEN

    2004-01-01

    AIM: To compare the effects of ketamine, midazolam, thiopental, and propofol on brain ischemia by the model of oxygen-glucose deprivation (OGD) in rat cerebral cortical slices. METHODS: Cerebral cortical slices were incu-bated in 2 % 2,3,5-triphenyltetrazolium chloride (TTC) solution after OGD, the damages and effects of ketamine,midazolam, thiopental, and propofol were quantitativlye evaluated by ELISA reader of absorbance (A) at 490 nm,which indicated the red formazan extracted from slices, lactic dehydrogenase (LDH) releases in the incubated supernate were also measured. RESULTS: Progressive prolongation of OGD resulted in decreases of TTC staining.The percentage of tissue injury had a positive correlation with LDH releases, r=0.9609, P<0.01. Two hours of reincubation aggravated the decrease of TTC staining compared with those slices stained immediately after OGD(P<0.01). These four anesthetics had no effects on the TTC staining of slices. Ketamine completely inhibited thedecrease of A value induced by 10 min of OGD injury. High concentrations of midazolam (10 μmol/L) and thiopental (400μmol/L) partly attenuated this decrease. Propofol at high concentration (100 μmol/L) enhanced the decrease of A value induced by 10 min of OGD injury (P<0.01). CONCLUSION; Ketamine, high concentration of midazolam and thiopental have neuroprotective effects against OGD injury in rat cerebral cortical slices, while high concentration of propofol augments OGD injury in rat cerebral cortical slices.

  8. Alteration in rectification of potassium channels in perinatal hypoxia ischemia brain damage.

    Science.gov (United States)

    Chen, Penghui; Wang, Liyan; Deng, Qiyue; Ruan, Huaizhen; Cai, Wenqin

    2015-01-15

    Oligodendrocyte progenitor cells (OPCs) are susceptible to perinatal hypoxia ischemia brain damage (HIBD), which results in infant cerebral palsy due to the effects on myelination. The origin of OPC vulnerability in HIBD, however, remains controversial. In this study, we defined the HIBD punctate lesions by MRI diffuse excessive high signal intensity (DEHSI) in postnatal 7-day-old rats. The electrophysiological functional properties of OPCs in HIBD were recorded by patch-clamp in acute cerebral cortex slices. The slices were intracellularly injected with Lucifer yellow and immunohistochemically labeled with NG2 antibody to identify local OPCs. Passive membrane properties and K(+) channel functions in OPCs were analyzed to estimate the onset of vulnerability in HIBD. The resting membrane potential, membrane resistance, and membrane capacitance of OPCs were increased in both the gray and white matter of the cerebral cortex. OPCs in both the gray and white matter exhibited voltage-dependent K(+) currents, which consisted of the initiated rectified potassium currents (IA) and the sustained rectified currents (IK). The significant alternation in membrane resistance was influenced by the diversity of potassium channel kinetics. These findings suggest that the rectification of IA and IK channels may play a significant role in OPC vulnerability in HIBD.

  9. Gap junction communication involved in brain protection following focal ischemia and reperfusion in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Wang; Jian Hai; Yuhong Jing

    2009-01-01

    BACKGROUND: Studies have suggested that gap junctions not only modulate the fate of the neocortex, but are also involved in maintaining homeostasis in the mature brain. However, the neuroprotective effects of gap junction communication following brain ischemic injury remain poorly understood. OBJECTIVE: To investigate the neuroprotective effects and possible mechanisms of gap junction communication following focal ischemia and reperfusion. DESIGN, TIME AND SETTING: A randomized, controlled, animal experiment was performed at the School of Basic Medical Sciences of Lanzhou University between June 2007 and May 2008.MATERIALS: Rabbit polyclonal anti-connexin 43 (Cx43) and gap junction blocking agent octanol were purchased from Sigma, USA;mouse monoclonal anti-rat glial fibrillary acidic protein (GFAP) was provided by Santa Cruz, USA;mouse monoclonal anti-rat CD11b was produced by Abcam, England. METHODS: A total of 52 adult, male, Sprague Dawley rats were randomly assigned to three groups: sham-operated (n=12), vehicle control (n=20), and octanol-treated (n=20). Brain ischemia and reperfusion were induced by transient middle cerebral artery occlusion (MCAO) in vehicle control and octanol-treated groups, while no MCAO was administered to the sham-operated group. In the octanol-treated group, 5 mmol/kg octanol was dissolved in dimethyl sulfoxide (0.005% v/v) and was intraperitoneally injected 30 minutes prior to ischemic onset. Sham-operated and vehicle groups received equivalent volumes of dimethyl sulfoxide. MAIN OUTCOME MEASURES: Infarct volumes in ipsilateral striatum after MCAO were measured using cresyl violet dye;GFAP, CD11b, and Cx43 expression in the ipsilateral striatum following MCAO were detected by immunohistochemistry;Western blot analysis was employed to determine Cx43 and GFAP expression. RESULTS: At 1 and 3 days following MCAO and reperfusion, ipsilateral striatum infarct volumes in the octanol group were significantly greater than in the vehicle group

  10. Human microglia transplanted in rat focal ischemia brain induce neuroprotection and behavioral improvement.

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    Dashdemberel Narantuya

    Full Text Available BACKGROUND AND PURPOSE: Microglia are resident immunocompetent and phagocytic cells of central nervous system (CNS, which produce various cytokines and growth factors in response to injury and thereby regulate disease pathology. The purpose of this study is to investigate the effects of microglial transplantation on focal cerebral ischemia model in rat. METHODS: Transient middle cerebral artery occlusion (MCAO in rats was induced by the intraluminal filament technique. HMO6 cells, human microglial cell line, were transplanted intravenously at 48 hours after MCAO. Functional tests were performed and the infarct volume was measured at 7 and 14 days after MCAO. Migration and cell survival of transplanted microglial cells and host glial reaction in the brain were studied by immunohistochemistry. Gene expression of neurotrophic factors, cytokines and chemokines in transplanted cells and host rat glial cells was determined by laser capture microdissection (LCM and quantitative real time-PCR. RESULTS: HMO6 human microglial cells transplantation group demonstrated significant functional recovery compared with control group. At 7 and 14 days after MCAO, infarct volume was significantly reduced in the HMO group. In the HMO6 group, number of apoptotic cells was time-dependently reduced in the infarct core and penumbra. In addition, number of host rat microglia/macrophages and reactive astrocytes was significantly decreased at 7 and 14 days after MCAO in the penumbra. Gene expression of various neurotrophic factors (GDNF, BDNF, VEGF and BMP7 and anti-inflammatory cytokines (IL4 and IL5 was up-regulated in transplanted HMO6 cells of brain tissue compared with those in culture. The expression of GDNF and VEGF in astrocytes in penumbra was significantly up-regulated in the HMO6 group. CONCLUSIONS: Our results indicate that transplantation of HMO6 human microglial cells reduces ischemic deficits and apoptotic events in stroke animals. The results were mediated

  11. Attenuation of Brain Inflammatory Response after Focal Cerebral Ischemia/Reperfusion with Xuesaitong Injection(血塞通注射液) in Rats

    Institute of Scientific and Technical Information of China (English)

    HE Wei; XU Xiao-jun

    2006-01-01

    Objective: To investigate the neuro-protective effect of Xuesaitong Injection ( 血塞通注射液 ,XST) on brain inflammatory response after transient focal cerebral ischemia/reperfusion in rats. Methods:Focal cerebral ischemia/reperfusion models of male rats were induced by transient occlusion for 2 h of middle cerebral artery (MCA) which was followed by 24 h reperfusion. XST was administered through intraperitoneal injection of 25 mg/kg or 50 mg/kg at 4 h after the onset of ischemia. After reperfusion for 24 h, the neurological function score was evaluated, the brain edema was detected with dry-wet weight method, the myeloperoxidase (MPO) activity and the expression of intercellular adhesion molecule-1 (ICAM-1) of ischemic cerebral cortex and caudate putamen was determined by spectrophotometry and immunohistochemistry respectively. Results: XST not only lowered neurological function score at the dose of 50 mg/kg, but reduced brain edema and inhibited MPO activity and ICAM-1 expression as compared with the ischemia/reperfusion model group ( P<0.01 ). Conclusion: XST has a definite effect on inhibiting the expression of ICAM-1 and neutrophil infiltration in rats with cerebral ischemia/reperfusion when treatment started at 4 h after ischemia onset, and also attenuates inflammation in the infarcted cerebral area.neutrophil, intercellular adhesion molecule-1 of ischemic cerebral cortex and caudate putamen was determined by spectrophotometry and immunohistochemistry respectively. Results: XST not only lowered neurological function score at the dose of 50 mg/kg, but reduced brain edema and inhibited MPO activity and ICAM-1 expression as compared with the ischemia/reperfusion model group ( P<0.01 ). Conclusion: XST has a definite effect on inhibiting the expression of ICAM-1 and neutrophil infiltration in rats with cerebral ischemia/reperfusion when treatment started at 4 h after ischemia onset, and also attenuates inflammation in the infarcted cerebral area.

  12. Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice

    Institute of Scientific and Technical Information of China (English)

    Li-sheng CHU; Er-qing WEI; Guo-liang YU; San-hua FANG; Yu ZHOU; Meng-ling WANG; Wei-ping ZHANG

    2006-01-01

    Aim:To determine whether pranlukast.a cysteinyl leukotriene receptor-1 antagonist,exerts an anti-inflammatory effect on focal cerebral ischemia in mice.Methods:Focal cerebral ischemia in mice was induced by permanent middle cerebral artery occlusion(MCAO).In addition to neurological deficits,infarct volume,degenerated neurons and endogenous IgG exudation,we detected accumulation of neutrophils and macrophage/microglia in the ischemic brain tissue 72 h after MCAO.Pranlukast was iP injected 30 min before and after MCAO.Results:Pranlukast significantly attenuated neurological deficits,infarct volume,neuron degeneration and IgG exudation.Importantly,pranlukast(0.01 and 0.1 mg/kg) inhibited myeloperoxidase-positive neutrophil,but not CDllb-positive macrophage/microglial accumulation in the ischemic cortical tissue.Conclusion:Pranlukast exerts an anti-inflammatory effect on focal cerebral ischemia in the subacute phase that is limited to neutrophil recruitment through the disrupted blood-brain barrier.

  13. EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice

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    Bo Young Choi

    2014-10-01

    Full Text Available EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.

  14. Information entropy-based fitting of the disease trajectory of brain ischemia-induced vascular cognitive impairment

    Institute of Scientific and Technical Information of China (English)

    Lin Liu; Ju Huo; Ying Zhao; Yu Tian

    2012-01-01

    The present study investigated the disease trajectory of vascular cognitive impairment using the entropy of information in a neural network mathematical simulation based on the free radical and excitatory amino acids theories.Glutamate, malondialdehyde, and inducible nitric oxide synthase content was significantly elevated, but acetylcholine, catalase, superoxide dismutase, glutathione peroxidase and constitutive nitric oxide synthase content was significantly decreased in our vascular cognitive impairment model.The fitting curves for each factor were obtained using Matlab software.Nineteen, 30 and 49 days post ischemia were the main output time frames of the influence of these seven factors.Our results demonstrated that vascular cognitive impairment involves multiple factors.These factors include excitatory amino acid toxicity and nitric oxide toxicity.These toxicities disrupt the dynamic equilibrium of the production and removal of oxygen free radicals after cerebral ischemia, reducing the ability to clear oxygen free radicals and worsening brain injury.

  15. Pre-existing interleukin 10 in cerebral arteries attenuates subsequent brain injury caused by ischemia/reperfusion.

    Science.gov (United States)

    Liang, Qiu-Juan; Jiang, Mei; Wang, Xin-Hong; Le, Li-Li; Xiang, Meng; Sun, Ning; Meng, Dan; Chen, Si-Feng

    2015-09-01

    Recurrent stroke is difficult to treat and life threatening. Transfer of anti-inflammatory gene is a potential gene therapy strategy for ischemic stroke. Using recombinant adeno-associated viral vector 1 (rAAV1)-mediated interleukin 10 (IL-10), we investigated whether transfer of beneficial gene into the rat cerebral vessels during interventional treatment for initial stroke could attenuate brain injury caused by recurrent stroke. Male Wistar rats were administered rAAV1-IL-10, rAAV1-YFP, or saline into the left cerebral artery. Three weeks after gene transfer, rats were subjected to occlusion of the left middle cerebral artery (MCAO) for 45 min followed by reperfusion for 24 h. IL-10 levels in serum were significantly elevated 3 weeks after rAAV1-IL-10 injection, and virus in the cerebral vessels was confirmed by in situ hybridization. Pre-existing IL-10 but not YFP decreased the neurological dysfunction scores, brain infarction volume, and the number of injured neuronal cells. AAV1-IL-10 transduction increased heme oxygenase (HO-1) mRNA and protein levels in the infarct boundary zone of the brain. Thus, transduction of the IL-10 gene in the cerebral artery prior to ischemia attenuates brain injury caused by ischemia/reperfusion in rats. This preventive approach for recurrent stroke can be achieved during interventional treatment for initial stroke.

  16. CYTOMETRIC ANALYSIS OF THE SPECTRUM SUBPOPULATION OF T LYMPHOCYTES IN THE EARLY FORMS OF CHRONIC BRAIN ISCHEMIA VETERANS OF MODERN WARS

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    A. V. Zurochka

    2015-01-01

    Full Text Available Formation of the earliest forms of chronic brain ischemia veterans of modern wars accompanied by an increase in the systemic circulation of the population of T lymphocytes and monocytes, reflecting the activation of central mechanisms lymphopoiesis. In step vascular encephalopathy is an increase in circulating pool of T lymphocytes expressing the activation markers early positive reflecting readiness cells to IL-2 dependent proliferation. When progessirovanii chronic brain ischemia decreased levels of circulating T-regulatory cells, which may reflect a violation of self-tolerance in relation to brain antigens.

  17. Phycocyanin for protecting brain ischemia-reperfusion injury and its effect on the expression of Caspase-3 mRNA

    Institute of Scientific and Technical Information of China (English)

    Xuewei Yang; Yunliang Guo; Hongbing Chen

    2006-01-01

    BACKGROUND: Phycocyanin can anti-oxidize and clear free radial. Whether its protective effect on brain is related to Caspase-3, the promoter and operator of apoptosis, is highly concerned.OBJECTIVE: To observe phycocyanin for protecting nerve function and reducing the size of cerebral infarction of rats with brain ischemia-reperfusion and its effect on the expression of Caspase-3 mRNA.DESIGN: A randomized controlled experiment.SETrING: Institute of Cerebrovascular Disease, Affiliated Hospital of Medical College of Qingdao University.MATERIALS: Totally 84 adult healthy female Wistar rats, weighing 210 to 250 g, of clean grade, were provided by the Animal Experimental Center of Shandong University. Phycocyanin (Institute of Oceanography of Chinese Academy of Sciences) was used.METHODS: This experiment was carried out in the Key Laboratory for Prevention and Treatment of Brain Diseases during May to December 2005. ① The rats were randomized into sham-operation group (n=4),control group (n=40) and phycocyanin-treated group (n=40). Middle cerebral artery occlusion/reperfusion (MACO/R) models were created on the rats of control and phycocyanin-treated groups with suture-occluded method by inserting a thread into left side external-internal carotid artery. In the sham-operation group, inserting suture was omitted. After ischemia for 1 hour and reperfusion for 2 hours, suspension of phycocyanin was intragastrically administrated into the rats of the phycocyanin-treated group at 100 mg/kg , and the same volume of normal saline was isochronously administrated into the rats of control group as the same. ② Six rats were chosen respectively from the control group and phycocyanin-treated group, then neurologic impairment degrees of rats were evaluated according to Bederson's grading. ③ Six rats were chosen respectively from the control and phycocyanin-treated groups. The isolated brain tissue was stained with triphenyltetrazolium chloride, and then the size of cerebral

  18. Electroacupuncture-attenuated ischemic brain injury increases insulin-like growth factor-1expression in a rat model of focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Huanmin Gao; Ling Wang; Yunliang Guo

    2010-01-01

    Acupuncture has recently gained popularity in many countries as an alternative and complementary therapeutic intervention.Previous studies have shown that changes in genes,proteins,and their metabolites were measureable during acupuncture for treatment of cerebral ischemia.Through the use of in situ hybridization and immunohistochemistry,the present study confirmed that electroacupuncture increased insulin-like growth factor-1 mRNA and protein expression in the corpus striatum following cerebral ischemia,reduced brain edema following middle cerebral artery occlusion repeffusion,and decreased infarct volume.Results suggested that electroacupuncture is effective in the relief of cerebral ischemia by increasing endogenous insulin-like growth factor-1 expression.

  19. Pathophysiology of brain ischemia as it relates to the therapy of acute ischemic stroke

    DEFF Research Database (Denmark)

    Lassen, N A

    1990-01-01

    Current knowledge of the pathophysiology of cerebral ischemia, summarized in the present study, predicts that neurological deficits caused by moderate ischemia (flows in the penumbral range between 23 and 10 ml/100 g/min) are reversible provided flow is restored within 3-4 h of onset. It also...... predicts that areas of dense ischemia cannot be salvaged and that reperfusion of such areas is risky, because massive edema or even hemorrhage may develop following reperfusion. On this basis, it is argued that selection of stroke cases for thrombolysis or surgical revascularization must be based not only...... on computed tomographic (CT) scanning to exclude hemorrhagic stroke, but also on cerebral blood flow (CBF) tomography to exclude lacunar infarcts, early reperfusion, and dense ischemia. The methods available for routing CBF tomography in acute stroke cases are discussed, and it is concluded that single photon...

  20. Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells.

    Science.gov (United States)

    Nakagomi, Takayuki; Kubo, Shuji; Nakano-Doi, Akiko; Sakuma, Rika; Lu, Shan; Narita, Aya; Kawahara, Maiko; Taguchi, Akihiko; Matsuyama, Tomohiro

    2015-06-01

    Brain vascular pericytes (PCs) are a key component of the blood-brain barrier (BBB)/neurovascular unit, along with neural and endothelial cells. Besides their crucial role in maintaining the BBB, increasing evidence shows that PCs have multipotential stem cell activity. However, their multipotency has not been considered in the pathological brain, such as after an ischemic stroke. Here, we examined whether brain vascular PCs following ischemia (iPCs) have multipotential stem cell activity and differentiate into neural and vascular lineage cells to reconstruct the BBB/neurovascular unit. Using PCs extracted from ischemic regions (iPCs) from mouse brains and human brain PCs cultured under oxygen/glucose deprivation, we show that PCs developed stemness presumably through reprogramming. The iPCs revealed a complex phenotype of angioblasts, in addition to their original mesenchymal properties, and multidifferentiated into cells from both a neural and vascular lineage. These data indicate that under ischemic/hypoxic conditions, PCs can acquire multipotential stem cell activity and can differentiate into major components of the BBB/neurovascular unit. Thus, these findings support the novel concept that iPCs can contribute to both neurogenesis and vasculogenesis at the site of brain injuries.

  1. Effects of exogenous ganglioside-1 on learning and memory in a neonatal rat model of hypoxia-ischemia brain injury

    Institute of Scientific and Technical Information of China (English)

    Shizhi Li; Nong Xiao; Xiaoping Zhang; Ling Liu; Liyun Lin; Siyuan Chen; Yuxia Chen; Bei Xu

    2008-01-01

    BACKGROUND: Exogenous ganglioside-1 (GM1) can cross the blood-brain barrier and play a protective role against hypoxia-ischemia-induced brain damage. OBJECTIVE: To examine the possible mechanisms of exogenous GM1 protection in hypoxia-ischemia-induced brain damage in a neonatal rat model by measuring changes in brain mass, pathological morphology, growth-associated protein-43 expression, and neurobehavioral manifestations. DESIGN, TIME AND SETTING: A randomized block-design study was performed at the lmmunohistochemistry Laboratory of the Pediatric Research Institute, Children's Hospital of Chongqing Medical University from August 2005 to August 2006. MATERIALS: A total of 36 neonatal, 7-day-old, Sprague Dawley rats were used in this experiment. The hypoxia-ischemia-induced brain damage model was established by permanently occluding the right carotid artery, followed by oxygen inhalation at a low concentration (8% O2, 92% N2) for 2 hours. METHODS: All rats were randomly divided into the following groups: GM1, model, and sham operation, with 12 rats each group. Rats in the GM1 and model groups received hypoxic/ischemic-induced brain damage. Rats in the GM1 group received injections ofGM1 (i.p., 20 mg/kg) at 0, 24, 48, 72, 96, 120, and 144 hours following models established, and rats in the model group were administered (i.p.) the same amount of saline. The right carotid artery was separated, but not ligated, in the sham operation group rats. MAIN OUTCOME MEASURES: At 1 week after surgery, expression of growth-associated protein-43, a marker of neural development and plasticity, was detected in the hippocampal CA3 region by immunohistochemistry. Brain mass was measured, and the pathological morphology was observed. At 4 weeks after surgery, behavioral changes in the remaining rats were tested by Morris water maze, and growth-associated protein-43 expression was measured. RESULTS: (1) In the GM 1 and sham operation groups, growth-associated protein-43 expression was

  2. Nimodipine pretreatment improves cerebral blood flow and reduces brain edema in conscious rats subjected to focal cerebral ischemia.

    Science.gov (United States)

    Jacewicz, M; Brint, S; Tanabe, J; Wang, X J; Pulsinelli, W A

    1990-11-01

    The effect of nimodipine pretreatment on CBF and brain edema was studied in conscious rats subjected to 2.5 h of focal cortical ischemia. An infusion of nimodipine (2 micrograms/kg/min i.v.) or its vehicle, polyethylene glycol 400, was begun 2 h before the ischemic interval and was continued throughout the survival period. Under brief halothane anesthesia, the animals' right middle cerebral and common carotid arteries were permanently occluded, and 2.5 h later, they underwent a quantitative CBF study ([14C]iodoantipyrine autoradiography followed by Quantimet 970 image analysis). Nimodipine treatment improved blood flow to the middle cerebral artery territory without evidence of a "vascular steal" and reduced the volume of the ischemic core (cortex with CBF of less than 25 ml/100 g/min) and accompanying edema by approximately 50% when compared with controls (p = 0.006 and 0.0004, respectively). Mild hypotension induced by nimodipine did not aggravate the ischemic insult. The ischemic core volumes, however, were 50-75% smaller than the 24-h infarct volumes generated in a similar paradigm that demonstrated 20-30% infarct reduction with continuous nimodipine treatment. These results suggest that nimodipine pretreatment attenuates the severity of early focal cerebral ischemia, but that with persistent ischemia, cortex surrounding the ischemic core undergoes progressive infarction and the early benefit of nimodipine treatment is only partly preserved.

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

    Institute of Scientific and Technical Information of China (English)

    Gang Chen; Qiang Fu; Jiangbei Cao; Weidong Mi

    2012-01-01

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

  4. Region-specific effects on brain metabolites of hypoxia and hyperoxia overlaid on cerebral ischemia in young and old rats: a quantitative proton magnetic resonance spectroscopy study

    Directory of Open Access Journals (Sweden)

    Giuliani Patricia

    2010-02-01

    Full Text Available Abstract Background Both hypoxia and hyperoxia, deregulating the oxidative balance, may play a role in the pathology of neurodegenerative disorders underlain by cerebral ischemia. In the present study, quantitative proton magnetic resonance spectroscopy was used to evaluate regional metabolic alterations, following a 24-hour hypoxic or hyperoxic exposure on the background of ischemic brain insult, in two contrasting age-groups of rats: young - 3 months old and aged - 24 months old. Methods Cerebral ischemia was induced by ligation of the right common carotid artery. Concentrations of eight metabolites (alanine, choline-containing compounds, total creatine, γ-aminobutyric acid, glutamate, lactate, myo-inositol and N-acetylaspartate were quantified from extracts in three different brain regions (fronto-parietal and occipital cortices and the hippocampus from both hemispheres. Results In the control normoxic condition, there were significant increases in lactate and myo-inositol concentrations in the hippocampus of the aged rats, compared with the respective values in the young ones. In the ischemia-hypoxia condition, the most prevalent changes in the brain metabolites were found in the hippocampal regions of both young and aged rats; but the effects were more evident in the aged animals. The ischemia-hyperoxia procedure caused less dedicated changes in the brain metabolites, which may reflect more limited tissue damage. Conclusions We conclude that the hippocampus turns out to be particularly susceptible to hypoxia overlaid on cerebral ischemia and that old age further increases this susceptibility.

  5. Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury

    Science.gov (United States)

    Vercelli, A; Biggi, S; Sclip, A; Repetto, I E; Cimini, S; Falleroni, F; Tomasi, S; Monti, R; Tonna, N; Morelli, F; Grande, V; Stravalaci, M; Biasini, E; Marin, O; Bianco, F; di Marino, D; Borsello, T

    2015-01-01

    Excitotoxicity following cerebral ischemia elicits a molecular cascade, which leads to neuronal death. c-Jun-N-terminal kinase (JNK) has a key role in excitotoxic cell death. We have previously shown that JNK inhibition by a specific cell-permeable peptide significantly reduces infarct size and neuronal death in an in vivo model of cerebral ischemia. However, systemic inhibition of JNK may have detrimental side effects, owing to blockade of its physiological function. Here we designed a new inhibitor peptide (growth arrest and DNA damage-inducible 45β (GADD45β-I)) targeting mitogen-activated protein kinase kinase 7 (MKK7), an upstream activator of JNK, which exclusively mediates JNK's pathological activation. GADD45β-I was engineered by optimizing the domain of the GADD45β, able to bind to MKK7, and by linking it to the TAT peptide sequence, to allow penetration of biological membranes. Our data clearly indicate that GADD45β-I significantly reduces neuronal death in excitotoxicity induced by either N-methyl-D-aspartate exposure or by oxygen–glucose deprivation in vitro. Moreover, GADD45β-I exerted neuroprotection in vivo in two models of ischemia, obtained by electrocoagulation and by thromboembolic occlusion of the middle cerebral artery (MCAo). Indeed, GADD45β-I reduced the infarct size when injected 30 min before the lesion in both models. The peptide was also effective when administrated 6 h after lesion, as demonstrated in the electrocoagulation model. The neuroprotective effect of GADD45β-I is long lasting; in fact, 1 week after MCAo the infarct volume was still reduced by 49%. Targeting MKK7 could represent a new therapeutic strategy for the treatment of ischemia and other pathologies involving MKK7/JNK activation. Moreover, this new inhibitor can be useful to further dissect the physiological and pathological role of the JNK pathway in the brain. PMID:26270349

  6. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

    Science.gov (United States)

    Wang, Justin; Wu, Chiping; Peng, Jessie; Patel, Nisarg; Huang, Yayi; Gao, Xiaoxing; Aljarallah, Salman; Eubanks, James H; McDonald, Robert; Zhang, Liang

    2015-01-01

    Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging

  7. Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

    Directory of Open Access Journals (Sweden)

    Justin Wang

    Full Text Available Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min. Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute

  8. Ischemic Postconditioning Alleviates Brain Edema After Focal Cerebral Ischemia Reperfusion in Rats Through Down-Regulation of Aquaporin-4.

    Science.gov (United States)

    Han, Dong; Sun, Miao; He, Ping-Ping; Wen, Lu-Lu; Zhang, Hong; Feng, Juan

    2015-07-01

    Cerebral edema is a serious complication associated with cerebral ischemia/reperfusion (I/R). Aquaporin-4 (AQP4) plays a role in generating postischemic edema after reperfusion. Recently, ischemic postconditioning (Postcond) has been shown to produce neuroprotective effects and reduce brain edema in rats after cerebral I/R. It is unclear if ischemic Postcond alleviates brain edema injury through regulation of AQP4. In this study, middle cerebral artery occlusion (MCAO) was induced in rats by filament insertion for 2 h following 24-h reperfusion: ischemic Postcond treatment was performed before reperfusion in the experimental group. We used the wet-dry weight ratio and transmission electron microscopy to evaluate brain edema after 24 h of reperfusion. We used immunohistochemistry and Western blot analyses to evaluate the distribution and expression of AQP4. Ischemic Postcond significantly reduced the water content of the brain tissue and swelling of the astrocytic foot processes. AQP4 expression increased in the I/R and Postcond groups compared to the sham group, but it decreased in the Postcond group compared to the I/R group. The results of our study suggest that ischemic Postcond effectively reduces brain edema after reperfusion by inhibiting AQP4 expression. The data in this study support the use of ischemic Postcond for alleviating brain edema after cerebral I/R.

  9. Effect of glutamate on inflammatory responses of intestine and brain after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Lei Xu; Jie Sun; Ran Lu; Qing Ji; Jian-Guo Xu

    2005-01-01

    AIM: To study the modulation of glutamate on post-ischemic intestinal and cerebral inflammatory responses in a ischemic and excitotoxic rat model.METHODS: Adult male rats were subjected to bilateral carotid artery occlusion for 15 min and injection of monosodium glutamate intraperitoneally, to decapitate them at selected time points. Tumor necrosis factor alpha (TNF-α) level and nuclear factor kappa B (NF-κB) activity were determined by enzyme-linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA), respectively.Hemodynamic parameters were monitored continuously during the whole process of cerebral ischemia and reperfusion.RESULTS: Monosodium glutamate (MSG) treated rats displayed statistically significant high levels of TNF-α in cerebral and intestinal tissuess within the first 6 h of ischemia. The rats with cerebral ischemia showed a minor decrease of TNF-α production in cerebral and intestinal tissuess. The rats with cerebral ischemia and treated with MSG displayed statistically significant low levels of TNF-α in cerebral and intestinal tissues. These results correlated significantly with NF-κB production calculated at the same intervals. During experiment, the mean blood pressure and heart rates in all groups were stable.CONCLUSION: Glutamate is involved in the mechanism of intestinal and cerebral inflammation responses. The effects of glutamate on cerebral and intestinal inflammatory responses after ischemia are up-regulated at the transcriptional level,through the NF-κB signal transduction pathway.

  10. Early MEK1/2 Inhibition after Global Cerebral Ischemia in Rats Reduces Brain Damage and Improves Outcome by Preventing Delayed Vasoconstrictor Receptor Upregulation

    DEFF Research Database (Denmark)

    Johansson, Sara Ellinor; Larsen, Stine Schmidt; Povlsen, Gro Klitgaard

    2014-01-01

    BACKGROUND: Global cerebral ischemia following cardiac arrest is associated with increased cerebral vasoconstriction and decreased cerebral blood flow, contributing to delayed neuronal cell death and neurological detriments in affected patients. We hypothesize that upregulation of contractile ETB...... and 5-HT1B receptors, previously demonstrated in cerebral arteries after experimental global ischemia, are a key mechanism behind insufficient perfusion of the post-ischemic brain, proposing blockade of this receptor upregulation as a novel target for prevention of cerebral hypoperfusion and delayed...... neuronal cell death after global cerebral ischemia. The aim was to characterize the time-course of receptor upregulation and associated neuronal damage after global ischemia and investigate whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and thereby...

  11. Evidence for neuroprotective effects of endogenous brain-derived neurotrophic factor after global forebrain ischemia in rats.

    Science.gov (United States)

    Larsson, E; Nanobashvili, A; Kokaia, Z; Lindvall, O

    1999-11-01

    The levels of brain-derived neurotrophic factor (BDNF) vary between different forebrain areas and show region-specific changes after cerebral ischemia. The present study explores the possibility that the levels of endogenous BDNF determine the susceptibility to ischemic neuronal death. To block BDNF activity the authors used the TrkB-Fc fusion protein, which was infused intraventricularly in rats during 1 week before and 1 week after 5 or 30 minutes of global forebrain ischemia. Ischemic damage was quantified in the striatum and hippocampal formation after 1 week of reperfusion using immunocytochemistry and stereological procedures. After the 30-minute insult, there was a significantly lower number of surviving CA4 pyramidal neurons, neuropeptide Y-immunoreactive dentate hilar neurons, and choline acetyltransferase- and TrkA-positive, cholinergic striatal interneurons in the TrkB-Fc-infused rats as compared to controls. In contrast, the TrkB-Fc treatment did not influence survival of CA1 or CA3 pyramidal neurons or striatal projection neurons. Also, after the mild ischemic insult (5 minutes), neuronal death in the CA1 region was similar in the TrkB-Fc-treated and control groups. These results indicate that endogenous BDNF can protect certain neuronal populations against ischemic damage. It is conceivable, though, that efficient neuroprotection after brain insults is dependent not only on this factor but on the concerted action of a large number of neurotrophic molecules.

  12. [How to evaluate recirculation effect on brain function after global ischemia--broad spectral EEG analysis by Fourier method].

    Science.gov (United States)

    Nakata, M

    1987-03-01

    EEG alterations after 5 or 10 minutes of global ischemia were investigated for 6 hours of postischemic period in 18 adult cats, together with biophysiological parameters such as cerebral blood flow, intracranial pressure, systemic blood pressure, heart rate, and blood gases. Our EEG analytical system is composed of high fidelity pre-amplifier, AA 6 MK II (Medelec Limited, England) and signal processor 7T 08 (NEC-SanEi, Japan). It is qualified to analyze frequencies up to 20 kHz within 3 dB cut-off. Particular features of our EEG analytical method are focused on Fourier analysis about broad frequency bands, frequency and amplitude spectra to be expressed on bi-logarithmic graph and direct EEG recordings from various structures of the brain. On the basis of fluctuation theory following 3 types were divided; Type f which corresponds to 1/f fluctuation, Type L which corresponds to Lorentzian fluctuation, Type f+L which is the sum of Type f and L. The distribution of these types in the central nervous system corresponds with cortical structures, spinal cord and brain stem respectively. In conclusion, there was a good correlation between EEG and blood flow in the motor cortex. The functional reversibility after ischemia was different according to the types. Type f structures, namely the motor cortex, hippocampus and amygdala were vulnerable and Type f+L structures namely ventrolateral nucleus of the thalamus and midbrain reticular formation tended to recover or stay in preservation.

  13. Ecdysterone protects gerbil brain from temporal global cerebral ischemia/reperfusion injury via preventing neuron apoptosis and deactivating astrocytes and microglia cells.

    Science.gov (United States)

    Wang, Wei; Wang, Tao; Feng, Wan-Yu; Wang, Zhan-You; Cheng, Mao-Sheng; Wang, Yun-Jie

    2014-01-01

    Ecdysterone (EDS), a common derivative of ecdysteroid, has shown its effects on alleviating cognitive impairment and improving the cognition and memory. However, the mechanisms remain unknown. Using temporal global forebrain ischemia and reperfusion-induced brain injury as a model system, we investigated the roles of EDS in improving cognitive impairment in gerbil. Our results demonstrated that intraperitoneal injection of EDS obviously increased the number of surviving neuron cells by Nissl and neuronal nuclei (NeuN) staining. Indeed, the protecting effects of EDS are because of its ability to prevent the apoptosis of neuron cells as evidenced by TUNEL staining and caspase-3 deactivation in the brain of temporal global forebrain ischemia/reperfusion-treated gerbil. Moreover, EDS administration suppressed the ischemia stimulated activity of astrocytes and microglia cells by inhibiting the production of tumor necrosis alpha (TNF-α) in the brain of gerbil. More importantly, these actions of neurons and astrocytes/microglia cells in response to EDS treatment played pivotal roles in ameliorating the cognitive impairment in the ischemia/reperfusion-injured gerbil. In view of these observations, we not only decipher the mechanisms of EDS in reducing the syndrome of ischemia, but also provide novel perspectives to combat ischemic stroke.

  14. Alpha-MSH decreases core and brain temperature during global cerebral ischemia in rats

    DEFF Research Database (Denmark)

    Spulber, S.; Moldovan, Mihai; Oprica, M.

    2005-01-01

    A key pathological event during cerebral ischemia is the excitotoxic release of glutamate. We have shown previously that alpha-melanocyte-stimulating hormone (alpha-MSH) enhances the hypothermia induced by kainic acid. We have investigated the effects of systemic administration of alpha-MSH on four...

  15. Effect of monoamine nervous transmitter and neuropeptide Y in the aged rats with myocardial injury after brain ischemia-reperfusion

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    AIM: To study the mechanism of myocardial injury after brain ischemia-reperfusion in aged rats from the changes in Dopamine (DA), Noradrenalin (NE), Epinephrine(E) and Neuropeptide Y(NPY).METHODS: Young (5 months) and aged (20 months or more) rats were divided into model groups and normal control groups, respectively. We observed the following items in rats with 60 minute reperfusion after 30 minute brain ischemia: the pathological changed of myocardium, the activities of lactic dehydrrogenase(LDH), creatine phosphokinase(CPK), the contents of NE, DA, E, NPY. RESULTS:The CPK and LDH activities in the young model rats were higher than those in the young control rats was higher than that in the young control rats (P<0.05). The serum CPK activity in the aged control rats was higher than that in the young control rats (P<0.05). The myocardial CPK activity was higher in the aged model rats compared with the young molel rats (P<0.05) and was higher in aged control rats compared with the young control rats (P<0.01). The myocardial LDH activity was lower in the aged control rats than that in the young control rats (P<0.05) and aged model rats (P<0.01). The serum NE level, the level of NE and DA in the hypothalamus were higher obviously than those in the young control rats. The serum NE contents in the two model groups (young and aged) were higher respectively than the two control rats (young and aged). The following items’ contents were higher in the aged model rats than in the young model rats: serum NE, serum E, hypothalamus NE. The hypothalamus NE and E content was lower in the aged model rats than in te aged control rats. NPY level in the brain tissue was lower in the aged control rats than that in the young control rats and aged model rats (P<0.05).CONCLUSION: The myocardial injury after brain ischemia-reperfusion was concerned with the enhanced excitability of sympathetic-adrenal system, espectially in the aged rats. However, the change in myocardial

  16. Intestinal Ischemia

    Science.gov (United States)

    ... some generally recognized patterns. Symptoms of acute intestinal ischemia Signs and symptoms of acute intestinal ischemia typically ... confusion in older adults Symptoms of chronic intestinal ischemia Signs and symptoms of chronic intestinal ischemia can ...

  17. β-Dystroglycan cleavage by matrix metalloproteinase-2/-9 disturbs aquaporin-4 polarization and influences brain edema in acute cerebral ischemia.

    Science.gov (United States)

    Yan, W; Zhao, X; Chen, H; Zhong, D; Jin, J; Qin, Q; Zhang, H; Ma, S; Li, G

    2016-06-21

    Dystroglycan (DG) is widely expressed in various tissues, and throughout the cerebral microvasculature. It consists of two subunits, α-DG and β-DG, and the cleavage of the latter by matrix metalloproteinase (MMP)-2 and -9 underlies a number of physiological and pathological processes. However, the involvement of MMP-2/-9-mediated β-DG cleavage in cerebral ischemia remains uncertain. In astrocytes, DG is crucial for maintaining the polarization of aquaporin-4 (AQP4), which plays a role in the regulation of cytotoxic and vasogenic edema. The present study aimed to explore the effects of MMP-2/-9-mediated β-DG cleavage on AQP4 polarization and brain edema in acute cerebral ischemia. A model of cerebral ischemia was established via permanent middle cerebral artery occlusion (pMCAO) in male C57BL/6 mice. Western blotting, real-time polymerase chain reaction (PCR), immunohistochemical staining, immunofluorescent staining, electron microscopy, and light microscopy were used. Captopril was applied as a selective MMP-2/-9 inhibitor. Recombinant mouse MMP (rmMMP)-2 and -9 were used in an in vitro cleavage experiment. The present study demonstrated evidence of β-DG cleavage by MMP-2/-9 in pMCAO mouse brains; this cleavage was implicated in AQP4 redistribution and brain edema in cerebral ischemia. In addition, captopril exacerbated cytotoxic edema and ameliorated vasogenic edema at 24h after pMCAO, and alleviated brain edema and neurological deficit at 48h and 72h. In conclusion, this study provides novel insight into the effects of MMP-2/-9-mediated β-DG cleavage in acute cerebral ischemia. Such findings might facilitate the development of a therapeutic strategy for the optimization of MMP-2/-9 targeted treatment in cerebral ischemia.

  18. Protein-energy malnutrition developing after global brain ischemia induces an atypical acute-phase response and hinders expression of GAP-43.

    Directory of Open Access Journals (Sweden)

    Shari E Smith

    Full Text Available Protein-energy malnutrition (PEM is a common post-stroke problem. PEM can independently induce a systemic acute-phase response, and pre-existing malnutrition can exacerbate neuroinflammation induced by brain ischemia. In contrast, the effects of PEM developing in the post-ischemic period have not been studied. Since excessive inflammation can impede brain remodeling, we investigated the effects of post-ischemic malnutrition on neuroinflammation, the acute-phase reaction, and neuroplasticity-related proteins. Male, Sprague-Dawley rats were exposed to global forebrain ischemia using the 2-vessel occlusion model or sham surgery. The sham rats were assigned to control diet (18% protein on day 3 after surgery, whereas the rats exposed to global ischemia were assigned to either control diet or a low protein (PEM, 2% protein diet. Post-ischemic PEM decreased growth associated protein-43, synaptophysin and synaptosomal-associated protein-25 immunofluorescence within the hippocampal CA3 mossy fiber terminals on day 21, whereas the glial response in the hippocampal CA1 and CA3 subregions was unaltered by PEM. No systemic acute-phase reaction attributable to global ischemia was detected in control diet-fed rats, as reflected by serum concentrations of alpha-2-macroglobulin, alpha-1-acid glycoprotein, haptoglobin, and albumin. Acute exposure to the PEM regimen after global brain ischemia caused an atypical acute-phase response. PEM decreased the serum concentrations of albumin and haptoglobin on day 5, with the decreases sustained to day 21. Serum alpha-2-macroglobulin concentrations were significantly higher in malnourished rats on day 21. This provides the first direct evidence that PEM developing after brain ischemia exerts wide-ranging effects on mechanisms important to stroke recovery.

  19. Human-derived physiological heat shock protein 27 complex protects brain after focal cerebral ischemia in mice.

    Directory of Open Access Journals (Sweden)

    Shinichiro Teramoto

    Full Text Available Although challenging, neuroprotective therapies for ischemic stroke remain an interesting strategy for countering ischemic injury and suppressing brain tissue damage. Among potential neuroprotective molecules, heat shock protein 27 (HSP27 is a strong cell death suppressor. To assess the neuroprotective effects of HSP27 in a mouse model of transient middle cerebral artery occlusion, we purified a "physiological" HSP27 (hHSP27 from normal human lymphocytes. hHSP27 differed from recombinant HSP27 in that it formed dimeric, tetrameric, and multimeric complexes, was phosphorylated, and contained small amounts of αβ-crystallin and HSP20. Mice received intravenous injections of hHSP27 following focal cerebral ischemia. Infarct volume, neurological deficit scores, physiological parameters, and immunohistochemical analyses were evaluated 24 h after reperfusion. Intravenous injections of hHSP27 1 h after reperfusion significantly reduced infarct size and improved neurological deficits. Injected hHSP27 was localized in neurons on the ischemic side of the brain. hHSP27 suppressed neuronal cell death resulting from cytochrome c-mediated caspase activation, oxidative stress, and inflammatory responses. Recombinant HSP27 (rHSP27, which was artificially expressed and purified from Escherichia coli, and dephosphorylated hHSP27 did not have brain protective effects, suggesting that the phosphorylation of hHSP27 may be important for neuroprotection after ischemic insults. The present study suggests that hHSP27 with posttranslational modifications provided neuroprotection against ischemia/reperfusion injury and that the protection was mediated through the inhibition of apoptosis, oxidative stress, and inflammation. Intravenously injected human HSP27 should be explored for the treatment of acute ischemic strokes.

  20. ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

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    Qian Yu

    2015-07-01

    Full Text Available Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

  1. Evidence of CCR2-independent transmigration of Ly6C(hi) monocytes into the brain after permanent cerebral ischemia in mice.

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    Chu, Hannah X; Kim, Hyun Ah; Lee, Seyoung; Broughton, Brad R S; Drummond, Grant R; Sobey, Christopher G

    2016-04-15

    Previously we showed that INCB3344, a CCR2 antagonist, inhibits transmigration of Ly6C(hi) monocytes into the brain after ischemia-reperfusion. Here we tested the effect of CCR2 inhibition during permanent cerebral ischemia. Mice were administered either vehicle (dimethyl sulfoxide/carboxymethylcellulose) or INCB3344 (30 or 100mg/kg IP) 1h before middle cerebral artery occlusion and at 2 and 6h after the initiation of ischemia. After 24h, we assessed functional outcome, infarct volume and quantified immune cells in blood and brain. The increase in circulating bone marrow-derived Ly6C(hi) monocytes, but not the infiltration of those cells into the brain, was blocked by the CCR2 antagonist. INCB3344 had no effect on either neurological deficit or infarct volume. Our data confirm that cerebral ischemia triggers a CCR2-dependent increase in circulating Ly6C(hi) monocytes, but suggest that in the absence of reperfusion these cells may transmigrate into the ischemic brain in a CCR2-independent manner.

  2. Role of nitric oxide synthases in early blood-brain barrier disruption following transient focal cerebral ischemia.

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    Zheng Jiang

    Full Text Available The role of nitric oxide synthases (NOSs in early blood-brain barrier (BBB disruption was determined using a new mouse model of transient focal cerebral ischemia. Ischemia was induced by ligating the middle cerebral artery (MCA at its M2 segment and reperfusion was induced by releasing the ligation. The diameter alteration of the MCA, arterial anastomoses and collateral arteries were imaged and measured in real time. BBB disruption was assessed by Evans Blue (EB and sodium fluorescein (Na-F extravasation at 3 hours of reperfusion. The reperfusion produced an extensive vasodilation and a sustained hyperemia. Although expression of NOSs was not altered at 3 hours of reperfusion, L-NAME (a non-specific NOS inhibitor abolished reperfusion-induced vasodilation/hyperemia and significantly reduced EB and Na-F extravasation. L-NIO (an endothelial NOS (eNOS inhibitor significantly attenuated cerebral vasodilation but not BBB disruption, whereas L-NPA and 7-NI (neuronal NOS (nNOS inhibitors significantly reduced BBB disruption but not cerebral vasodilation. In contrast, aminoguanidine (AG (an inducible NOS (iNOS inhibitor had less effect on either cerebral vasodilation or BBB disruption. On the other hand, papaverine (PV not only increased the vasodilation/hyperemia but also significantly reduced BBB disruption. Combined treatment with L-NAME and PV preserved the vasodilation/hyperemia and significantly reduced BBB disruption. Our findings suggest that nNOS may play a major role in early BBB disruption following transient focal cerebral ischemia via a hyperemia-independent mechanism.

  3. Influence of ischemic preconditioning on levels of nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors in hippocampus following forebrain ischemia.

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    Lee, Tsong-Hai; Yang, Jen-Tsung; Ko, Yu-Shien; Kato, Hiroyuki; Itoyama, Yasuto; Kogure, Kyuya

    2008-01-02

    Preconditioning of gerbil brain with a sublethal forebrain ischemia is known to protect hippocampal CA1 neurons following a subsequent lethal ischemia (the second ischemia) which usually damages neurons (ischemic tolerance). Present report using a confocal laser scanning microscope demonstrated that the hippocampal cells of sham operation gerbils contained immunofluorescent NGF and BDNF and their high-affinity receptors (TrkA and TrkB). A 2-min ischemia caused little change of these proteins (ANOVA test, PBDNF but not NGF and their high-affinity receptors showed a transient reduction at 4 h (ANOVA test, PBDNF and TrkB decreased transiently from 4 h to 1 day (ANOVA test, PCA3 and dentate gyrus areas, only BDNF decreased significantly at 7 days in the CA3 area without ischemic preconditioning (ANOVA test, PCA3 and dentate gyrus areas with and without ischemic preconditioning. Western blot study showed that in the hippocampal formation with ischemic preconditioning, preconditioning prevented the decline of these protein levels from 1 day to 7 days after the second lethal ischemia (ANOVA test, P>0.05). Results of this study demonstrate that ischemic preconditioning recovers the initial decline in NGF and BDNF and their corresponding receptors in the vulnerable CA1 neurons after the second lethal ischemia, suggesting that growth factors might play a role in the protective mechanism of ischemic preconditioning.

  4. Erythropoietin reduces apoptosis of brain tissue cells in rats after cerebral ischemia/reperfusion injury: a characteristic analysis using magnetic resonance imaging

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    Chun-juan Jiang

    2016-01-01

    Full Text Available Some in vitro experiments have shown that erythropoietin (EPO increases resistance to apoptosis and facilitates neuronal survival following cerebral ischemia. However, results from in vivo studies are rarely reported. Perfusion-weighted imaging (PWI and diffusion-weighted imaging (DWI have been applied successfully to distinguish acute cerebral ischemic necrosis and penumbra in living animals; therefore, we hypothesized that PWI and DWI could be used to provide imaging evidence in vivo for the conclusion that EPO could reduce apoptosis in brain areas injured by cerebral ischemia/reperfusion. To validate this hypothesis, we established a rat model of focal cerebral ischemia/reperfusion injury, and treated with intra-cerebroventricular injection of EPO (5,000 U/kg 20 minutes before injury. Brain tissue in the ischemic injury zone was sampled using MRI-guided localization. The relative area of abnormal tissue, changes in PWI and DWI in the ischemic injury zone, and the number of apoptotic cells based on TdT-mediated dUTP-biotin nick end-labeling (TUNEL were assessed. Our findings demonstrate that EPO reduces the relative area of abnormally high signal in PWI and DWI, increases cerebral blood volume, and decreases the number of apoptotic cells positive for TUNEL in the area injured by cerebral ischemia/reperfusion. The experiment provides imaging evidence in vivo for EPO treating cerebral ischemia/reperfusion injury.

  5. Erythropoietin reduces apoptosis of brain tissue cells in rats after cerebral ischemia/reperfusion injury:a characteristic analysis using magnetic resonance imaging

    Institute of Scientific and Technical Information of China (English)

    Chun-juan Jiang; Zhong-juan Wang; Yan-jun Zhao; Zhui-yang Zhang; Jing-jing Tao; Jian-yong Ma

    2016-01-01

    Somein vitro experiments have shown that erythropoietin (EPO) increases resistance to apoptosis and facilitates neuronal survival follow-ing cerebral ischemia. However, results fromin vivo studies are rarely reported. Perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) have been applied successfully to distinguish acute cerebral ischemic necrosis and penumbra in living animals; therefore, we hypothesized that PWI and DWI could be used to provide imaging evidencein vivo for the conclusion that EPO could reduce apoptosis in brain areas injured by cerebral ischemia/reperfusion. To validate this hypothesis, we established a rat model of focal cerebral ischemia/reperfusion injury, and treated with intra-cerebroventricular injection of EPO (5,000 U/kg) 20 minutes before injury. Brain tissue in the ischemic injury zone was sampled using MRI-guided localization. The relative area of abnormal tissue, changes in PWI and DWI in the ischemic injury zone, and the number of apoptotic cells based on TdT-mediated dUTP-biotin nick end-labeling (TUNEL) were assessed. Our ifndings demonstrate that EPO reduces the relative area of abnormally high signal in PWI and DWI, increases cerebral blood volume, and decreases the number of apoptotic cells positive for TUNEL in the area injured by cerebral ischemia/reperfusion. The experiment pro-vides imaging evidencein vivo for EPO treating cerebral ischemia/reperfusion injury.

  6. Erythropoietin reduces apoptosis of brain tissue cells in rats after cerebral ischemia/reperfusion injury: a characteristic analysis using magnetic resonance imaging.

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    Jiang, Chun-Juan; Wang, Zhong-Juan; Zhao, Yan-Jun; Zhang, Zhui-Yang; Tao, Jing-Jing; Ma, Jian-Yong

    2016-09-01

    Some in vitro experiments have shown that erythropoietin (EPO) increases resistance to apoptosis and facilitates neuronal survival following cerebral ischemia. However, results from in vivo studies are rarely reported. Perfusion-weighted imaging (PWI) and diffusion-weighted imaging (DWI) have been applied successfully to distinguish acute cerebral ischemic necrosis and penumbra in living animals; therefore, we hypothesized that PWI and DWI could be used to provide imaging evidence in vivo for the conclusion that EPO could reduce apoptosis in brain areas injured by cerebral ischemia/reperfusion. To validate this hypothesis, we established a rat model of focal cerebral ischemia/reperfusion injury, and treated with intra-cerebroventricular injection of EPO (5,000 U/kg) 20 minutes before injury. Brain tissue in the ischemic injury zone was sampled using MRI-guided localization. The relative area of abnormal tissue, changes in PWI and DWI in the ischemic injury zone, and the number of apoptotic cells based on TdT-mediated dUTP-biotin nick end-labeling (TUNEL) were assessed. Our findings demonstrate that EPO reduces the relative area of abnormally high signal in PWI and DWI, increases cerebral blood volume, and decreases the number of apoptotic cells positive for TUNEL in the area injured by cerebral ischemia/reperfusion. The experiment provides imaging evidence in vivo for EPO treating cerebral ischemia/reperfusion injury.

  7. Neuroprotective Effects of Sesamin and Sesamolin on Gerbil Brain in Cerebral Ischemia

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    Cheng, Fu-Chou; Jinn, Tzyy-Rong; Hou, Rolis C. W.; Tzen, Jason T. C.

    2006-01-01

    Sesamin and sesamolin, abundant lignans found in sesame oil, have been demonstrated to possess several bioactivities beneficial for human health. Excess generation of nitric oxide in lipopolysaccharide-stimulated rat primary microglia cells was significantly attenuated when they were pretreated with sesamin or sesamolin. The neuroprotective effect of sesamin and sesamolin was also observed in vivo using gerbils subjected to a focal cerebral ischemia induced by occlusion of the right common ca...

  8. Protein kinase C inhibition attenuates vascular ETB receptor upregulation and decreases brain damage after cerebral ischemia in rat

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    Vikman Petter

    2007-01-01

    Full Text Available Abstract Background Protein kinase C (PKC is known to be involved in the pathophysiology of experimental cerebral ischemia. We have previously shown that after transient middle cerebral artery occlusion, there is an upregulation of endothelin receptors in the ipsilateral middle cerebral artery. The present study aimed to examine the effect of the PKC inhibitor Ro-32-0432 on endothelin receptor upregulation, infarct volume and neurology outcome after middle cerebral artery occlusion in rat. Results At 24 hours after transient middle cerebral artery occlusion (MCAO, the contractile endothelin B receptor mediated response and the endothelin B receptor protein expression were upregulated in the ipsilateral but not the contralateral middle cerebral artery. In Ro-32-0432 treated rats, the upregulated endothelin receptor response was attenuated. Furthermore, Ro-32-0432 treatment decreased the ischemic brain damage significantly and improved neurological scores. Immunohistochemistry showed fainter staining of endothelin B receptor protein in the smooth muscle cells of the ipsilateral middle cerebral artery of Ro-32-0432 treated rats compared to control. Conclusion The results suggest that treatment with Ro-32-0432 in ischemic stroke decreases the ischemic infarction area, neurological symptoms and associated endothelin B receptor upregulation. This provides a new perspective on possible mechanisms of actions of PKC inhibition in cerebral ischemia.

  9. The Specific Protein Kinase R (PKR) Inhibitor C16 Protects Neonatal Hypoxia-Ischemia Brain Damages by Inhibiting Neuroinflammation in a Neonatal Rat Model

    Science.gov (United States)

    Xiao, Jinglei; Tan, Yongchang; Li, Yinjiao; Luo, Yan

    2016-01-01

    Background Brain injuries induced by hypoxia-ischemia in neonates contribute to increased mortality and lifelong neurological dysfunction. The specific PKR inhibitor C16 has been previously demonstrated to exert a neuroprotective role in adult brain injuries. However, there is no recent study available concerning its protective role in hypoxia-ischemia-induced immature brain damage. Therefore, we investigated whether C16 protects against neonatal hypoxia-ischemia injuries in a neonatal rat model. Material/Methods Postnatal day 7 (P7) rats were used to establish classical hypoxia-ischemia animal models, and C16 postconditioning with 100 ug/kg was performed immediately after hypoxia. Western blot analysis was performed to quantify the phosphorylation of the PKR at 0 h, 3 h, 6 h, 12 h, 24 h, and phosphorylation of NF-κB 24h after hypoxia exposure. The TTC stain for infarction area and TUNEL stain for apoptotic cells were assayed 24 h after the brain hypoxia. Gene expression of IL-1β, IL-6, and TNF-α was performed at 3 h, 6 h, 12 h, and 24 h. Results The level of PKR autophosphorylation was increased dramatically, especially at 3 h (C16 group vs. HI group, P<0.01). Intraperitoneal C16 administration reduced the infarct volume and apoptosis ratio after this insult (C16 group vs. HI group<0.01), and C16 reduced proinflammatory cytokines mRNA expression, partly through inhibiting NF-κB activation (C16 group vs. HI group<0.05). Conclusions C16 can protect immature rats against hypoxia-ischemia-induced brain damage by modulating neuroinflammation. PMID:28008894

  10. YiQiFuMai powder injection ameliorates blood-brain barrier dysfunction and brain edema after focal cerebral ischemia-reperfusion injury in mice.

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    Cao, Guosheng; Ye, Xinyi; Xu, Yingqiong; Yin, Mingzhu; Chen, Honglin; Kou, Junping; Yu, Boyang

    2016-01-01

    YiQiFuMai powder injection (YQFM) is a modern preparation derived from the traditional Chinese medicine Sheng-Mai-San. YQFM is widely used in clinical practice in the People's Republic of China, mainly for the treatment of microcirculatory disturbance-related diseases. However, little is known about its role in animals with ischemic stroke. The aim of this study was to examine the effect of YQFM on brain edema and blood-brain barrier (BBB) dysfunction induced by cerebral ischemia-reperfusion (I/R) injury. Male C57BL/6J mice underwent right middle cerebral artery occlusion for 1 hour with a subsequent 24-hour reperfusion to produce I/R injury. YQFM (three doses: 0.336, 0.671, and 1.342 g/kg) was then given intraperitoneally (IP). The results demonstrated that YQFM significantly decreased infarct size, improved neurological deficits, reduced brain water content, and increased cerebral blood flow after I/R injury. 18F-fluorodeoxyglucose micro-positron emission tomography imaging and hematoxylin and eosin staining results indicated that YQFM is able to ameliorate brain metabolism and histopathological damage after I/R. Moreover, YQFM administration reduced BBB leakage and upregulated the expression of zona occludens-1 (ZO-1) and occludin, which was confirmed by Evans Blue extravasation, Western blotting, and immunofluorescence assay. Our findings suggest that YQFM provides protection against focal cerebral I/R injury in mice, possibly by improving BBB dysfunction via upregulation of the expression of tight junction proteins.

  11. Early environmental enrichment affects neurobehavioral development and prevents brain damage in rats submitted to neonatal hypoxia-ischemia.

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    Schuch, Clarissa Pedrini; Diaz, Ramiro; Deckmann, Iohanna; Rojas, Joseane Jiménez; Deniz, Bruna Ferrary; Pereira, Lenir Orlandi

    2016-03-23

    Our previous results demonstrated improved cognition in adolescent rats housed in environmental enrichment (EE) that underwent neonatal hypoxia-ischemia (HI). The aim of this study was to investigate the effects of early EE on neurobehavioral development and brain damage in rats submitted to neonatal HI. Wistar rats were submitted to the HI procedure on the 7th postnatal day (PND) and housed in an enriched environment (8th-20th PND). The maturation of physical characteristics and the neurological reflexes were evaluated and the volume of striatum, corpus callosum and neocortex was measured. Data analysis demonstrated a clear effect of EE on neurobehavioral development; also, daily performance was improved in enriched rats on righting, negative geotaxis and cliff aversion reflex. HI caused a transient motor deficit on gait latency. Brain atrophy was found in HI animals and this damage was partially prevented by the EE. In conclusion, early EE stimulated neurobehavioral development in neonate rats and also protects the neocortex and the corpus callosum from atrophy following HI. These findings reinforce the potential of EE as a strategy for rehabilitation following neonatal HI and provide scientific support to the use of this therapeutic strategy in the treatment of neonatal brain injuries in humans.

  12. nNOS expression of hippocampal neurons in aged rats after brain ischemia/reperfusion and its role in DND development

    Institute of Scientific and Technical Information of China (English)

    杨传红; 赖晃文; 詹纯列; 肖育华; 郑文岭

    2002-01-01

    To study the role of neuronal nitric oxide synthase (nNOS) in aged rats' hippocampal delayed neuronal death (DND) following brain ischemia. Methods: Models of incomplete brain ischemia were induced by clipping common carotid artery. A total of 46 aged SD rats were divided into 8 groups: normal control group ( Group A, n = 5 ), sham-operation group ( Group B, n = 5), reperfusion 1, 6, 12, 24, 48, and 96 hours groups after brain ischemia for 30 minutes ( Group C, D,E, F, G, and H, n = 6/group). The expression of nNOS was examined by immunohistochemistry and neuronal ultrastructural changes were observed by the transmission electron microscopy (TEM) at different time points after reperfusion. Results: Immunohistochemistry showed that nNOS expression in the hippocampal neurons was high in Group E, iow expression in Group D, moderate expression in Group F and G. There was nearly no expression of nNOS in Group A, B, C, and H. UItrastructure of hippocampal neurons was damaged more severely in reperfusion over 24 hours groups. Conclusions: Nitric oxide (NO) may be one of the important factors in inducing DND after ischemia/reperfusion.

  13. Phenolic alkaloids from Menispermum dauricum rhizome protect against brain ischemia injury via regulation of GLT-1, EAAC1 and ROS generation.

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    Zhao, Bo; Chen, Yang; Sun, Xi; Zhou, Mei; Ding, Jie; Zhan, Jin-Jin; Guo, Lian-Jun

    2012-03-06

    Menispermum dauricum rhizome has been widely used in China to treat various cardiovascular and thrombosis disorders. Some studies have reported that the phenolic alkaloids of Menispermum dauricum rhizome (PAM) have protective effects against brain ischemia injury, but the mechanism of this action remains to be clarified. In the present study, we investigated the possible mechanisms of action of PAM on experimental brain ischemia injury. Oxygen and glucose deprivation (OGD) in rat primary cortical cultures and middle cerebral artery occlusion in rats were used to mimic ischemia-reperfusion injury, respectively. The results suggested that PAM protected rat primary cortical cultures against OGD-reoxygenation induced cytotoxicity. PAM decreased extracellular glutamate content and markedly prevented the effects induced by OGD on protein level of GLT-1 and EAAC1 glutamate transporters. In addition, it reduced intracellular ROS generation. In vivo, PAM significantly reduced cerebral infarct area and ameliorated neurological functional deficits at different time points. Our findings revealed that the possible mechanism of action of PAM protected against brain ischemia injury involves regulation of GLT-1, EAAC1 and ROS generation.

  14. Phenolic Alkaloids from Menispermum dauricum Rhizome Protect against Brain Ischemia Injury via Regulation of GLT-1, EAAC1 and ROS Generation

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    Lian-Jun Guo

    2012-03-01

    Full Text Available Menispermum dauricum rhizome has been widely used in China to treat various cardiovascular and thrombosis disorders. Some studies have reported that the phenolic alkaloids of Menispermum dauricum rhizome (PAM have protective effects against brain ischemia injury, but the mechanism of this action remains to be clarified. In the present study, we investigated the possible mechanisms of action of PAM on experimental brain ischemia injury. Oxygen and glucose deprivation (OGD in rat primary cortical cultures and middle cerebral artery occlusion in rats were used to mimic ischemia-reperfusion injury, respectively. The results suggested that PAM protected rat primary cortical cultures against OGD-reoxygenation induced cytotoxicity. PAM decreased extracellular glutamate content and markedly prevented the effects induced by OGD on protein level of GLT-1 and EAAC1 glutamate transporters. In addition, it reduced intracellular ROS generation. In vivo, PAM significantly reduced cerebral infarct area and ameliorated neurological functional deficits at different time points. Our findings revealed that the possible mechanism of action of PAM protected against brain ischemia injury involves regulation of GLT-1, EAAC1 and ROS generation.

  15. Role of hydrogen sulfide in early blood-brain barrier disruption following transient focal cerebral ischemia.

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    Zheng Jiang

    Full Text Available We determined the role of endogenous hydrogen sulfide (H2S in cerebral vasodilation/hyperemia and early BBB disruption following ischemic stroke. A cranial window was prepared over the left frontal, parietal and temporal cortex in mice. Transient focal cerebral Ischemia was induced by directly ligating the middle cerebral artery (MCA for two hours. Regional vascular response and cerebral blood flow (CBF during ischemia and reperfusion were measured in real time. Early BBB disruption was assessed by Evans Blue (EB and sodium fluorescein (Na-F extravasation at 3 hours of reperfusion. Topical treatment with DL-propargylglycine (PAG, an inhibitor for cystathionine γ-lyase (CSE and aspartate (ASP, inhibitor for cysteine aminotransferase/3-mercaptopyruvate sulfurtransferase (CAT/3-MST, but not O-(Carboxymethylhydroxylamine hemihydrochloride (CHH, an inhibitor for cystathionine β-synthase (CBS, abolished postischemic cerebral vasodilation/hyperemia and prevented EB and Na-F extravasation. CSE knockout (CSE-/- reduced postischemic cerebral vasodilation/hyperemia but only inhibited Na-F extravasation. An upregulated CBS was found in cerebral cortex of CSE-/- mice. Topical treatment with CHH didn't further alter postischemic cerebral vasodilation/hyperemia, but prevented EB extravasation in CSE-/- mice. In addition, L-cysteine-induced hydrogen sulfide (H2S production similarly increased in ischemic side cerebral cortex of control and CSE-/- mice. Our findings suggest that endogenous production of H2S by CSE and CAT/3-MST during reperfusion may be involved in postischemic cerebral vasodilation/hyperemia and play an important role in early BBB disruption following transient focal cerebral ischemia.

  16. Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain.

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    Muramatsu, K; Sheldon, R A; Black, S M; Täuber, M; Ferriero, D M

    2000-10-28

    Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.

  17. Transient ischemic attack induced by melted solid lipid microparticles protects rat brains from permanent focal ischemia.

    Science.gov (United States)

    Tsai, M-J; Kuo, Y-M; Tsai, Y-H

    2014-09-01

    This study aims to develop a transient ischemic attack (TIA) model in conscious animals and uses this model to investigate the effect of TIA on subsequent permanent ischemia. TIA was induced by injecting designed temperature-sensitive melted solid lipid microparticles with a melting point around body temperature into male Wistar rats via arterial cannulation. Neurologic deficit was monitored immediately after the injection without anesthesia. According to the clinical definition of TIA, rats were divided into neurologic symptom durations ischemic stroke was induced 3d after the induction of TIA by injecting a different kind of embolic particle manufactured by blending chitin and PLGA. The ischemic stroke.

  18. Effect of propofol pretreatment on apoptosis in rat brain cortex after focal cerebral ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Haiyan Xu; Chengwei Zhang; Chunxiao Zhang

    2011-01-01

    The present study aimed to observe cortical expression of Bcl-2 and Bax, cysteine-dependent aspartate directed proteases-3 activity and apoptotic cell death in a rat model of middle cerebral artery occlusion pretreated with propofol. Results showed that, propofol pretreatment significantly reduced oxidative stress levels and attenuated neuronal apoptosis in the cortex of rats. Propofol pretreatment upregulated Bcl-2 expression, and downregulated Bax expression and cysteine-dependent aspartate directed proteases-3 activity. These findings indicate that propofol pretreatment inhibits cell apoptosis during focal cerebral ischemia/reperfusion injury. This neuroprotective effect is most likely achieved through the Bcl-2/Bax/cysteine-dependent aspartate directed proteases-3 pathway.

  19. Bilobalide inhibits the expression of aquaporin 1, 4 and glial fibrillary acidic protein in rat brain tissue after permanent focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Haiming Qin; Fulin Song; Hongguang Han; Hong Qu; Xingwen Zhai; Bin Qin; Song You

    2011-01-01

    The present results demonstrated that in an adult rat model of permanent middle cerebral artery occlusion (pMCAO), pretreatment with bilobalide reduced brain water content and infarct area, down-regulated aquaporin 1, 4 mRNA expression in brain edema tissue, then inhibited their synthesis in the striatum, in particular at the early stage of ischemia (at 8 hours after pMCAO), inhibited glial fibrillary acidic protein expression, and lightened reactive gliosis. These data sug-gest that bilobalide attenuates brain edema formation due to reduced expression of aquaporins.

  20. Effect of propofol post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats.

    Science.gov (United States)

    Lee, Jae Hoon; Cui, Hui Song; Shin, Seo Kyung; Kim, Jeong Min; Kim, So Yeon; Lee, Jong Eun; Koo, Bon-Nyeo

    2013-11-01

    Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post-treatment on blood-brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1α. Cerebral ischemia was induced in male Sprague-Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol, 1 mg kg(-1) min(-1) of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1α was determined 8 h after reperfusion. Propofol post-treatment significantly reduced cerebral edema (P cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP-9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1α expression.

  1. Mesenchymal stem cells induce T-cell tolerance and protect the preterm brain after global hypoxia-ischemia.

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    Reint K Jellema

    Full Text Available Hypoxic-ischemic encephalopathy (HIE in preterm infants is a severe disease for which no curative treatment is available. Cerebral inflammation and invasion of activated peripheral immune cells have been shown to play a pivotal role in the etiology of white matter injury, which is the clinical hallmark of HIE in preterm infants. The objective of this study was to assess the neuroprotective and anti-inflammatory effects of intravenously delivered mesenchymal stem cells (MSC in an ovine model of HIE. In this translational animal model, global hypoxia-ischemia (HI was induced in instrumented preterm sheep by transient umbilical cord occlusion, which closely mimics the clinical insult. Intravenous administration of 2 x 10(6 MSC/kg reduced microglial proliferation, diminished loss of oligodendrocytes and reduced demyelination, as determined by histology and Diffusion Tensor Imaging (DTI, in the preterm brain after global HI. These anti-inflammatory and neuroprotective effects of MSC were paralleled by reduced electrographic seizure activity in the ischemic preterm brain. Furthermore, we showed that MSC induced persistent peripheral T-cell tolerance in vivo and reduced invasion of T-cells into the preterm brain following global HI. These findings show in a preclinical animal model that intravenously administered MSC reduced cerebral inflammation, protected against white matter injury and established functional improvement in the preterm brain following global HI. Moreover, we provide evidence that induction of T-cell tolerance by MSC might play an important role in the neuroprotective effects of MSC in HIE. This is the first study to describe a marked neuroprotective effect of MSC in a translational animal model of HIE.

  2. Methylophiopogonanone A Protects against Cerebral Ischemia/Reperfusion Injury and Attenuates Blood-Brain Barrier Disruption In Vitro.

    Directory of Open Access Journals (Sweden)

    Mingbao Lin

    Full Text Available Methylophiopogonanone A (MO-A, an active homoisoflavonoid of the Chinese herb Ophiopogon japonicus which has been shown to have protective effects on cerebral ischemia/reperfusion (I/R injury, has been demonstrated to have anti-inflammatory and anti-oxidative properties. However, little is known about its role in cerebral I/R injury. Therefore, in this study, by using a middle cerebral artery occlusion (MCAO and reperfusion rat model, the effect of MO-A on cerebral I/R injury was examined. The results showed that MO-A treatment reduced infarct volume and brain edema, improved neurological deficit scores, reversed animal body weight decreases, and increased animal survival time in the stroke groups. Western blotting showed that MO-A suppressed MMP-9, but restored the expression of claudin-3 and claudin-5. Furthermore, transmission electron microscopy were monitored to determine the blood-brain barrier (BBB alterations in vitro. The results showed that MO-A markedly attenuated BBB damage in vitro. Additionally, MO-A inhibited ROS production in ECs and MMP-9 release in differentiated THP-1 cells in vitro, and suppressed ICAM-1 and VCAM-1 expression in ECs and leukocyte/EC adhesion. In conclusion, our data indicate that MO-A has therapeutic potential against cerebral I/R injury through its ability to attenuate BBB disruption by regulating the expression of MMP-9 and tight junction proteins.

  3. Accumulation of N-acyl-ethanolamine phospholipids in rat brains during post-decapitative ischemia

    DEFF Research Database (Denmark)

    Moesgaard, B.; Hansen, Harald S.; Jaroszewski, J.W.

    1999-01-01

    ethylenediaminetetraacetic acid (EDTA). The lower organic phases were isolated and evaporated to dryness under a stream of nitrogen and the lipids were redissolved in CDCl-CHOH-HO 100.0:29.9:5.2 (v/v/v) for NMR analysis. Increasing the period of post-decapitative ischemia resulted in an accumulation of two signals......-phospho(N-acyl)-ethanolamine (NAPE(PLAS)), respectively, by spiking with authentic materials. Additionally, the identification was verified by thin-layer chromatography, which also showed the accumulation of N-acyl-ethanolamine phospholipids. The use of K-EDTA instead of the commonly used Cs-EDTA...... in the preparation of the NMR samples allowed the separation of the chemical shifts of N-acyl-ethanolamine phospholipids from those of the ethanolamine phospholipids. Moreover, the chemical shift of cardiolipin was moved from 0.15 ppm observed with Cs-EDTA to about 0.31 ppm with K-EDTA. The present study...

  4. Moderately delayed post-insult treatment with normobaric hyperoxia reduces excitotoxin-induced neuronal degeneration but increases ischemia-induced brain damage

    Directory of Open Access Journals (Sweden)

    Haelewyn Benoit

    2011-04-01

    Full Text Available Abstract Background The use and benefits of normobaric oxygen (NBO in patients suffering acute ischemic stroke is still controversial. Results Here we show for the first time to the best of our knowledge that NBO reduces both NMDA-induced calcium influxes in vitro and NMDA-induced neuronal degeneration in vivo, but increases oxygen and glucose deprivation-induced cell injury in vitro and ischemia-induced brain damage produced by middle cerebral artery occlusion in vivo. Conclusions Taken together, these results indicate that NBO reduces excitotoxin-induced calcium influx and subsequent neuronal degeneration but favors ischemia-induced brain damage and neuronal death. These findings highlight the complexity of the mechanisms involved by the use of NBO in patients suffering acute ischemic stroke.

  5. Vasodilation by in vivo activation of astrocyte endfeet via two-photon calcium uncaging as a strategy to prevent brain ischemia

    Science.gov (United States)

    Chen, Yuanxin; Mancuso, James; Zhao, Zhen; Li, Xuping; Cheng, Jie; Roman, Gustavo; Wong, Stephen T. C.

    2013-12-01

    Decreased cerebral blood flow causes brain ischemia and plays an important role in the pathophysiology of many neurodegenerative diseases, including Alzheimer's disease and vascular dementia. In this study, we photomodulated astrocytes in the live animal by a combination of two-photon calcium uncaging in the astrocyte endfoot and in vivo imaging of neurovasculature and astrocytes by intravital two-photon microscopy after labeling with cell type specific fluorescent dyes. Our study demonstrates that photomodulation at the endfoot of a single astrocyte led to a 25% increase in the diameter of a neighboring arteriole, which is a crucial factor regulating cerebral microcirculation in downstream capillaries. Two-photon uncaging in the astrocyte soma or endfoot near veins does not show the same effect on microcirculation. These experimental results suggest that infrared photomodulation on astrocyte endfeet may be a strategy to increase cerebral local microcirculation and thus prevent brain ischemia.

  6. miR-203 protects microglia mediated brain injury by regulating inflammatory responses via feedback to MyD88 in ischemia.

    Science.gov (United States)

    Yang, Zhao; Zhong, Lina; Zhong, Shanchuan; Xian, Ronghua; Yuan, Bangqing

    2015-06-01

    Much evidence demonstrates that microglia mediated inflammatory responses play an important role in brain injury in ischemia. miRNA is the important factor in regulation of inflammation. However, the effect of miRNA in microglia mediated inflammatory responses has not been well studied. In the study, we demonstrate that miR-203 negatively regulates ischemia induced microglia activation by targeting MyD88, an important adapter protein involved in most Toll-like receptors (TLRs) and interleukin-1 receptor (IL-1R) pathways. Through negative feedback, enforced expression of miR-203 or MyD88 siRNA silencing inhibits downstream NF-κβ signaling and microglia activation, thereby alleviating neuronal injury. These findings reveal that miR-203 represents a novel target regulating neuroinflammation and brain injury, thus offering a new therapeutical strategy for cerebral hypoxic diseases.

  7. Insulin-like growth factor-1 secreted by brain microvascular endothelial cells attenuates neuron injury upon ischemia.

    Science.gov (United States)

    Wang, Jun; Tang, Yibo; Zhang, Wei; Zhao, Haiping; Wang, Runjun; Yan, Yangyang; Xu, Liwei; Li, Pengtao

    2013-08-01

    Insulin-like growth factor (IGF)-1 is essential for the development of the nervous system, and is present in many cell types. Relatively little is known about IGF-1 expression in brain microvascular endothelial cells (BMECs). For in vivo studies, we examined the expression of IGF-1 and insulin-like growth factor-binding protein (IGFBP)-2 after focal cerebral ischemia for 12 h, 24 h, 3 days and 7 days, utilizing a permanent middle cerebral artery occlusion (MCAO) model in rats. For in vitro studies, we examined the levels of IGF-1 and IGFBP-2 in the culture medium or primary culture of BMECs injured by oxygen-glucose deprivation (OGD). Then, we elucidated the protective effects of IGF-1 on cortical neurons injured by OGD and the possible mechanism. In addition, we investigated the effect of BMEC-conditioned medium on IGF-1 receptor expression in neurons. The results showed that IGF-1 expression increased in serum and brain tissue, whereas IGFBP-2 expression decreased in brain tissue of MCAO-injured rats. In primary culture of BMECs, the expression levels of IGF-1 and IGFBP-2 were significantly higher under OGD conditions in culture. IGF-1 administration improved neuron viability upon normoxia or OGD, and upregulated p-Akt expression. This effect was reversed by LY294002, a specific inhibitor of the phosphoinositide 3-kinase-Akt signaling pathway. Furthermore, conditioned medium from OGD-treated BMECs substantially suppressed neuron viability and the expression of IGF-1 receptor simultaneously. These data demonstrate that therapeutic strategies that prioritize the early recovery of the IGF-1 system in BMECs might be promising in ischemic injury.

  8. The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model.

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    Zheng Ke

    Full Text Available BACKGROUND: Stroke rehabilitation with different exercise paradigms has been investigated, but which one is more effective in facilitating motor recovery and up-regulating brain neurotrophic factor (BDNF after brain ischemia would be interesting to clinicians and patients. Voluntary exercise, forced exercise, and involuntary muscle movement caused by functional electrical stimulation (FES have been individually demonstrated effective as stroke rehabilitation intervention. The aim of this study was to investigate the effects of these three common interventions on brain BDNF changes and motor recovery levels using a rat ischemic stroke model. METHODOLOGY/PRINCIPAL FINDINGS: One hundred and seventeen Sprague-Dawley rats were randomly distributed into four groups: Control (Con, Voluntary exercise of wheel running (V-Ex, Forced exercise of treadmill running (F-Ex, and Involuntary exercise of FES (I-Ex with implanted electrodes placed in two hind limb muscles on the affected side to mimic gait-like walking pattern during stimulation. Ischemic stroke was induced in all rats with the middle cerebral artery occlusion/reperfusion model and fifty-seven rats had motor deficits after stroke. Twenty-four hours after reperfusion, rats were arranged to their intervention programs. De Ryck's behavioral test was conducted daily during the 7-day intervention as an evaluation tool of motor recovery. Serum corticosterone concentration and BDNF levels in the hippocampus, striatum, and cortex were measured after the rats were sacrificed. V-Ex had significantly better motor recovery in the behavioral test. V-Ex also had significantly higher hippocampal BDNF concentration than F-Ex and Con. F-Ex had significantly higher serum corticosterone level than other groups. CONCLUSION/SIGNIFICANCE: Voluntary exercise is the most effective intervention in upregulating the hippocampal BDNF level, and facilitating motor recovery. Rats that exercised voluntarily also showed less

  9. Tetramethylpyrazine suppresses HIF-1α, TNF-α, and activated caspase-3 expression in middle cerebral artery occlusion-induced brain ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Yi CHANG; George HSIAO; Seu-hwa CHEN; Yi-cheng CHEN; Jiing-han LIN; Kuang-hung LIN; Duen-suey CHOU; Joen-rong SHEU

    2007-01-01

    Aim: To examine the detailed mechanisms underlying the inhibitory effect of tetramethylpyrazine (TMPZ) in inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAO) in rats. Methods: MCAO-induced focal cerebral ischemia in rats was used in this study. The hypoxia-inducible factor-1α (HIF-1α), activation of caspase-3, and TNF- mRNA transcription in ischemic regions were detected by immunoblotting and RT-PCR, respectively.Anti-oxidative activity was investigated using a thiobarbituric acid-reactive sub-stance (TBARS) test in rat brain homogenate preparations. Results: We showed the statistical results of the infarct areas of solvent- and TMPZ (20 mg/kg)-treated groups at various distances from the frontal pole in MCAO-induced focal cerebral ischemia in rats. Treatment with TMPZ (20 mg/kg) markedly reduced the infarct area in all regions, especially in the third to fifth sections. MCAO-induced focal cerebral ischemia was associated with increases in HIF-1α and the activation of caspase-3, as well as TNF-α transcription in ischemic regions. These expressions were markedly inhibited by treatment with TMPZ (20 mg/kg). However, TMPZ (0.5-5 mmol/L) did not significantly inhibit TBARS reaction in rat brain homogenates.Conclusion: The neuroprotective effect of TMPZ may be mediated at least by a portion of the inhibition of HIF-let and TNF-α activations, followed by the inhibi-tion of apoptosis formation (active caspase-3), resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. Thus, TMPZ treatment may represent an ideal approach to lowering the risk of or improving function in is-chemia-reperfusion brain injury-related disorders.

  10. Effects of Choto-san and hooks and stems of Uncaria sinensis on antioxidant enzyme activities in the gerbil brain after transient forebrain ischemia.

    Science.gov (United States)

    Yokoyama, Koichi; Shimada, Yutaka; Hori, Etsuro; Nakagawa, Takako; Takagi, Shinobu; Sekiya, Nobuyasu; Kouta, Kazufumi; Nishijo, Hisao; Yokozawa, Takako; Terasawa, Katsutoshi

    2004-12-01

    Previously, we revealed that oral administrations of Choto-san, a Kampo formula, and the hooks and stems of Uncaria sinensis Haviland (Rubiaceae), a medicinal plant comprising Choto-san, enhanced superoxide anion and hydroxyl radical scavenging activities in the hippocampus, and prevented delayed neuronal death of pyramidal cells in the hippocampal CA1 region in a transient forebrain ischemia gerbil model. In the present study, for the purpose of clarifying whether the endogenous antioxidant enzymes contribute to these mechanisms, we investigated the effects of Choto-san extract (CSE) and Uncaria sinensis extract (USE) on superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities in the brain by using the same experimental model. 1.0% CSE or 3.0% USE were dissolved in water and provided to gerbils ad libitum from 7 days prior to ischemia/reperfusion (i/rp). Seven days of continuous administrations of CSE or USE without i/rp procedure enhanced CAT activity but not SOD and GSH-Px activities in both the hippocampus and cortex. CSE elevated CAT activity in the hippocampus at 7 days and in the cortex at 3h after i/rp. USE raised CAT activity in both the hippocampus and cortex at 3 h and 7 days after i/rp. These results suggest that one of the mechanisms of the protective effects of CSE and USE against transient brain ischemia-induced neuronal damage may be their enhancing effect on CAT activity in the brain.

  11. 5′-Adenosine Monophosphate-Induced Hypothermia Attenuates Brain Ischemia/Reperfusion Injury in a Rat Model by Inhibiting the Inflammatory Response

    Directory of Open Access Journals (Sweden)

    Yi-Feng Miao

    2015-01-01

    Full Text Available Hypothermia treatment is a promising therapeutic strategy for brain injury. We previously demonstrated that 5′-adenosine monophosphate (5′-AMP, a ribonucleic acid nucleotide, produces reversible deep hypothermia in rats when the ambient temperature is appropriately controlled. Thus, we hypothesized that 5′-AMP-induced hypothermia (AIH may attenuate brain ischemia/reperfusion injury. Transient cerebral ischemia was induced by using the middle cerebral artery occlusion (MCAO model in rats. Rats that underwent AIH treatment exhibited a significant reduction in neutrophil elastase infiltration into neuronal cells and matrix metalloproteinase 9 (MMP-9, interleukin-1 receptor (IL-1R, tumor necrosis factor receptor (TNFR, and Toll-like receptor (TLR protein expression in the infarcted area compared to euthermic controls. AIH treatment also decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL- positive neuronal cells. The overall infarct volume was significantly smaller in AIH-treated rats, and neurological function was improved. By contrast, rats with ischemic brain injury that were administered 5′-AMP without inducing hypothermia had ischemia/reperfusion injuries similar to those in euthermic controls. Thus, the neuroprotective effects of AIH were primarily related to hypothermia.

  12. Four different types of protease-activated receptors are widely expressed in the brain and are up-regulated in hippocampus by severe ischemia.

    Science.gov (United States)

    Striggow, F; Riek-Burchardt, M; Kiesel, A; Schmidt, W; Henrich-Noack, P; Breder, J; Krug, M; Reymann, K G; Reiser, G

    2001-08-01

    A variety of extracellular serine proteases are expressed in the central nervous system or might permeate the blood-brain barrier under pathological conditions. However, their intracerebral targets and physiological functions are largely unknown. Here, we show that four distinct subtypes of protease-activated receptors (PARs) are abundantly expressed in the adult rat brain and in organotypic hippocampal slice cultures. PAR-1 expression was significant in the hippocampus, cortex and amygdala. Highest densities of PAR-2 and PAR-3 were observed in hippocampus, cortex, amygdala, thalamus, hypothalamus and striatum. Apart from the striatum, a similar localization was found for PAR-4. Within the hippocampal formation, each PAR subtype was predominantly localized in the pyramidal cell layers. Additionally, we identified PAR-2 in mossy fibers between dentate gyrus and CA3, PAR-3 in the subiculum and PAR-4 in CA3 and in mossy fibres as well as in the stratum lacunosum moleculare. After exposing hippocampal slice cultures to a severe experimental ischemia (oxygen-glucose deprivation), the expression of PARs 1-3 was up-regulated with subtype-specific kinetics. The localization of PARs in brain regions particularly vulnerable to ischemic insults as well as distinct alterations in the expression pattern after experimental ischemia support the notion of an important role of extracellular serine proteases and PARs in cerebral ischemia.

  13. A type-II positive allosteric modulator of α7 nAChRs reduces brain injury and improves neurological function after focal cerebral ischemia in rats.

    Directory of Open Access Journals (Sweden)

    Fen Sun

    Full Text Available In the absence of clinically-efficacious therapies for ischemic stroke there is a critical need for development of new therapeutic concepts and approaches for prevention of brain injury secondary to cerebral ischemia. This study tests the hypothesis that administration of PNU-120596, a type-II positive allosteric modulator (PAM-II of α7 nicotinic acetylcholine receptors (nAChRs, as long as 6 hours after the onset of focal cerebral ischemia significantly reduces brain injury and neurological deficits in an animal model of ischemic stroke. Focal cerebral ischemia was induced by a transient (90 min middle cerebral artery occlusion (MCAO. Animals were then subdivided into two groups and injected intravenously (i.v. 6 hours post-MCAO with either 1 mg/kg PNU-120596 (treated group or vehicle only (untreated group. Measurements of cerebral infarct volumes and neurological behavioral tests were performed 24 hrs post-MCAO. PNU-120596 significantly reduced cerebral infarct volume and improved neurological function as evidenced by the results of Bederson, rolling cylinder and ladder rung walking tests. These results forecast a high therapeutic potential for PAMs-II as effective recruiters and activators of endogenous α7 nAChR-dependent cholinergic pathways to reduce brain injury and improve neurological function after cerebral ischemic stroke.

  14. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

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    Priscilla L Omouendze

    Full Text Available Hypoxia-ischemia (HI and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9 activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1 genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂. Excitotoxic lesions were produced by intra parenchymal cortical (i.c. injections of 10 µg ibotenate (Ibo. Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL. In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have

  15. Hypoxia-ischemia or excitotoxin-induced tissue plasminogen activator- dependent gelatinase activation in mice neonate brain microvessels.

    Science.gov (United States)

    Omouendze, Priscilla L; Henry, Vincent J; Porte, Baptiste; Dupré, Nicolas; Carmeliet, Peter; Gonzalez, Bruno J; Marret, Stéphane; Leroux, Philippe

    2013-01-01

    Hypoxia-ischemia (HI) and excitotoxicity are validated causes of neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor-mediated pathways. Brain microvascular endothelial cells from neonates in culture, contain and release more t-PA and gelatinases upon glutamate challenge than adult cells. We have studied t-PA to gelatinase (MMP-2 and MMP-9) activity links in HI and excitotoxicity lesion models in 5 day-old pups in wild type and in t-PA or its inhibitor (PAI-1) genes inactivated mice. Gelatinolytic activities were detected in SDS-PAGE zymograms and by in situ fluorescent DQ-gelatin microscopic zymographies. HI was achieved by unilateral carotid ligature followed by a 40 min hypoxia (8%O₂). Excitotoxic lesions were produced by intra parenchymal cortical (i.c.) injections of 10 µg ibotenate (Ibo). Gel zymograms in WT cortex revealed progressive extinction of MMP-2 and MMP-9 activities near day 15 or day 8 respectively. MMP-2 expression was the same in all strains while MMP-9 activity was barely detectable in t-PA⁻/⁻ and enhanced in PAI-1⁻/⁻ mice. HI or Ibo produced activation of MMP-2 activities 6 hours post-insult, in cortices of WT mice but not in t-PA⁻/⁻ mice. In PAI-1⁻/⁻ mice, HI or vehicle i.c. injection increased MMP-2 and MMP-9 activities. In situ zymograms using DQ-gelatin revealed vessel associated gelatinolytic activity in lesioned areas in PAI-1⁻/⁻ and in WT mice. In WT brain slices incubated ex vivo, glutamate (200 µM) induced DQ-gelatin activation in vessels. The effect was not detected in t-PA⁻/⁻ mice, but was restored by concomitant exposure to recombinant t-PA (20 µg/mL). In summary, neonatal brain lesion paradigms and ex vivo excitotoxic glutamate evoked t-PA-dependent gelatinases activation in vessels. Both MMP-2 and MMP-9 activities appeared t-PA-dependent. The data suggest that vascular directed protease inhibition may have neuroprotection

  16. Influence of mild hypothermia on vascular endothelial growth factor and infarct volume in brain tissues after cerebral ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Fei Ye; Gangming Xi; Biyong Qin; Shifeng Wang; Chengyan Li

    2006-01-01

    BACKGROUND: It has been demonstrated that mild hypothermia has obvious protective effect on both whole and local cerebral ischemia. However, the definite mechanism is still unclear for the brain protection of mild hypothermia on cerebral edema, inhibiting inflammatory reaction, stabilizing blood brain barrier, etc.OBJECTIVE: To investigate the effect of mild hypothermia on the expression of vascular endothelial growth factor and the infarct volume after cerebral ischemia in rats, and analyze the brain protective mechanism of mild hypothermia.DESIGN: A randomized grouping and controlled animal trial.SETTING: Department of Neurology, People's Hospital of Yunyang Medical College.MATERIALS: Twenty adult male SD rats of clean degree, weighing (250±30) g, were provided by the animal experimental center, School of Medicine, Wuhan University. The kits for SP immunohistochemistry were purchased from Beijing Zhongshan Golden Bridge Biotechnology Co., Ltd.METHODS: The experiments were carried out in the laboratory of Department of Neurology, Renmen Hospital of Wuhan University from May to July 2005. ① The 20 rats were divided randomly into normal temperature group (n =10) and mild hypothermia group (n =10). Models of permanent middle cerebral artery occlusion were established with modified nylon suture embolization. The rats were assessed with the Longa standards: O point for without nerve dysfunction; 1 for mild neurological deficit (fore claws could no extend completely); 2 for moderate neurological deficit (circling towards the affected side); 3 for severe neurological deficit (tilting towards the affected side); 4 for coma and unconscious; 1 -3 points represented that models were successfully established. The rats of the normal temperature group were fed at room temperature, and those in the mild hypothermia group were induced by hypothermia from 2 hours postoperatively, and the rectal temperature was kept at 34-35 ℃ for 72 hours. ② Measurement of infarct volume

  17. Cortical and brain stem changes in neural activity during static handgrip and postexercise ischemia in humans

    DEFF Research Database (Denmark)

    Sander, Mikael; Macefield, Vaughan G; Henderson, Luke A

    2010-01-01

    , and to differentiate between central command and reflex inputs, we used blood oxygen level-dependent (BOLD) functional MRI (fMRI) of the whole brain (3 T). Subjects performed submaximal static handgrip exercise for 2 min followed by 6 min of PEI; MSNA was recorded on a separate day. During the contraction phase...

  18. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia

    DEFF Research Database (Denmark)

    Astrup, J; Symon, L; Branston, N M;

    1977-01-01

    As shown previously, the electrical function of the brain is critically dependent on cerebral blood flow in the sense that reduction beyond an ischemic threshold of approximately 15 ml/100 gm per minute (approximately 35% of control) in the baboon leads to complete failure of the somatosensory...

  19. Experimental models of brain ischemia: a review of techniques, magnetic resonance imaging and investigational cell-based therapies

    Directory of Open Access Journals (Sweden)

    Alessandra eCanazza

    2014-02-01

    Full Text Available Stroke continues to be a significant cause of death and disability worldwide. Although major advances have been made in the past decades in prevention, treatment and rehabilitation, enormous challenges remain in the way of translating new therapeutic approaches from bench to bedside. Thrombolysis, while routinely used for ischemic stroke, is only a viable option within a narrow time window. Recently, progress in stem cell biology has opened up avenues to therapeutic strategies aimed at supporting and replacing neural cells in infarcted areas. Realistic experimental animal models are crucial to understand the mechanisms of neuronal survival following ischemic brain injury and to develop therapeutic interventions. Current studies on experimental stroke therapies evaluate the efficiency of neuroprotective agents and cell-based approaches using primarily rodent models of permanent or transient focal cerebral ischemia. In parallel, advancements in imaging techniques permit better mapping of the spatial-temporal evolution of the lesioned cortex and its functional responses. This review provides a condensed conceptual review of the state of the art of this field, from models and magnetic resonance imaging techniques through to stem cell therapies.

  20. Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia.

    Science.gov (United States)

    Aoki, Ichio; Naruse, Shoji; Tanaka, Chuzo

    2004-12-01

    Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.

  1. 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), ...

  2. Blood -brain barrier disruption was less under isoflurane than pentobarbital anesthesia via a PI3K/Akt pathway in early cerebral ischemia.

    Science.gov (United States)

    Chi, Oak Z; Mellender, Scott J; Kiss, Geza K; Liu, Xia; Weiss, Harvey R

    2017-02-24

    One of the important factors altering the degree of blood-brain barrier (BBB) disruption in cerebral ischemia is the anesthetic used. The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway has been reported to be involved in modulating BBB permeability and in isoflurane induced neuroprotection. This study was performed to compare the degree of BBB disruption in focal cerebral ischemia under isoflurane vs pentobarbital anesthesia and to determine whether inhibition of PI3K/Akt would affect the disruption in the early stage of focal cerebral ischemia. Permanent middle cerebral artery (MCA) occlusion was performed in rats under 1.4% isoflurane or pentobarbital (50mg/kg i.p.) anesthesia with controlled ventilation. In half of each group LY294002, which is a PI3K/Akt inhibitor, was applied on the ischemic cortex immediately after MCA occlusion. After one hour of MCA occlusion, the transfer coefficient (Ki) of (14)C-α-aminoisobutyric acid ((14)C-AIB) was determined to quantify the degree of BBB disruption. MCA occlusion increased the Ki both in the isoflurane and pentobarbital anesthetized rats. However, the value of Ki was lower under isoflurane (11.5±6.0μL/g/min) than under pentobarbital (18.3±7.1μL/g/min) anesthesia. The Ki of the contralateral cortex of the pentobarbital group was higher (+74%) than that of the isoflurane group. Application of LY294002 on the ischemic cortex increased the Ki (+99%) only in the isoflurane group. The degree of BBB disruption by MCA occlusion was significantly lower under isoflurane than pentobarbital anesthesia in the early stage of cerebral ischemia. Our data demonstrated the importance of choice of anesthetics and suggest that PI3K/Akt signaling pathway plays a significant role in altering BBB disruption in cerebral ischemia during isoflurane but not during pentobarbital anesthesia.

  3. Protective effect of ultrashortwave versus radix salviae miltiorrhizae on brains of rats with cerebral ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Lixin Zhang; Zhiqiang Wang; Zhiqiang Zhang; Xiuhua Yuan; Xiaojie Tong

    2006-01-01

    intraperitoneally injected with 0.01 mL/g RSM parenteral solution at 30 minutes before reperfusion and given small dosage of USW on head for 10 minutes once at 6 hours after reperfusion; sixteen rats in sham operation group did not receive any treatment. All 80 rats were taken brains at 24 hours after reperfusion to measure wet and dry weights to calculate water content: Cerebral water content (%) = (1-dry/wet weight) × 100%. Superoxide dismutase (SOD) activity was measured by hydroxylamine method and malondialdehyde (MDA) content was measured by TBA photometric method.MAIN OUTCOME MEASURES: Cerebral water content, SOD activity and MDA content.RESULTS: All 160 rats except 80 failing in modeling were involved in the final analysis. ① The cerebral water content of left hemisphere made no significant difference (P > 0.05). The cerebral water content of right hemisphere in the control group and the three treatment groups was obviously higher than that of the sham operation group [(81.26±0.77)%, (79.74±0.68)%, (79.76±0.81)%, (79.61 ±0.79)%, (77.43±0.61)%, P < 0.05].The cerebral water content of right hemisphere in the three treatment groups was obviously lower than that of the control group (P < 0.05). There was no significant difference among the three treatment groups (P > 0.05).② Compared with the control group, SOD activity (right) of the control group decreased obviously (P < 0.05),while MDA content increased obviously (P < 0.05). SOD activity in the three therapeutic groups increased obviously, while MDA content decreased obviously (P < 0.05); there was no significant difference among the three treatment groups (P > 0.05).CONCLUSION: ① USW and RSM therapy have neuroprotective effects against focal cerebral ischemia-reperfusion injuries by means of decreasing cerebral water content and MDA and increasing the activity of SOD. ② Synergistic action was not observed between these two therapeutic methods.

  4. Cannabidiol reduces neuroinflammation and promotes neuroplasticity and functional recovery after brain ischemia.

    Science.gov (United States)

    Mori, Marco Aurélio; Meyer, Erika; Soares, Ligia Mendes; Milani, Humberto; Guimarães, Francisco Silveira; de Oliveira, Rúbia Maria Weffort

    2017-04-03

    This study investigated the effects of cannabidiol (CBD), a non-psychotomimetic phytochemical present in Cannabis sativa, on the cognitive and emotional impairments induced by bilateral common carotid artery occlusion (BCCAO) in mice. Using a multi-tiered behavioral testing battery during 21days, we found that BCCAO mice exhibited long-lasting functional deficits reflected by increase in anxiety-like behavior (day 9), memory impairments (days 12-18) and despair-like behavior (day 21). Short-term CBD 10mg/kg treatment prevented the cognitive and emotional impairments, attenuated hippocampal neurodegeneration and white matter (WM) injury, and reduced glial response that were induced by BCCAO. In addition, ischemic mice treated with CBD exhibited an increase in the hippocampal brain derived neurotrophic factor (BDNF) protein levels. CBD also stimulated neurogenesis and promoted dendritic restructuring in the hippocampus of BCCAO animals. Collectively, the present results demonstrate that short-term CBD treatment results in global functional recovery in ischemic mice and impacts multiple and distinct targets involved in the pathophysiology of brain ischemic injury.

  5. Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions.

    Science.gov (United States)

    Boscia, Francesca; Gala, Rosaria; Pignataro, Giuseppe; de Bartolomeis, Andrea; Cicale, Maria; Ambesi-Impiombato, Alberto; Di Renzo, Gianfranco; Annunziato, Lucio

    2006-04-01

    Dysregulation of sodium [Na+]i and calcium [Ca2+]i homeostasis plays a pivotal role in the pathophysiology of cerebral ischemia. Three gene products of the sodium-calcium exchanger family NCX1, NCX2, and NCX3 couple, in a bidirectional way, the movement of these ions across the cell membrane during cerebral ischemia. Each isoform displays a selective distribution in the rat brain. To determine whether NCX gene expression can be regulated after cerebral ischemia, we used NCX isoform-specific antisense radiolabeled probes to analyze, by radioactive in situ hybridization histochemistry, the pattern of NCX1, NCX2, and NCX3 transcripts in the ischemic core, periinfarct area, as well as in nonischemic brain regions, after 6 and 24 h of permanent middle cerebral artery occlusion (pMCAO) in rats. We found that in the focal region, comprising divisions of the prefrontal, somatosensory, and insular cortices, all three NCX transcripts were downregulated. In the periinfarct area, comprising part of the motor cortex and the lateral compartments of the caudate-putamen, NCX2 messenger ribonucleic acid (mRNA) was downregulated, whereas NCX3 mRNA was significantly upregulated. In remote nonischemic brain regions such as the prelimbic and infralimbic cortices, and tenia tecta, both NCX1 and NCX3 transcripts were upregulated, whereas in the medial caudate-putamen only NCX3 transcripts increased. In all these intact regions, NCX2 signal strongly decreased. These results indicate that NCX gene expression is regulated after pMCAO in a differential manner, depending on the exchanger isoform and region involved in the insult. These data may provide a better understanding of each NCX subtype's pathophysiologic role and may allow researchers to design appropriate pharmacological strategies to treat brain ischemia.

  6. Neuroprotective profile of enoxaparin, a low molecular weight heparin, in in vivo models of cerebral ischemia or traumatic brain injury in rats: a review.

    Science.gov (United States)

    Stutzmann, Jean-Marie; Mary, Veronique; Wahl, Florence; Grosjean-Piot, Odile; Uzan, André; Pratt, Jeremy

    2002-01-01

    The development of treatments for acute neurodegenerative diseases (stroke and brain trauma) has focused on (i) reestablishing blood flow to ischemic areas as quickly as possible (i.e. mainly antithrombotics or thrombolytics for stroke therapy) and (ii) on protecting neurons from cytotoxic events (i.e. neuroprotective therapies such as anti-excitotoxic or anti-inflammatory agents for stroke and neurotrauma therapies). This paper reviews the preclinical data for enoxaparin in in vivo models of ischemia and brain trauma in rats. Following a photothrombotic lesion in the rat, enoxaparin significantly reduced edema at 24 h after lesion when the treatment was started up to 18 h after insult. Enoxaparin was also tested after an ischemic insult using the transient middle cerebral artery occlusion (tMCAO) model in the rat. Enoxaparin, 2 x 1.5 mg/kg i.v., significantly reduced the lesion size and improved the neuroscore when the treatment was started up to 5 h after ischemia. Enoxaparin, administered at 5 h after insult, reduced cortical lesion size in a dose-dependent manner. In permanent MCAO, enoxaparin (5 and 24 h after insult) significantly reduced lesion size and improved neuroscore. A slight and reversible elevation of activated partial thromboplastin time (APTT) suggests that enoxaparin is neuroprotective at a non-hemorrhagic dose. Traumatic brain injury (TBI) is often accompanied by secondary ischemia due in part to edema-induced compression of blood vessels. When enoxaparin, at 0.5 mg/kg i.v. + 4 x 1 mg/kg s.c., was administered later than 30 h after TBI, it significantly reduced edema in hippocampus and parietal cortex. At one week after TBI the lesion size was significantly reduced and the neurological deficit significantly improved in enoxaparin treated animals. Finally, the cognitive impairment was significantly improved by enoxaparin at 48 h to 2 weeks after TBI. The anticoagulant properties of unfractionated heparin and specifically enoxaparin can explain

  7. Moringa Oleifera Lam Mitigates Oxidative Damage and Brain Infarct Volume in Focal Cerebral Ischemia

    OpenAIRE

    Woranan Kirisattayakul; Jintanaporn Wattanathorn; Terdthai Tong-Un; Supaporn Muchimapura; Panakaporn Wannanon

    2012-01-01

    Problem statement: At present, the therapeutic outcome of cerebral ischemia is still not in the satisfaction level. Therefore, the preventive strategy is considered. Based on the protective effect against oxidative damage of Moringa oleifera Lam. Leaves extract, we hypothesized that this plant extract might protect against cerebral ischemia, one of the challenge problems nowadays. In order to test this hypothesis, we aimed to determine the protective effect of M.oleifera leaves extract in ani...

  8. Mild hypothermia effects on intercellular adhesion molecule-1 and serum interleukin-6 expression in brain tissues of a rat focal ischemia model

    Institute of Scientific and Technical Information of China (English)

    Shengqi Fu; Lei Yang; Shuling Zhang; Shilong Sun; Xingai Mao

    2008-01-01

    BACKGROUND: Previous studies have confirmed the neuroprotective effect of mild hypothermia on ischemic brain injury.OBJECTIVE: To investigate the effects of mild hypothermia on intercellular adhesion molecule-1 expression and serum interleukin-6 levels in ischemic brain tissues of focal brain ischemia rats, and to explore the neuroprotective effects of mild hypothermia on ischemic brain injury.DESIGN, TIME AND SETTING: A randomized, controlled, neurobiological experiment was performed at the Central Laboratory, First Affiliated Hospital, Xinxiang Medical College, China from February to July 2006.MATERIALS: Thirty healthy, adult, Sprague Dawley rats were used to establish middle cerebral artery occlusion models using the suture method. The immunohistochemistry (streptavidin-biotin-peroxidase complex method) kit was purchased from Boster, China. Interleukin-6 radioimmunoassay was supplied by Institute of Radioimmunity, Technology Development Center, General Hospital of Chinese PLA. METHODS: The rats were equally and randomly assigned into mild hypothermia and control groups, and middle cerebral artery occlusion models were established. The rectal temperature was maintained at (37 ± 0.5)℃ in the control group. In the mild hypothermia group, the rectal temperature was maintained at (33±1)℃.MAIN OUTCOME MEASURES: At 12 hours after model establishment, the ischemic brain hemispheres were coronally sliced at the level of the optic chiasm. The number of intercellular adhesion molecule- 1 -positive vessels per high-power field was observed with an optical microscope. Serum interleukin-6 levels were measured by radioimmunoassay.RESULTS: Compared with the control group, intercellular adhesion molecule-I and serum interleukin-6 expressions were significantly decreased in ischemic brain tissues of the mild hypothermia group (P < 0.01).CONCLUSION: Mild hypothermia exhibits a neuroprotective effect by reducing serum interleukin-6 and intercellular adhesion molecule- 1

  9. 脑源性神经营养因子与脑缺血%Brain-derived neurotrophic factor and cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    李影; 黄永璐; 高宗良

    2013-01-01

    Brain-derived neurotrophic factor (BDNF) is one of the most prevalent growth factors in the central nervous system (CNS).In the development and maturation processes of the nervous system,BDNF plays an important role in maintaining neuronal function,promoting neuronal regeneration after injury,and preventing neuronal degeneration,etc.At present,many researchers are being dedicated to the research of BDNF for treatment of brain ischemia and have achieved some progress.This article reviews the molecular biological characteristics and biological function of BDNF,roles and mechanisms in cerebral ischemia,and the possibility as an intervention target of cerebral ischemia.%脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)是中枢神经系统中最普遍的神经营养因子之一.在神经系统的发育和成熟过程中,BDNF在维持神经元功能、促进神经元损伤后再生修复以及防止神经元变性等方面均发挥着重要作用.目前,很多学者正致力于BDNF治疗脑缺血的研究,并已取得了一些进展.文章对BDNF的分子生物学特征、生物学功能、在脑缺血中的作用和机制以及作为脑缺血干预靶点的可能性进行了综述.

  10. The phosphodiesterase type 2 inhibitor BAY 60-7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity.

    Science.gov (United States)

    Soares, Ligia Mendes; Meyer, Erika; Milani, Humberto; Steinbusch, Harry W M; Prickaerts, Jos; de Oliveira, Rúbia M Weffort

    2017-02-01

    Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60-7550, a selective phosphodiesterase type 2 inhibitor (PDE2-I), presents memory-enhancing and anxiolytic-like properties. The behavioral effects of BAY 60-7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2-I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60-7550 were evaluated on neuronal nuclei (NeuN), caspase-9, cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB) and brain-derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus-dependent cognitive function and induced despair-like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase-9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60-7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60-7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.

  11. In vitro model of cerebral ischemia by using brain microvascular endothelial cells derived from human induced pluripotent stem cells.

    Science.gov (United States)

    Kokubu, Yasuhiro; Yamaguchi, Tomoko; Kawabata, Kenji

    2017-04-29

    Brain-derived microvascular endothelial cells (BMECs), which play a central role in blood brain barrier (BBB), can be used for the evaluation of drug transport into the brain. Although human BMEC cell lines have already been reported, they lack original properties such as barrier integrity. Pluripotent stem cells (PSCs) can be used for various applications such as regenerative therapy, drug screening, and pathological study. In the recent study, an induction method of BMECs from PSCs has been established, making it possible to more precisely study the in vitro human BBB function. Here, using induced pluripotent stem (iPS) cell-derived BMECs, we examined the effects of oxygen-glucose deprivation (OGD) and OGD/reoxygenation (OGD/R) on BBB permeability. OGD disrupted the barrier function, and the dysfunction was rapidly restored by re-supply of the oxygen and glucose. Interestingly, TNF-α, which is known to be secreted from astrocytes and microglia in the cerebral ischemia, prevented the restoration of OGD-induced barrier dysfunction in an apoptosis-independent manner. Thus, we could establish the in vitro BBB disease model that mimics the cerebral ischemia by using iPS cell-derived BMECs.

  12. Sodium-dependent vitamin C transporter 2 (SVCT2 expression and activity in brain capillary endothelial cells after transient ischemia in mice.

    Directory of Open Access Journals (Sweden)

    Burkhard Gess

    Full Text Available Expression and transport activity of Sodium-dependent Vitamin C Transporter 2 (SVCT2 was shown in various tissues and organs. Vitamin C was shown to be cerebroprotective in several animal models of stroke. Data on expression, localization and transport activity of SVCT2 after cerebral ischemia, however, has been scarce so far. Thus, we studied the expression of SVCT2 after middle cerebral artery occlusion (MCAO in mice by immunohistochemistry. We found an upregulation of SVCT2 after stroke. Co-stainings with Occludin, Von-Willebrand Factor and CD34 demonstrated localization of SVCT2 in brain capillary endothelial cells in the ischemic area after stroke. Time-course analyses of SVCT2 expression by immunohistochemistry and western blots showed upregulation in the subacute phase of 2-5 days. Radioactive uptake assays using (14C-labelled ascorbic acid showed a significant increase of ascorbic acid uptake into the brain after stroke. Taken together, these results provide evidence for the expression and transport activity of SVCT2 in brain capillary endothelial cells after transient ischemia in mice. These results may lead to the development of novel neuroprotective strategies in stroke therapy.

  13. Effect of Ligustrazine and Shenmai Injection on ATPase and free radical metabolism in the aged rats with myocardial injury after brain ischemia/reperfusion

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    AIM: To study the protecitve mechanism of Ligustrazine (LT), Shenmai Parenteral Injection (SPI), combination of Ligustrazine and Shenmai Parenteral Injection (LSP) to myocardial injury after brain ischemia-reperfusion in aged rats from the change in ATPase and free radical in order to provide theoretical basic for prevention and cure of cerebral infarction. METHODS: Aged rats (more than 20 months) were divided into model group, control group, Nimotop group, LT group, SPI group and LSP group. We measured the following items in aged rats with 60 min of reperfusion after 30 min of brain ischemia: the content of MDA, the activities of superoxide dismutase (SOD), lactic dehydrrogenase (LDH), creatine phosphokinase (CPK), ATPase. RESUTLS: The CPK and LDH activities in the model rats increased obviously. The serum CPK activity in the LSP group, the LT group, nimotop group was lower than those in the model group obviously. The serum LDH activities in LT group and SPI group were obviously lower compared with those in the model group. The activity of Na+-K+-ATPase and Ca2+-ATPase in model group was decreased. Contrast to the model group, the activity of Na+-K+-ATPase in LSP group, Nimotop group, LT group and the activities of Ca2+-ATPase in the LSP group were higher. The serum MDA/SOD ratio was larger than that in the control group. The decrease in myocardial SOD activity and the increase in the MDA level, MDA/SOD ratio in the model group showed significant difference compared with that in the control. The MDA level in the LSP group was lower than that in the model group. The increase in myocardial SOD activity and decrease in MDA, MDA/SOD ratio were obvious in the LSP group compared with the model group. CONCLUSION: The myocardial injury after brain ischemia-reperfusion in aged rats was related to the decrease in the activity of Na+-K+-ATPase and injury of free radical. LT, SPI, LSP and Nimotop could prevent this inury. Nimotop and LT could enhanced the

  14. Effects of Chuanxiongqin hydrochloride on increasing the fluidity of brain cell membrane and scavenging free radicals in model rats with ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Chenxu Li

    2006-01-01

    BACKGROUND: The fluidity of cell membrane can be affected by various factors. Many experiments have confirmed that the ischemia/reperfusion of organic tissue can increase the contents of free radicals, which lead to high rigidity and Iow fluidity of cell membrane, and the conditions can be changed by Chuanxiongqin.OBJECTIVE: To observe the effect and mechanism of Chuanxiongqin hydrochloride on the fluidity of brain cell membrane in rat models of ischemia/reperfusion.DESIGN: A completely randomized controlled animal trial.SETTINGS: Institute of Brain Sciences; Department of Physiology, Medical College, Datong University.MATERIALS: Twenty male grade I Wistar rats of 170-220 g were randomly divided into model group (n =10)and control group (n =10). Chuanxiongqin hydrochloride (molecular mass was 172.2) was purchased from the National Institute for the Control of Pharmaceutical and Biological Products (batch number; 0817-9803); Spin labelers: 5-cfoxyl-stearlic acid methylester (5DS), 16-doxyl-stearlic acid methylester (16DS), xanthine, xanthine oxidase (XOD) and 5,5-dimeth-1-pyrroline- N-oxide (DMPO) from Sigma Company; Bruker ESP 300 electron paramagnetic resonance (EPR) spectrometer by Bruker Company (Germany).METHODS: The experiments were carried out in the State Key Laboratory of Natural and Biomimetic Drugs,Peking University from June 2001 to July 2002. In the model group, rats were made into models of cerebral ischemia by 30-minute ligation and 2-hour reperfusion of common carotid arteries; The rats in the control group were not made into models. The order parameter (S) and rotational correlation time (тc) were detected with the ESR spectrometer by means of spin labeling. The greater the S and тc, the smaller the fluidity. Meanwhile, the clearance rate of free radicals was detected with ESR spin trapping. The measurement data were compared using the ttest.MAIN OUTCOME MEASURES: The S, тc and clearance rates of O2 and OH free radicals were compared between the

  15. Induction of transforming growth factor beta receptors following focal ischemia in the rat brain.

    Directory of Open Access Journals (Sweden)

    Gabriella Pál

    Full Text Available Transforming growth factor-βs (TGF-βs regulate cellular proliferation, differentiation, and survival. TGF-βs bind to type I (TGF-βRI and II receptors (TGF-βRII, which are transmembrane kinase receptors, and an accessory type III receptor (TGF-βRIII. TGF-β may utilize another type I receptor, activin-like kinase receptor (Alk1. TGF-β is neuroprotective in the middle cerebral artery occlusion (MCAO model of stroke. Recently, we reported the expression pattern of TGF-β1-3 after MCAO. To establish how TGF-βs exert their actions following MCAO, the present study describes the induction of TGF-βRI, RII, RIII and Alk1 at 24 h, 72 h and 1 mo after transient 1 h MCAO as well as following 24 h permanent MCAO using in situ hybridization histochemistry. In intact brain, only TGF-βRI had significant expression: neurons in cortical layer IV contained TGF-βRI. At 24 h after the occlusion, no TGF-β receptors showed induction. At 72 h following MCAO, all four types of TGF-β receptors were induced in the infarct area, while TGF-βRI and RII also appeared in the penumbra. Most cells with elevated TGF-βRI mRNA levels were microglia. TGF-βRII co-localized with both microglial and endothelial markers while TGF-βRIII and Alk1 were present predominantly in endothels. All four TGF-β receptors were induced within the lesion 1 mo after the occlusion. In particular, TGF-βRIII was further induced as compared to 72 h after MCAO. At this time point, TGF-βRIII signal was predominantly not associated with blood vessels suggesting its microglial location. These data suggest that TGF-β receptors are induced after MCAO in a timely and spatially regulated fashion. TGF-β receptor expression is preceded by increased TGF-β expression. TGF-βRI and RII are likely to be co-expressed in microglial cells while Alk1, TGF-βRII, and RIII in endothels within the infarct where TGF-β1 may be their ligand. At later time points, TGF-βRIII may also appear in glial cells

  16. Electroacupuncture stimulation of the brachial plexus trunk on the healthy side promotes brain-derived neurotrophic factor mRNA expression in the ischemic cerebral cortex of a rat model of cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Zongjun Guo; Lumin Wang

    2012-01-01

    A rat model of cerebral ischemia/reperfusion was established by suture occlusion of the left middle cerebral artery. In situ hybridization results showed that the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic rat cerebral cortex increased after cerebral ischemia/ reperfusion injury. Low frequency continuous wave electroacupuncture (frequency 2-6 Hz, current intensity 2 mA) stimulation of the brachial plexus trunk on the healthy (right) side increased the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic cerebral cortex 14 days after cerebral ischemia/reperfusion injury. At the same time, electroacupuncture stimulation of the healthy brachial plexus truck significantly decreased neurological function scores and alleviated neurological function deficits. These findings suggest that electroacupuncture stimulation of the brachial plexus trunk on the healthy (right) side can greatly increase brain-derived neurotrophic factor mRNA expression and improve neurological function.

  17. Electroacupuncture stimulation of the brachial plexus trunk on the healthy side promotes brain-derived neurotrophic factor mRNA expression in the ischemic cerebral cortex of a rat model of cerebral ischemia/reperfusion injury.

    Science.gov (United States)

    Guo, Zongjun; Wang, Lumin

    2012-07-25

    A rat model of cerebral ischemia/reperfusion was established by suture occlusion of the left middle cerebral artery. In situ hybridization results showed that the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic rat cerebral cortex increased after cerebral ischemia/ reperfusion injury. Low frequency continuous wave electroacupuncture (frequency 2-6 Hz, current intensity 2 mA) stimulation of the brachial plexus trunk on the healthy (right) side increased the number of brain-derived neurotrophic factor mRNA-positive cells in the ischemic cerebral cortex 14 days after cerebral ischemia/reperfusion injury. At the same time, electroacupuncture stimulation of the healthy brachial plexus truck significantly decreased neurological function scores and alleviated neurological function deficits. These findings suggest that electroacupuncture stimulation of the brachial plexus trunk on the healthy (right) side can greatly increase brain-derived neurotrophic factor mRNA expression and improve neurological function.

  18. Inhibition of Brain Swelling after Ischemia-Reperfusion by β-Adrenergic Antagonists: Correlation with Increased K+ and Decreased Ca2+ Concentrations in Extracellular Fluid

    Directory of Open Access Journals (Sweden)

    Dan Song

    2014-01-01

    Full Text Available Infarct size and brain edema following ischemia/reperfusion are reduced by inhibitors of the Na+, K+, 2Cl−, and water cotransporter NKCC1 and by β1-adrenoceptor antagonists. NKCC1 is a secondary active transporter, mainly localized in astrocytes, driven by transmembrane Na+/K+ gradients generated by the Na+,K+-ATPase. The astrocytic Na+,K+-ATPase is stimulated by small increases in extracellular K+ concentration and by the β-adrenergic agonist isoproterenol. Larger K+ increases, as occurring during ischemia, also stimulate NKCC1, creating cell swelling. This study showed no edema after 3 hr medial cerebral artery occlusion but pronounced edema after 8 hr reperfusion. The edema was abolished by inhibitors of specifically β1-adrenergic pathways, indicating failure of K+-mediated, but not β1-adrenoceptor-mediated, stimulation of Na+,K+-ATPase/NKCC1 transport during reoxygenation. Ninety percent reduction of extracellular Ca2+ concentration occurs in ischemia. Ca2+ omission abolished K+ uptake in normoxic cultures of astrocytes after addition of 5 mM KCl. A large decrease in ouabain potency on K+ uptake in cultured astrocytes was also demonstrated in Ca2+-depleted media, and endogenous ouabains are needed for astrocytic K+ uptake. Thus, among the ionic changes induced by ischemia, the decrease in extracellular Ca2+ causes failure of the high-K+-stimulated Na+,K+-ATPase/NKCC1 ion/water uptake, making β1-adrenergic activation the only stimulus and its inhibition effective against edema.

  19. [Cerebral ischemia and histamine].

    Science.gov (United States)

    Adachi, Naoto

    2002-10-01

    Cerebral ischemia induces excess release of glutamate and an increase in the intracellular Ca2+ concentration, which provoke catastrophic enzymatic processes leading to irreversible neuronal injury. Histamine plays the role of neurotransmitter in the central nervous system, and histaminergic fibers are widely distributed in the brain. In cerebral ischemia, release of histamine from nerve endings has been shown to be enhanced by facilitation of its activity. An inhibition of the histaminergic activity in ischemia aggravates the histologic outcome. In contrast, intracerebroventricular administration of histamine improves the aggravation, whereas blockade of histamine H2 receptors aggravates ischemic injury. Furthermore, H2 blockade enhances ischemic release of glutamate and dopamine. These findings suggest that central histamine provides beneficial effects against ischemic neuronal damage by suppressing release of excitatory neurotransmitters. However, histaminergic H2 action facilitates the permeability of the blood-brain barrier and shows deleterious effects on cerebral edema.

  20. Metallothionein-II Inhibits Lipid Peroxidation and Improves Functional Recovery after Transient Brain Ischemia and Reperfusion in Rats

    Directory of Open Access Journals (Sweden)

    Araceli Diaz-Ruiz

    2014-01-01

    Full Text Available After transient cerebral ischemia and reperfusion (I/R, damaging mechanisms, such as excitotoxicity and oxidative stress, lead to irreversible neurological deficits. The induction of metallothionein-II (MT-II protein is an endogenous mechanism after I/R. Our aim was to evaluate the neuroprotective effect of MT-II after I/R in rats. Male Wistar rats were transiently occluded at the middle cerebral artery for 2 h, followed by reperfusion. Rats received either MT (10 μg per rat i.p. or vehicle after ischemia. Lipid peroxidation (LP was measured 22 h after reperfusion in frontal cortex and hippocampus; also, neurological deficit was evaluated after ischemia, using the Longa scoring scale. Infarction area was analyzed 72 hours after ischemia. Results showed increased LP in frontal cortex (30.7% and hippocampus (26.4%, as compared to control group; this effect was fully reversed by MT treatment. Likewise, we also observed a diminished neurological deficit assessed by the Longa scale in those animals treated with MT compared to control group values. The MT-treated group showed a significant (P<0.05 reduction of 39.9% in the infarction area, only at the level of hippocampus, as compared to control group. Results suggest that MT-II may be a novel neuroprotective treatment to prevent ischemia injury.

  1. Oxygen-glucose deprivation and reoxygenation as an in vitro ischemia-reperfusion injury model for studying blood-brain barrier dysfunction.

    Science.gov (United States)

    Alluri, Himakarnika; Anasooya Shaji, Chinchusha; Davis, Matthew L; Tharakan, Binu

    2015-05-07

    Ischemia-Reperfusion (IR) injury is known to contribute significantly to the morbidity and mortality associated with ischemic strokes. Ischemic cerebrovascular accidents account for 80% of all strokes. A common cause of IR injury is the rapid inflow of fluids following an acute/chronic occlusion of blood, nutrients, oxygen to the tissue triggering the formation of free radicals. Ischemic stroke is followed by blood-brain barrier (BBB) dysfunction and vasogenic brain edema. Structurally, tight junctions (TJs) between the endothelial cells play an important role in maintaining the integrity of the blood-brain barrier (BBB). IR injury is an early secondary injury leading to a non-specific, inflammatory response. Oxidative and metabolic stress following inflammation triggers secondary brain damage including BBB permeability and disruption of tight junction (TJ) integrity. Our protocol presents an in vitro example of oxygen-glucose deprivation and reoxygenation (OGD-R) on rat brain endothelial cell TJ integrity and stress fiber formation. Currently, several experimental in vivo models are used to study the effects of IR injury; however they have several limitations, such as the technical challenges in performing surgeries, gene dependent molecular influences and difficulty in studying mechanistic relationships. However, in vitro models may aid in overcoming many of those limitations. The presented protocol can be used to study the various molecular mechanisms and mechanistic relationships to provide potential therapeutic strategies. However, the results of in vitro studies may differ from standard in vivo studies and should be interpreted with caution.

  2. Gene expression profile induced by oral administration of baicalin and gardenin after focal brain ischemia in rats

    Institute of Scientific and Technical Information of China (English)

    Zhan-jun ZHANG; Zhong WANG; Xiao-yan ZHANG; Kang YING; Jian-xun LIU; Yong-yan WANG

    2005-01-01

    Aim: To investigate differential gene expression and the pharmacological mechanism of baicalin and gardenin in focal cerebral ischemia in rats with high-density cDNA microarray. Methods: Rat left middle cerebral arteries were occluded and treated with either baicalin or gardenin. The pharmacological effects were investigated using the difference in infarction areas before and after treatment, which were determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Gene expression was demonstrated using a "Biostar40S" gene microarray. Semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to verify the result of the selected genes. Results: Both baicalin and gardenin reduced the infarction areas in focal cerebral ischemia rats (P<0.05). The differential genes were 211,177, and 70 (upregulated or downregulated) in the model group, baicalin,and gardenin treatment groups compared with the sham-operated group,respectively. Gene expression of RpL19 and Csnk2 underwent an approximately 1.9 and 2.1-fold increase, respectively, verified by semiquantitative RT-PCR, which was the same trend as the cDNA microarray. Conclusion: Differential gene expression with respect to the pharmacological effects of baicalin and gardenin on focal cerebral ischemia by cDNA microarray revealed a number of clues with respect to the therapeutic mechanisms of Chinese traditional medicine. In addition,the present study provided theoretical and experimental evidence that will aid future studies examining cerebral ischemia.

  3. Changes in brain levels of N-acylethanolamines and 2-arachidonoylglycerol in focal cerebral ischemia in mice

    DEFF Research Database (Denmark)

    Degn, Matilda; Lambertsen, Kate L.; Petersen, Gitte;

    2007-01-01

    The N-acylethanolamines (NAEs) and 2-arachidonoylglycerol (2-AG) are bioactive lipids that can modulate inflammatory responses and protect neurons against glutamatergic excitotoxicity. We have used a model of focal cerebral ischemia in young adult mice to investigate the relationship between foca...

  4. Visualization of early infarction in rat brain after ischemia using a translocator protein (18 kDa) PET ligand [11C]DAC with ultra-high specific activity.

    Science.gov (United States)

    Yui, Joji; Hatori, Akiko; Kawamura, Kazunori; Yanamoto, Kazuhiko; Yamasaki, Tomoteru; Ogawa, Masanao; Yoshida, Yuichiro; Kumata, Katsushi; Fujinaga, Masayuki; Nengaki, Nobuki; Fukumura, Toshimitsu; Suzuki, Kazutoshi; Zhang, Ming-Rong

    2011-01-01

    The aim of this study was to visualize early infarction in the rat brain after ischemia using a translocator protein (TSPO) (18 kDa) PET ligand [(11)C]DAC with ultra-high specific activity (SA) of 3670-4450 GBq/μmol. An infarction model of rat brain was prepared by ischemic surgery and evaluated 2 days after ischemia using small-animal PET and in vitro autoradiography. Early infarction with a small increase of TSPO expression in the brain was visualized using PET with high SA [(11)C]DAC (average 4060 GBq/μmol), but was not distinguished clearly with usually reported SA [(11)C]DAC (37 GBq/μmol). Infarction in the rat brain 4 days after ischemia was visualized using high and usually reported SAs [(11)C]DAC. Displacement experiments with unlabeled TSPO-selective AC-5216 or PK11195 diminished the difference in radioactivity between ipsilateral and contralateral sides, confirming that the increased uptake on the infracted brain was specific to TSPO. In vitro autoradiography with high SA [(11)C]DAC showed that the TSPO expression increased on early infarction in the rat brain. High SA [(11)C]DAC is a useful and sensitive biomarker for the visualization of early infarction and the characterization of TSPO expression which was slightly elevated in the infarcted brain using PET.

  5. Activation of autophagy in rat brain cells following focal cerebral ischemia reperfusion through enhanced expression of Atg1/pULK and LC3.

    Science.gov (United States)

    Yu, Jingwei; Bao, Cuifen; Dong, Yanru; Liu, Xia

    2015-09-01

    The present study aimed to investigate the activation of Atg1/pULK, and LC3 in the cerebral cortex following focal cerebral ischemia reperfusion (CIR) injury, thereby examining its effect on autophagy in brain cells. Rat CIR models were established using the technique of middle cerebral artery occlusion. The neurological function score, TTC staining and the water content of brain tissue were used to evaluate the CIR model. Levels of autophagy in the brain cells were examined at different time‑points following CIR damage using electron microscopy. Immunohistochemistry and western blot analysis were also used for the qualitative and quantitative detection of levels of Atg1/pULK and LC3 in the cerebral cortex. Autophagy was observed in the early stage of CIR, and the expression of Atg1/pULK and LC3 were observed 1 h following CIR in the rats and reached peak expression levels after12 h, which following which the they gradually decreased. These results suggested Atg1/pULK and LC3 are key in the regulation of autophagy following CIR in the rat brain.

  6. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.

    Science.gov (United States)

    Damman, Jeffrey; Daha, Mohamed R; van Son, Willem J; Leuvenink, Henri G; Ploeg, Rutger J; Seelen, Marc A

    2011-04-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.

  7. PET Imaging with [(18)F]FSPG Evidences the Role of System xc(-) on Brain Inflammation Following Cerebral Ischemia in Rats.

    Science.gov (United States)

    Domercq, Maria; Szczupak, Boguslaw; Gejo, Jon; Gómez-Vallejo, Vanessa; Padro, Daniel; Gona, Kiran Babu; Dollé, Frédéric; Higuchi, Makoto; Matute, Carlos; Llop, Jordi; Martín, Abraham

    2016-01-01

    In vivo Positron Emission Tomography (PET) imaging of the cystine-glutamate antiporter (system xc(-)) activity with [(18)F]FSPG is meant to be an attractive tool for the diagnosis and therapy evaluation of brain diseases. However, the role of system xc(-) in cerebral ischemia and its involvement in inflammatory reaction has been scarcely explored. In this work, we report the longitudinal investigation of the neuroinflammatory process following transient middle cerebral artery occlusion (MCAO) in rats using PET with [(18)F]FSPG and the translocator protein (TSPO) ligand [(18)F]DPA-714. In the ischemic territory, [(18)F]FSPG showed a progressive binding increase that peaked at days 3 to 7 and was followed by a progressive decrease from days 14 to 28 after reperfusion. In contrast, [(18)F]DPA-714 evidenced maximum binding uptake values over day 7 after reperfusion. Ex vivo immnunohistochemistry confirmed the up-regulation of system xc(-) in microglial cells and marginally in astrocytes. Inhibition of system xc(-) with sulfasalazine and S-4-CPG resulted in increased arginase (anti-inflammatory M2 marker) expression at day 7 after ischemia, together with a decrease in TSPO and microglial M1 proinflammatory markers (CCL2, TNF and iNOS) expression. Taken together, these results suggest that system xc(-) plays a key role in the inflammatory reaction underlying experimental stroke.

  8. Color-coded perfused blood volume imaging using multidetector CT: initial results of whole-brain perfusion analysis in acute cerebral ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Kloska, Stephan P.; Fischer, Tobias; Fischbach, Roman; Heindel, Walter [University of Muenster, Department of Clinical Radiology, Muenster (Germany); Nabavi, Darius G.; Dittrich, Ralf; Ringelstein, E.B. [University of Muenster, Department of Neurology, Muenster (Germany); Ditt, Hendrik; Klotz, Ernst [Siemens AG, Medical Solutions, Forchheim (Germany)

    2007-09-15

    Computed tomography (CT) is still the primary imaging modality following acute stroke. To evaluate a prototype of software for the calculation of color-coded whole-brain perfused blood volume (PBV) images from CT angiography (CTA) and nonenhanced CT (NECT) scans, we studied 14 patients with suspected acute ischemia of the anterior cerebral circulation. PBV calculations were performed retrospectively. The detection rate of ischemic changes in the PBV images was compared with NECT. The volume of ischemic changes in PBV was correlated with the infarct volume on follow-up examination taking potential vessel recanalization into account. PBV demonstrated ischemic changes in 12/12 patients with proven infarction and was superior to NECT (8/12) in the detection of early ischemia. Moreover, PBV demonstrated the best correlation coefficient with the follow-up infarct volume (Pearson's R = 0.957; P = 0.003) for patients with proven recanalization of initially occluded cerebral arteries. In summary, PBV appears to be more accurate in the detection of early infarction compared to NECT and mainly visualizes the irreversibly damaged ischemic tissue. (orig.)

  9. Depressed glucose consumption at reperfusion following brain ischemia does not correlate with mitochondrial dysfunction and development of infarction: an in vivo positron emission tomography study.

    Science.gov (United States)

    Martín, Abraham; Rojas, Santiago; Pareto, Deborah; Santalucia, Tomàs; Millán, Olga; Abasolo, Ibane; Gómez, Vanessa; Llop, Jordi; Gispert, Joan D; Falcon, Carles; Bargalló, Núria; Planas, Anna M

    2009-05-01

    Glucose consumption is severely depressed in the ischemic core, whereas it is maintained or even increased in penumbral regions during ischemia. Conversely, glucose utilization is severely reduced early after reperfusion in spite that glucose and oxygen are available. Experimental studies suggest that glucose hypometabolism might be an early predictor of brain infarction. However, the relationship between early glucose hypometabolism with later development of infarction remains to be further studied in the same subjects. Here, glucose consumption was assessed in vivo by positron emission tomography (PET) with (18)F-fluorodeoxyglucose ((18)F-FDG) in a rat model of ischemia/reperfusion. Perfusion was evaluated by PET with (13)NH(3) during and after 2-hour (h) middle cerebral artery occlusion, and (18)F-FDG was given after 2h of reperfusion. Brain infarction was evaluated at 24h. Mitochondrial oxygen consumption was examined ex vivo using a biochemical method. Cortical (18)F-FDG uptake was reduced by 45% and 25% in the ischemic core and periphery, respectively. However, substantial alteration of mitochondrial respiration was not apparent until 24h, suggesting that mitochondria retained the ability to consume oxygen early after reperfusion. These results show reduced glucose use at early reperfusion in regions that will later develop infarction and, to a lesser extent, in adjacent regions. Depressed glucose metabolism in the ischemic core might be attributable to reduced metabolic requirement due to irreversible cellular injury. However, reduced glucose metabolism in peripheral regions suggests either an impairment of glycolysis or reduced glucose demand. Thus, our study supports that glycolytic depression early after reperfusion is not always related to subsequent development of infarction.

  10. Inhibition of nuclear factor-κB by 6-O-acetyl shanzhiside methyl ester protects brain against injury in a rat model of ischemia and reperfusion

    Directory of Open Access Journals (Sweden)

    Jiang Wanglin

    2010-09-01

    Full Text Available Abstract Background Recent studies have demonstrated an inflammatory response associated with the pathophysiology of cerebral ischemia. The beneficial effects of anti-inflammatory drugs in cerebral ischemia have been documented. When screening natural compounds for drug candidates in this category, we isolated 6-O-acetyl shanzhiside methyl ester (ND02, an iridoid glucoside compound, from the leaves of Lamiophlomis rotata (Benth. Kudo. The objectives of this study were to determine the effects of ND02 on a cultured neuronal cell line, SH-SY5Y, in vitro, and on experimental ischemic stroke in vivo. Methods For TNF-α-stimulated SH-SY5Y cell line experiments in vitro, SH-SY5Y cells were pre-incubated with ND02 (20 μM or 40 μM for 30 min and then incubated with TNF-α (20 ng/ml for 15 min. For in vivo experiments, rats were subjected to middle cerebral artery occlusion (MCAO for 1 h followed by reperfusion for 23 h. Results ND02 treatment of SH-SY5Y cell lines blocked TNF-α-induced nuclear factor-κB (NF-κB and IκB-α phosphorylation and increased Akt phosphorylation. LY294002 blocked TNF-α-induced phosphorylation of Akt and reduced the phosphorylation of both IκB-α and NF-κB. At doses higher than 10 mg/kg, ND02 had a significant neuroprotective effect in rats with cerebral ischemia and reperfusion (I/R. ND02 (25 mg/kg demonstrated significant neuroprotective activity even after delayed administration 1 h, 3 h and 5 h after I/R. ND02, 25 mg/kg, attenuated histopathological damage, decreased cerebral Evans blue extravasation, inhibited NF-κB activation, and enhanced Akt phosphorylation. Conclusion These data show that ND02 protects brain against I/R injury with a favorable therapeutic time-window by alleviating cerebral I/R injury and attenuating blood-brain barrier (BBB breakdown, and that these protective effects may be due to blocking of neuronal inflammatory cascades through an Akt-dependent NF-κB signaling pathway.

  11. The effect of hyperglycemia on blood brain barrier of rats with focal cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    Objective: To determine whether hyperglycemia could aggravate the microvascular damage in ischemic stroke.Methods: Hyperglycemia model was made by injection of streptozocin through subcutaneous injection in wistar rats. Using the suture model, the rats were subjected to 3 h of focal ischemia and different times of reperfusion,including 6,12,24,48,96 h and 7 d. TTC dyeing was used to show the infarction area of rats. The infarctive volume of rats were calculated by computer imaging analysis system;Matrix metalloproteinase (MMP-2) and (MMP-9)were detected by immunohistochemistry and in situ hybridization histochemistry in Wistar rats.Results: The infarctive volume was siginificantly larger in hyperglycemic rats than that of nonhyperglycemic rats. The level of MMP-2,MMP-9 expression in the group of hyperglycemic rats was higher than that of nonhyperglycemic rats. Conclusion: Hyperglycemia aggravated the injury of focal ischmia-reperfusion in wistar rats and the higher expression of MMP-2, MMP-9 might be one of the mechanism in aggravation of focal ischemia/reperfusion injury.

  12. Ischemic brain cell-derived conditioned medium protects astrocytes against ischemia through GDNF/ERK/NF-kB signaling pathway.

    Science.gov (United States)

    Chu, Lan-Feng; Wang, Wei-Ti; Ghanta, Vithal K; Lin, Chi-Hsin; Chiang, Yung-Yen; Hsueh, Chi-Mei

    2008-11-06

    Conditioned medium (CM) collected from cultures of ischemic microglia, astrocytes, and neurons were protective to astrocytes under the in vitro ischemic condition (deprivation of oxygen, glucose and serum). Molecular and signaling pathway(s) responsible for the CMs protective activity were investigated. Results showed that CMs from the ischemic microglia (MCM), astrocytes (ACM) and neurons (NCM) contained glial cell line-derived neurotrophic factor (GDNF), which protects astrocytes against the in vitro ischemia. Expression of extra cellular signal-regulated kinase (ERK1/2) and nuclear factor-kappa B (NF-kB) by GDNF led to the inhibition of apoptosis of the ischemic astrocytes in a caspase 3-independent manner. However, CMs- and GDNF-mediated protection of the ischemic astrocytes was protein kinase B (Akt) independent. These results provided mechanistic data regarding how GDNF- and CMs-mediated protection of the ischemic astrocytes is taking place. These observations provide information for the use of GDNF and GDNF containing CMs in the control of cerebral ischemia.

  13. Novel bio-spectroscopic imaging reveals disturbed protein homeostasis and thiol redox with protein aggregation prior to hippocampal CA1 pyramidal neuron death induced by global brain ischemia in the rat.

    Science.gov (United States)

    Hackett, Mark J; Smith, Shari E; Caine, Sally; Nichol, Helen; George, Graham N; Pickering, Ingrid J; Paterson, Phyllis G

    2015-12-01

    Global brain ischemia resulting from cardiac arrest and cardiac surgery can lead to permanent brain damage and mental impairment. A clinical hallmark of global brain ischemia is delayed neurodegeneration, particularly within the CA1 subsector of the hippocampus. Unfortunately, the biochemical mechanisms have not been fully elucidated, hindering optimization of current therapies (i.e., therapeutic hypothermia) or development of new therapies. A major limitation to elucidating the mechanisms that contribute to neurodegeneration and understanding how these are influenced by potential therapies is the inability to relate biochemical markers to alterations in the morphology of individual neurons. Although immunocytochemistry allows imaging of numerous biochemical markers at the sub-cellular level, it is not a direct chemical imaging technique and requires successful "tagging" of the desired analyte. Consequently, important biochemical parameters, particularly those that manifest from oxidative damage to biological molecules, such as aggregated protein levels, have been notoriously difficult to image at the cellular or sub-cellular level. It has been hypothesized that reactive oxygen species (ROS) generated during ischemia and reperfusion facilitate protein aggregation, impairing neuronal protein homeostasis (i.e., decreasing protein synthesis) that in turn promotes neurodegeneration. Despite indirect evidence for this theory, direct measurements of morphology and ROS induced biochemical damage, such as increased protein aggregates and decreased protein synthesis, within the same neuron is lacking, due to the unavailability of a suitable imaging method. Our experimental approach has incorporated routine histology with novel wide-field synchrotron radiation Fourier transform infrared imaging (FTIRI) of the same neurons, ex vivo within brain tissue sections. The results demonstrate for the first time that increased protein aggregation and decreased levels of total protein

  14. Combination of early and delayed ischemic postconditioning enhances brain-derived neurotrophic factor production by upregulating the ERK-CREB pathway in rats with focal ischemia.

    Science.gov (United States)

    Wu, Hui; Yang, Shao-Feng; Dai, Jiong; Qiu, Yong-Ming; Miao, Yi-Feng; Zhang, Xiao-Hua

    2015-11-01

    cortex, following focal ischemia. The results of the present study suggest that the combination of early and delayed ischemic postconditioning may further reduce brain ischemic reperfusion injury following focal ischemia, compared with either treatment alone. In addition, it induces the production of BDNF in neurons and astrocytes. Furthermore, the effects of combinative ischemic postconditioning may be mediated by the activation of ERK1/2 and CREB.

  15. Reperfusion of the rat brain tissues following acute ischemia: the correlation among diffusion-weighted imaging, histopathology,and aquaporin-4 expression

    Institute of Scientific and Technical Information of China (English)

    LU Hong; HU Hui; HE Zhan-ping

    2011-01-01

    Background Although some studies have reported that aquaporin-4 (AQP4) plays a role in the post-ischemic edema formation and diffusion-weighted imaging (DWI), little is known about the AQP4 expression in stage of the reperfusion following acute cerebral ischemia, as well as the correlation between histopathology and DWl. The aim of the study was to investigate the correlation among DWl, histopathology and the AQP4 expression in the reperfused rat brain tissues following acute ischemia.Methods Seventy Wistar rats were randomly divided into a control group (group A), and several occluded and reperfusion groups. They had their middle cerebral artery unilaterally occluded (MCAO) for 30 minutes (group B) followed by 30 minutes (group D) or 60 minutes (group E) of reperfusion, or 60 minutes of MCAO (group C) followed by 30 minutes (group F), or 60 minutes (group G) of reperfusion (n=10 for each group). All rats underwent DWl scanning.The relative apparent diffusion coefficient (rADC) value of each rat was calculated. All the rats were sacrificed and the cerebral ischemic tissues were examined for histopathology. Real-time fluro-quantitative polymerase chain reaction (RT-PCR) and Western-blotting were performed. The amount of AQP4 mRNA (Ex △△Ct) and AQP4 protein (Q) was statistically analyzed. The correlation between rADC values and AQP4 mRNA expression was analyzed with the Pearson correlation test.Results In all the reperfusion groups, the areas of hyper-intensity signal in DWl were decreased, and the rADC value increased and the AQP4 expression decreased significantly compared with the occluded group (t=26.89, t=18.26, P<0.01). There was a negative correlation between AQP4 mRNA expression and rADC values (r=-0.72, P<0.01). A mixed edema, composed of cerebral intracelluar edema and vasogenic brain edema, was observed in all the reperfusion groups.It was more prevalent in groups D and F than in the groups E and G. With the reperfusion time postponed, the cerebral

  16. Interaction of ARC and Daxx: A Novel Endogenous Target to Preserve Motor Function and Cell Loss after Focal Brain Ischemia in Mice

    Science.gov (United States)

    Donath, Stefan; An, Junfeng; Lee, Sabrina Lin Lin; Gertz, Karen; Datwyler, Anna Lena; Harms, Ulrike; Müller, Susanne; Farr, Tracy Deanne; Füchtemeier, Martina; Lättig-Tünnemann, Gisela; Lips, Janet; Foddis, Marco; Mosch, Larissa; Bernard, René; Grittner, Ulrike; Balkaya, Mustafa; Kronenberg, Golo; Dirnagl, Ulrich; Endres, Matthias

    2016-01-01

    The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD). TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30 ± 8% (mean ± SD; p = 0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1 μg intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.β-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20 ± 7% (mean ± SD; p < 0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX–ASK1–JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1–JNK activation. Our work identifies for the first time ARC–DAXX binding to block ASK1–JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. SIGNIFICANCE STATEMENT Up to now, the only successful pharmacological target of human ischemic stroke is thrombolysis. Neuroprotective pharmacological strategies are needed to accompany therapies aiming to achieve reperfusion. We describe that apoptosis

  17. Magnetic resonance imaging tracing of transplanted bone marrow mesenchymal stem cells in a rat model of cardiac arrest-induced global brain ischemia

    Institute of Scientific and Technical Information of China (English)

    Yue Fu; Xiangshao Fang; Tong Wang; Jiwen Wang; Jun Jiang; Zhigang Luo; Xiaohui Duan; Jun Shen; Zitong Huang

    2009-01-01

    BACKGROUND: Numerous studies have shown that magnetic resonance imaging (MRI) can detect survival and migration of super paramagnetic iron oxide-labeled stem cells in models of focal cerebral infarction. OBJECTIVE: To observe distribution of bone marrow mesenchymal stem cells (BMSCs) in a rat model of global brain ischemia following cardiac arrest and resuscitation, and to investigate the feasibility of tracing iron oxide-labeled BMSCs using non-invasive MRI. DESIGN, TIME AND SETTING: The randomized, controlled, molecular imaging study was performed at the Linbaixin Medical Research Center, Second Affiliated Hospital, Sun Yat-sen University, and the Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, China from October 2006 to February 2009.MATERIALS: A total of 40 clean, Sprague Dawley rats, aged 6 weeks and of either gender, were supplied by the Experimental Animal Center, Sun Yat-sen University, China, for isolation of BMSCs. Feridex (iron oxide), Gyroscan Inetra 1.5T MRI system, and cardiopulmonary resuscitation device were used in this study. METHODS: A total of 30 healthy, male Sprague Dawley rats, aged 6 months, were used to induce ventricular fibrillation using alternating current. After 8 minutes, the rats underwent 6-minute chest compression and mechanical ventilation, followed by electric defibrillation, to establish rat models of global brain ischemia due to cardiac arrest and resuscitation. A total of 24 successful models were randomly assigned to Feridex-labeled and non-labeled groups (n=12 for each group). At 2 hours after resuscitation, 5 x 10 6 Feddex-labeled BMSCs, with protamine sulfate as a carrier, and 5 × 10 6 non-labeled BMSCs were respectively transplanted into both groups of rats through the right carotid artery (cells were harvested in 1 mL phosphate buffered saline). MAIN OUTCOME MEASURES: Feridex-labeled BMSCs were observed by Prussian blue staining and electron microscopy. Signal intensity, celluar viability

  18. 短暂脑缺血诱导成年大鼠纹状体内CRMP-4的表达%Induction of CRMP-4 in striatum of adult rat after transient brain ischemia

    Institute of Scientific and Technical Information of China (English)

    刘鹏翀; 杨增进; 邱梅红; 张玲妹; 孙凤艳

    2003-01-01

    AIM: To study the expression of collapsing response mediated protein-4 (CRMP-4) and nestin in the ischemic adult rat brain following transient brain ischemia. METHODS: Brain ischemia was induced by transient left middle cerebral artery occlusion (MCAO) for 60 min in adult rats. The expression of CRMP-4, nestin and bromodeoxyuridine (BrdU) was analyzed by immunohistochemical method. The co-localization of CRMP-4 and nestin or BrdU was analyzed by double staining combined with confocal laser scanning microscopy. RESULTS: CRMP-4, a marker of immature neuron, could be expressed in the ipsilateral striatum and cerebral cortex at 1st and 2nd week after the ischemia-reperfusion; nestin, a marker of neural stem cell, occurred in above regions from several hours to 2 weeks. CRMP-4 costained with nestin and with BrdU incorporation. CONCLUSION: Neural stem cells may present in the striatum and cerebral cortex of adult rat and can be triggered to differentiate into newborn neuron there by ischemic brain trauma.

  19. Limb Ischemic Perconditioning Attenuates Blood-Brain Barrier Disruption by Inhibiting Activity of MMP-9 and Occludin Degradation after Focal Cerebral Ischemia

    Science.gov (United States)

    Ren, Changhong; Li, Ning; Wang, Brian; Yang, Yong; Gao, Jinhuan; Li, Sijie; Ding, Yuchuan; Jin, Kunlin; Ji, Xunming

    2015-01-01

    Remote ischemic perconditioning (PerC) has been proved to have neuroprotective effects on cerebral ischemia, however, the effect of PerC on the BBB disruption and underlying mechanisms remains largely unknown. To address these issues, total 90 adult male Sprague Dawley (SD) rats were used. The rats underwent 90-min middle cerebral artery occlusion (MCAO), and the limb remote ischemic PerC was immediately applied after the onset of MCAO. We found that limb remote PerC protected BBB breakdown and brain edema, in parallel with reduced infarct volume and improved neurological deficits, after MCAO. Immunofluorescence studies revealed that MCAO resulted in disrupted continuity of claudin-5 staining in the cerebral endothelial cells with significant gap formation, which was significantly improved after PerC. Western blot analysis demonstrated that expression of tight junction (TJ) protein occludin was significantly increased, but other elements of TJ proteins, claudin-5 and ZO-1, in the BBB endothelial cells were not altered at 48 h after PerC, compared to MCAO group. The expression of matrix metalloproteinase (MMP-9), which was involved in TJ protein degradation, was decreased after PerC. Interestingly, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), an upstream of MMP-9 signaling, was significantly reduced in the PerC group. Our data suggest that PerC inhibits MMP-9-mediated occludin degradation, which could lead to decreased BBB disruption and brain edema after ischemic stroke. PMID:26618042

  20. Neural stem cell transplantation in the hippocampus of rats with cerebral ischemia/reperfusion injury Activation of the phosphatidylinositol-3 kinase/Akt pathway and increased brain-derived neurotrophic factor expression

    Institute of Scientific and Technical Information of China (English)

    Yu Zhao; Shengtao Yao; Shijun Wang

    2010-01-01

    The phosphatidylinositol-3 kinase (PI3K)/Akt pathway and brain-derived neurotrophic factor (BDNF) are involved in neurological functional recovery following cerebral ischemia. Therefore, we hypothesized that mechanisms of neuroprotection by transplantation of neural stem cells (NSCs) on cerebral ischemia contributed to activation of the PI3K/Akt pathway and enhanced BDNF expression. In the present study, Wortmannin (a specific, covalent inhibitor of PI3K) was administered adjacent to ischemic hippocampus by stereotactic transplantation to further confirm the neuroprotective mechanisms of NSC transplantation following cerebral ischemia. Results showed that focal infarct volume was significantly smaller in the NSCs group, but the neurological behavior score in the NSC group was significantly greater than the middle cerebral artery occlusion model group, Wortmannin treatment group, and NSCs + Wortmannin treatment group. Protein expression of RDNF was significantly greater in the NSC group compared with the Wortmannin treatment group and NSCs + Wortmannin treatment group. These results suggest that the neuroprotective role of NSC transplantation in the cerebral ischemia activated the PI3K/Akt pathway and upregulated BDNF expression in lesioned brains.

  1. Neurovascular pathophysiology in cerebral ischemia, dementia and the ageing brain – current trends in basic, translational and clinical research

    Directory of Open Access Journals (Sweden)

    Boltze Johannes

    2012-08-01

    Full Text Available Abstract The 7th International Symposium on Neuroprotection and Neurorepair was held from May 2nd to May 5th, 2012 in Potsdam, Germany. The symposium, which directly continues the successful Magdeburg meeting series, attracted over 330 colleagues from 29 countries to discuss recent findings and advances in the field. The focus of the 2012 symposium was widened from stroke and traumatic brain injury to neurodegenerative diseases, notably dementia, and more generally the ageing brain. Thereby, emphasis was given on neurovascular aspects of neurodegeneration and stroke including the blood–brain barrier, recent findings regarding the pathomechanism of Alzheimer’s disease, and brain imaging approaches. In addition, neurobiochemical aspects of neuroprotection, the role of astrogliosis, the clinical progress of cell-based approaches as well as translational hurdles and opportunities were discussed in-depth. This review summarizes some of the most stimulating discussions and reports from the meeting.

  2. In vivo diagnostic imaging using micro-CT: sequential and comparative evaluation of rodent models for hepatic/brain ischemia and stroke.

    Directory of Open Access Journals (Sweden)

    Naoto Hayasaka

    Full Text Available BACKGROUND: There is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report. METHODOLOGY: We performed contrast-enhanced CT (CECT on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA, indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT. PRINCIPAL FINDINGS: In the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data. CONCLUSIONS: This study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is

  3. Traumatic brain ischemia during neuro intensive care: myth rather than fact Isquemia cerebral tráumatica durante neuro terapia intensiva: mito ao invés de fato

    Directory of Open Access Journals (Sweden)

    Julio Cruz

    2001-09-01

    Full Text Available In non-missile severe acute brain trauma, brain ischemia was a frequent finding in cadavers. Studies during neuro intensive care, however, have failed to disclose brain ischemia under most circumstances, except when cerebral hemodynamic and metabolic parameters have been misinterpreted, or when cerebral blood flow (CBF alone has been addressed in a biased fashion, without mandatory metabolic data. Indeed, comprehensive and unbiased studies focusing on global cerebral metabolic activity have invariably revealed a condition of normal coupling between reduced CBF and oxygen consumption in the early postinjury hours, which is then followed by a prolonged, sustained pattern of relative cerebral hyperperfusion (the opposite of ischemia. Accordingly, traumatic brain ischemia during intensive care represents myth rather than fact.Em traumatismo cerebral agudo grave excluindo-se ferimentos por arma de fogo, isquemia cerebral foi achado frequente em cadáveres. Entretanto, estudos durante neuro terapia intensiva não têm revelado isquemia cerebral, exceto quando parâmetros hemodinâmicos e metabólicos cerebrais tem sido mal interpretados, ou quando fluxo sanguíneo cerebral (FSC sozinho tem sido enfocado de forma tendenciosa, sem dados metabólicos mandatórios. De fato, estudos abrangentes e não tendenciosos enfocando a atividade metabólica cerebral têm invariavelmente revelado uma condição de ajustamento normal entre FSC e consumo cerebral de oxigênio reduzidos nas primeiras horas após o traumatismo, um padrão seguido de prolongada hiperperfusão relativa (o oposto da isquemia. Assim sendo, isquemia cerebral traumática durante terapia intensiva representa um mito ao invés de um fato.

  4. 酒精对缺血-再灌注大鼠脑组织的保护作用%Protection of Alcohol to Ischemia-reperfusion Brain Tissue in Rats

    Institute of Scientific and Technical Information of China (English)

    王彬; 刘志辉; 张培; 李健

    2013-01-01

      结果治疗组大鼠脑梗死面积较对照组明显减小[(35.336.06)mm2 vs (55.503.62)mm2, P  结论1.5 g/kg酒精对缺血-再灌注大鼠脑组织具有保护作用,可能是通过减少细胞凋亡而减轻脑损伤.%Objective To investigate the influence of alcohol on the infarction area and expression of apoptosis induced factor(AIF), hypoxia induced factor-1α(HIF-1α) in the brain tissue of rats with cerebral-reperfusion. Methods Fifty-four healthy male Wistar rats were randomly divided into 3 groups, sham operation group, ischemia-reperfusion group(control group), and ischemia-reperfusion with alcohol group(therapy group). The infarction models were established by blocking the middle cerebral artery, after 2 hours the line was pulled out, forming ischemia-reperfusion in the brain tissue of the rats. Alcohol(absolute alcohol was diluted to 50%alcohol) 1.5 g/kg was intraperitoneally injected to the therapy group when reperfusion, and the control group and sham operation group with the same amount of saline. The infarct size was stained by 2, 3, 5-triphenyltetrazolium chlorice and the expression of AIF and HIF-1αin the brain tissue of the rats was tested by the immunohistochemical method. Results The infarction area in the therapy group was significantly smaller than that in the control group([35.33   6.06]mm2 vs [55.50   3.62]mm2, P Conclusion Alcohol(1.5 g/kg) has neuroprotective effects on brain tissue of rats with ischemia-reperfusion. In brain ischemia -reperfusion injury, alcohol may reduce the brain damage by the enhancement of nerve cells to adapt the anaerobic environment and reducing apoptosis of the nerve cells.

  5. Animal models of cerebral ischemia

    Science.gov (United States)

    Khodanovich, M. Yu.; Kisel, A. A.

    2015-11-01

    Cerebral ischemia remains one of the most frequent causes of death and disability worldwide. Animal models are necessary to understand complex molecular mechanisms of brain damage as well as for the development of new therapies for stroke. This review considers a certain range of animal models of cerebral ischemia, including several types of focal and global ischemia. Since animal models vary in specificity for the human disease which they reproduce, the complexity of surgery, infarct size, reliability of reproduction for statistical analysis, and adequate models need to be chosen according to the aim of a study. The reproduction of a particular animal model needs to be evaluated using appropriate tools, including the behavioral assessment of injury and non-invasive and post-mortem control of brain damage. These problems also have been summarized in the review.

  6. Plasminogen activator inhibitor-1 mitigates brain injury in a rat model of infection-sensitized neonatal hypoxia-ischemia.

    Science.gov (United States)

    Yang, Dianer; Sun, Yu-Yo; Nemkul, Niza; Baumann, Jessica M; Shereen, Ahmed; Dunn, R Scott; Wills-Karp, Marsha; Lawrence, Daniel A; Lindquist, Diana M; Kuan, Chia-Yi

    2013-05-01

    Intrauterine infection exacerbates neonatal hypoxic-ischemic (HI) brain injury and impairs the development of cerebral cortex. Here we used low-dose lipopolysaccharide (LPS) pre-exposure followed by unilateral cerebral HI insult in 7-day-old rats to study the pathogenic mechanisms. We found that LPS pre-exposure blocked the HI-induced proteolytic activity of tissue-type plasminogen activator (tPA), but significantly enhanced NF-κB signaling, microglia activation, and the production of pro-inflammatory cytokines in newborn brains. Remarkably, these pathogenic responses were all blocked by intracerebroventricular injection of a stable-mutant form of plasminogen activator protein-1 called CPAI. Similarly, LPS pre-exposure amplified, while CPAI therapy mitigated HI-induced blood-brain-barrier damage and the brain tissue loss with a therapeutic window at 4 h after the LPS/HI insult. The CPAI also blocks microglia activation following a brain injection of LPS, which requires the contribution by tPA, but not the urinary-type plasminogen activator (uPA), as shown by experiments in tPA-null and uPA-null mice. These results implicate the nonproteolytic tPA activity in LPS/HI-induced brain damage and microglia activation. Finally, the CPAI treatment protects near-normal motor and white matter development despite neonatal LPS/HI insult. Together, because CPAI blocks both proteolytic and nonproteolytic tPA neurotoxicity, it is a promising therapeutics of neonatal HI injury either with or without infection.

  7. Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries.

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    Brint, S; Jacewicz, M; Kiessling, M; Tanabe, J; Pulsinelli, W

    1988-08-01

    This article describes a 3-year experience with focal neocortical ischemia in three rat strains. Multiple groups of adult Wistar (n = 50), Fisher 344 (n = 31), and spontaneously hypertensive (n = 72) rats were subjected to permanent occlusion of the distal middle cerebral (MCA) and ipsilateral common carotid arteries (CCA). Twenty-four hours later the animals were killed, and frozen brain sections were stained with hematoxylin and eosin to demarcate infarcted tissue. The infarct volume for each section was quantified with an image analyzer, and the total infarct volume was calculated with an iterative program that summed all interval volumes. Neocortical infarct volume was the largest and most reproducible in the spontaneously hypertensive rats (SHR). Statistical power analysis to project the numbers of animals necessary to detect a 25 or 50% change in infarct volume with alpha = 0.05 and beta = 0.2 revealed that only the SHR model was practical in terms of requisite animals: i.e., less than 10 animals per group. Tandem occlusion of the distal MCA and ipsilateral CCA in the SHR strain provides a surgically simple method for causing large neocortical infarcts with reproducible topography and volume. The interanimal variability in infarct volume that occurs even in the SHR strain dictates that randomized, concomitant controls are necessary in each study to ensure the accurate assessment of experimental manipulations or pharmacologic therapies.

  8. Imaging brain inflammation with [(11)C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats.

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    Rojas, Santiago; Martín, Abraham; Arranz, Maria J; Pareto, Deborah; Purroy, Jesús; Verdaguer, Esther; Llop, Jordi; Gómez, Vanessa; Gispert, Joan D; Millán, Olga; Chamorro, Angel; Planas, Anna M

    2007-12-01

    [(11)C]PK11195 is used in positron emission tomography (PET) studies for imaging brain inflammation in vivo as it binds to the peripheral-type benzodiazepine receptor (PBR) expressed by reactive glia and macrophages. However, features of the cellular reaction required to induce a positive [(11)C]PK11195 signal are not well characterized. We performed [(11)C]PK11195 PET and autoradiography in rats after transient focal cerebral ischemia. We determined [(3)H]PK11195 binding and PBR expression in brain tissue and examined the lesion with several markers. [(11)C]PK11195 standard uptake value increased at day 4 and grew further at day 7 within the ischemic core. Accordingly, ex vivo [(3)H]PK11195 binding increased at day 4, and increases further at day 7. The PET signal also augmented in peripheral regions, but to a lesser extent than in the core. Binding in the region surrounding infarction was supported by [(11)C]PK11195 autoradiography at day 7 showing that the radioactive signal extended beyond the infarcted core. Enhanced binding was preceded by increases in PBR mRNA expression in the ipsilateral hemisphere, and a 18-kDa band corresponding to PBR protein was detected. Peripheral-type benzodiazepine receptor immunohistochemistry showed subsets of ameboid microglia/macrophages within the infarcted core showing a distinctive strong PBR expression from day 4. These cells were often located surrounding microhemorrhages. Reactive astrocytes forming a rim surrounding infarction at day 7 also showed some PBR immunostaining. These results show cellular heterogeneity in the level of PBR expression, supporting that PBR is not a simple marker of inflammation, and that the extent of [(11)C]PK11195 binding depends on intrinsic features of the inflammatory cells.

  9. Delayed hyperoxic ventilation attenuates oxygen-induced free radical accumulation during early reperfusion after global brain ischemia.

    Science.gov (United States)

    Wang, Yan; Yuan, Li; Liu, Ping; Zhao, Min

    2015-02-11

    To compare the effect of immediate and delayed administration of oxygen on the accumulation of free radicals in ischemia-reperfusion animal models. Thirty-two adult male Mongolian gerbils with microdialysis probes implanted in the right hippocampal CA1 were divided randomly into four groups (eight each). One group was sham-operated (Sham group) whereas the other three groups were subjected to 10 min bilateral carotid artery occlusion (BCAO). BCAO-treated animals were then subjected to the following: (a) immediate 30% O2 (near normoxia, NO group), (b) immediate 100% O2 (hyperoxia, HO group), and (c) 30% O2 for 60 min, followed by 100% O2 for 60 min (delayed hyperoxia, DHO group). Hippocampal accumulation of hydroxyl radicals (•OH) during reperfusion was estimated by measuring 2,3-dihydroxybenzoic acid (DHBA) and 2,5-DHBA in microdialysis perfusate. Hippocampi were removed 2 h after perfusion to measure malondialdehyde, pyruvate dehydrogenase activity, indices of lipid peroxidation, and cellular respiration. At 24 h after BCAO, the histology of hippocampi was analyzed to rate the injury. Immediately after the onset of reperfusion, all groups showed markedly elevated DHBA, which returned to baseline over 1-2 h. Compared with the NO group, the HO group showed significantly higher peak DHBA and slower recovery. In contrast, the DHO group was not significantly different from the NO group in terms of the DHBA level. DHO animals also showed significantly lower hippocampal malondialdehyde accumulation and higher pyruvate dehydrogenase activity at 2 h after reperfusion versus the HO group. Histology analysis also showed animals in the DHO group with ameliorated injury compared with the HO group. Hydroxyl radical accumulation was more sensitive to O2 during early reperfusion. Delayed hyperoxia may re-establish oxidative metabolism while minimizing oxidative stress after CA.

  10. Forebrain Ischemia-Reperfusion Simulating Cardiac Arrest in Mice Induces Edema and DNA Fragmentation in the Brain

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    Christina H. Liu

    2007-05-01

    Full Text Available Brain injury affects one-third of persons who survive after heart attack, even with restoration of spontaneous circulation by cardiopulmonary resuscitation. We studied brain injury resulting from transient bilateral carotid artery occlusion (BCAO and reperfusion by simulating heart attack and restoration of circulation, respectively, in live C57Black6 mice. This model is known to induce neuronal death in the hippocampus, striatum, and cortex. We report the appearance of edema after transient BCAO of 60 minutes and 1 day of reperfusion. Hyperintensity in diffusion-weighted magnetic resonance imaging (MRI was detectable in the striatum, thalamus, and cortex but not in the hippocampus. To determine whether damage to the hippocampus can be detected in live animals, we infused a T2 susceptibility magnetic resonance contrast agent (superparamagnetic iron oxide nanoparticles [SPIONs] that was linked to single-stranded deoxyribonucleic acid (DNA complementary in sequence to c-fos messenger ribonucleic acid (SPION-cfos; we acquired in vivo T2*-weighted MRI 3 days later. SPION retention was measured as T2* (milliseconds signal reduction or R2* value (s−1 elevation. We found that animals treated with 60-minute BCAO and 7-day reperfusion exhibited significantly less SPION retention in the hippocampus and cortex than sham-operated animals. These findings suggest that brain injury induced by cardiac arrest can be detected in live animals.

  11. EFFECTS OF CANNABIDIOL PLUS HYPOTHERMIA ON SHORT-TERM NEWBORN PIG BRAIN DAMAGE AFTER ACUTE HYPOXIA-ISCHEMIA

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    Hector Lafuente

    2016-07-01

    Full Text Available Background: Hypothermia is standard treatment for neonatal encephalopathy, but near 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms to hypothermia and would improve neuroprotection. Cannabidiol could be a good candidate.Objective: To test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets.Methods: Hypoxic-ischemic animals were randomized to receive 30 min after the insult: 1 normothermia- and vehicle-treated group; 2 normothermia- and cannabidiol-treated group; 3 hypothermia- and vehicle-treated group; and 4 hypothermia- and cannabidiol-treated group. Six hours after treatment, brains were processed to qualify the number of neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate and excitotoxicity (glutamate/Nacetyl-aspartate. Western blot studies were performed to quantify protein nitrosylation (oxidative stress and expression of caspase-3 (apoptosis and TNFα (inflammation.Results: Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on histological damage, was greater than either hypothermia or cannabidiol alone.Conclusion: Cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage.

  12. Avaliação da isquemia cerebral pela respiração mitocondrial: modelo experimental Study of brain ischemia by mitochondrial respiration: experimental model

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    Carlos Gilberto Carlotti Junior

    2001-06-01

    Full Text Available A isquemia cerebral acontece em várias doenças. Um dos fatores críticos para a recuperação de um paciente é a duração do processo isquêmico. A atividade cerebral depende do suprimento de energia, isto sugere que o estudo da função mitocondrial pode ser utilizado para a avaliação do dano neuronal. O objetivo deste trabalho foi o de estudar a respiração mitocondrial pela oclusão da artéria cerebral média esquerda pela técnica do fio intraluminal. Ratos da raça Wistar foram subdivididos em 4 grupos: controle e 15, 30 e 60 minutos de oclusão. Os resultados mostraram que não há diferença estatisticamente significativa entre o grupo de 15 minutos e o grupo controle. O grupo de 30 minutos teve diminuição do estado III da respiração mitocondrial comparado com o grupo controle. O grupo de 60 minutos teve diminuição dos estados III e IV comparados com o grupo controle. A respiração mitocondrial permitiu uma avaliação efetiva e precoce do processo isquêmico focal no cérebro do rato.Brain ischemia occurs in several diseases. One of the critical factors for recovery of patients is the duration of the ischemic process. Brain activity depends on the energetic supply, it suggests that the study of mitochondrial function can be useful for evaluation of neuronal damage. The purpose of the present research was to study the mitochondrial respiration by occlusion of the left middle cerebral artery by intraluminal suture technique. Adults Wistar rats were subdivided in 4 groups: control, 15, 30 and 60 minutes of occlusion. Results showed that there was no significant difference between the group of 15 minutes and the control group. The group of 30 minutes had significant decrease of state III of mitochondrial respiration compared with control group. The group of 60 minutes had significant decrease in state III and IV of mitochondrial respiration compared with control group. Mitochondrial respiration allowed an early and effective

  13. Evaluation of Porin Interaction with Adenine Nucleotide Translocase and Cyclophilin-D Proteins after Brain Ischemia and Reperfusion

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    Mohammad Ali Atlasi

    2011-01-01

    Full Text Available Objective (s Porin is a mitochondrial outer membrane channel, which usually functions as the pathway for the movement of various substances in and out of the mitochondria and is considered to be a component of the permeability transition (PT pore complex that plays a role in the PT. We addressed the hypothesis that porin interacts with other mitochondrial proteins after ischemic injury.Materials and MethodsFor this purpose, we used in vivo 4-vessel occlusion model of rat brain and porin purification method by hydroxyapatite column. After SDS gel electrophoresis and silver nitrate staining, Western blotting was done for porin, adenine nucleotide translocase and cyclophilin-D proteins.Results Porin was purified from mitochondrial mixture in ischemic brain and control groups. Investigation of interaction of adenine nucleotide transposes (ANT and cyclophilin-D with porin by Western blotting showed no proteins co-purified with porin from injured tissues.Conclusion The present study implies that there may not be interaction between porin, and ANT or cyclophilin-D, and if there is any, it is not maintained during the purification procedure.

  14. Early whole-brain CT perfusion for detection of patients at risk for delayed cerebral ischemia after subarachnoid hemorrhage.

    Science.gov (United States)

    Malinova, Vesna; Dolatowski, Karoline; Schramm, Peter; Moerer, Onnen; Rohde, Veit; Mielke, Dorothee

    2016-07-01

    OBJECT This prospective study investigated the role of whole-brain CT perfusion (CTP) studies in the identification of patients at risk for delayed ischemic neurological deficits (DIND) and of tissue at risk for delayed cerebral infarction (DCI). METHODS Forty-three patients with aneurysmal subarachnoid hemorrhage (aSAH) were included in this study. A CTP study was routinely performed in the early phase (Day 3). The CTP study was repeated in cases of transcranial Doppler sonography (TCD)-measured blood flow velocity (BFV) increase of > 50 cm/sec within 24 hours and/or on Day 7 in patients who were intubated/sedated. RESULTS Early CTP studies revealed perfusion deficits in 14 patients, of whom 10 patients (72%) developed DIND, and 6 of these 10 patients (60%) had DCI. Three of the 14 patients (21%) with early perfusion deficits developed DCI without having had DIND, and the remaining patient (7%) had neither DIND nor DCI. There was a statistically significant correlation between early perfusion deficits and occurrence of DIND and DCI (p 50 cm/sec within 24 hours, revealing a perfusion deficit in 3 of them (38%). Two of the 3 patients (67%) developed DCI without preceding DIND and 1 patient (33%) had DIND without DCI. In 4 of the 7 patients (57%) who were sedated and/or comatose, additional CTP studies on Day 7 showed perfusion deficits. All 4 patients developed DCI. CONCLUSIONS Whole-brain CTP on Day 3 after aSAH allows early and reliable identification of patients at risk for DIND and tissue at risk for DCI. Additional CTP investigations, guided by TCD-measured BFV increase or persisting coma, do not contribute to information gain.

  15. The Impact of Ischemia/Reperfusion Injury on Liver Allografts from Deceased after Cardiac Death versus Deceased after Brain Death Donors.

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    Jin Xu

    Full Text Available The shortage of organs for transplantation has led to increased use of organs procured from donors after cardiac death (DCD. The effects of cardiac death on the liver remain poorly understood, however. Using livers obtained from DCD versus donors after brain death (DBD, we aimed to understand how ischemia/reperfusion (I/R injury alters expression of pro-inflammatory markers ceramides and influences graft leukocyte infiltration.Hepatocyte inflammation, as assessed by ceramide expression, was evaluated in DCD (n = 13 and DBD (n = 10 livers. Allograft expression of inflammatory and cell death markers, and allograft leukocyte infiltration were evaluated from a contemporaneous independent cohort of DCD (n = 22 and DBD (n = 13 livers.When examining the differences between transplant stages in each group, C18, C20, C24 ceramides showed significant difference in DBD (p<0.05 and C22 ceramide (p<0.05 were more pronounced for DCD. C18 ceramide is correlated to bilirubin, INR, and creatinine after transplant in DCD. Prior to transplantation, DCD livers have reduced leukocyte infiltration compared to DBD allografts. Following reperfusion, the neutrophil infiltration and platelet deposition was less prevalent in DCD grafts while cell death and recipients levels of serum aspartate aminotransferase (AST of DCD allografts had significantly increased.These data suggest that I/R injury generate necrosis in the absence of a strong inflammatory response in DCD livers with an appreciable effect on early graft function. The long-term consequences of increased inflammation in DBD and increased cell death in DCD allografts are unknown and warrant further investigation.

  16. Neuronal autophagy in cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Feng Xu; Jin-Hua Gu; Zheng-Hong Qin

    2012-01-01

    Autophagy has evolved as a conserved process for the bulk degradation and recycling of cytosolic components,such as long-lived proteins and organelles.In neurons,autophagy is important for homeostasis and protein quality control and is maintained at relatively low levels under normal conditions,while it is upregulated in response to pathophysiological conditions,such as cerebral ischemic injury.However,the role of autophagy is more complex.It depends on age or brain maturity,region,severity of insult,and the stage of ischemia.Whether autophagy plays a beneficial or a detrimental role in cerebral ischemia depends on various pathological conditions.In this review,we elucidate the role of neuronal autophagy in cerebral ischemia.

  17. Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents.

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    Lin-na Pan

    Full Text Available BACKGROUND: Cerebral ischemic preconditioning (IPC protects brain against ischemic injury. Activation of Toll-like receptor 3 (TLR3 signaling can induce neuroprotective mediators, but whether astrocytic TLR3 signaling is involved in IPC-induced ischemic tolerance is not known. METHODS: IPC was modeled in mice with three brief episodes of bilateral carotid occlusion. In vitro, IPC was modeled in astrocytes by 1-h oxygen-glucose deprivation (OGD. Injury and components of the TLR3 signaling pathway were measured after a subsequent protracted ischemic event. A neutralizing antibody against TLR3 was used to evaluate the role of TLR3 signaling in ischemic tolerance. RESULTS: IPC in vivo reduced brain damage from permanent middle cerebral artery occlusion in mice and increased expression of TLR3 in cortical astrocytes. IPC also reduced damage in isolated astrocytes after 12-h OGD. In astrocytes, IPC or 12-h OGD alone increased TLR3 expression, and 12-h OGD alone increased expression of phosphorylated NFκB (pNFκB. However, IPC or 12-h OGD alone did not alter the expression of Toll/interleukin receptor domain-containing adaptor-inducing IFNβ (TRIF or phosphorylated interferon regulatory factor 3 (pIRF3. Exposure to IPC before OGD increased TRIF and pIRF3 expression but decreased pNFκB expression. Analysis of cytokines showed that 12-h OGD alone increased IFNβ and IL-6 secretion; 12-h OGD preceded by IPC further increased IFNβ secretion but decreased IL-6 secretion. Preconditioning with TLR3 ligand Poly I:C increased pIRF3 expression and protected astrocytes against ischemic injury; however, cells treated with a neutralizing antibody against TLR3 lacked the IPC- and Poly I:C-induced ischemic protection and augmentation of IFNβ. CONCLUSIONS: The results suggest that IPC-induced ischemic tolerance is mediated by astrocytic TLR3 signaling. This reprogramming of TLR3 signaling by IPC in astrocytes may play an important role in suppression of the post

  18. Silencing CHOP Gene gene Reduced reduced The the Acute acute Brain brain Injury injury in Cerebral cerebral Ischemia ischemia Reperfusion reperfusion in rRats%沉默CHOP基因减轻脑缺血再灌注大鼠的急性脑损伤

    Institute of Scientific and Technical Information of China (English)

    郑胜哲; 谷月; 何春珂; 王婷婷; 贾丽君

    2013-01-01

    目的 研究大鼠脑缺血再灌注后急性脑损伤中CHOP蛋白的作用.方法 将36只SD大鼠随机分为对照组、vector组和LV-shRNA组,经微型注射泵向control组左脑室中注射PBS,vector组注射入LV-CMV-control 质粒,向LV-shRNA组注射入LV-CMV-CHOP shRNA质粒.线栓法制作大鼠缺血再灌注模型后,TTC染色检测各组大鼠脑梗死体积,Western Blot检测所有大鼠脑内CHOP、Bcl-2和Caspase 3的表达,TUNEL染色检测梗死区细胞凋亡.结果 LV-shRNA组大鼠脑梗死体积明显小于对照组和vector组(P<0.01);Western Blot结果显示LV-shRNA组大鼠脑内CHOP和Caspase3含量明显低于对照组和vector组(P<0.01),而Bcl-2高于对照组和vector组(P>0.05);TUNEL染色显示LV-shRNA组大鼠脑梗死区域内凋亡细胞明显少于对照组和vector组(P<0.01).结论 CHOP在脑缺血后具有促进急性脑损伤的作用,沉默CHOP可通过减轻细胞凋亡反应发挥神经保护作用.%Objective ive To investigate the role of CHOP in the acute cerebral injury in rats with focal cerebral ischemia/reperfusion. Methods 36 rats were randomly divided into control group, vector group and LV-shRNA group. PBS was injected into the left ventricle of rats in control group via micro-injection pump,whereas LV-CMV-control plasmid and LV-CMV-CHOP shRNA plasmid were injected into the rats brain of vector group and LV-CMV-control group respectively. The animal model of the left MCA ischemia/reperfusion was established by suture method. Cerebral infarct volume was measured by TTC staining and the expression of CHOP, Bcl-2 and Caspase 3 in rats brain were detected by Western Blot-blot. In addition,TUNEL staining was utilized to examine cell apoptosis in infarct zone. Results The infarction volume of rats in LV-shRNA group was obviously less than control group and vector group (P 0.05). TUNEL staining showed that the apoptosis cells in LV-shRNA group rats' infarction area was markedly less than those in control

  19. Análise da respiração mitocondrial em tecido cerebral de gato após isquemia e reperfusão Analysis of mitochondrial respiration in brain cerebral tissue of cats after ischemia and reperfusion

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    Hiroshi Nakano

    2002-01-01

    Full Text Available INTRODUÇÃO: A isquemia cerebral é uma doença freqüente e de difícil tratamento médico. De particular interesse neurocirúrgico são as situações de vasoespasmo após hemorragia subaracnóidea, de oclusão temporária de vasos nas neurocirurgias e de tromboses de artérias intracranianas. A lesão cerebral resultante da isquemia depende da sua duração e pode ser agravada pela reperfusão do território isquêmico. Vários estudos clínicos e experimentais têm sido realizados para melhor entender esses fenômenos. OBJETIVO: Este trabalho visou a avaliação precoce dos efeitos da isquemia focal seguida da reperfusão no cérebro de gatos. MÉTODOS: A isquemia cerebral foi provocada por clipagem temporária da artéria cerebral média por tempos determinados com reperfusão durante 10 minutos, e avaliação foi efetuada através da análise da respiração mitocondrial no tecido isquemiado. Resultados - Houve redução significativa no consumo de O2 nas amostras de tecido cerebral isquemiado por 60 minutos, seguidos de 10 minutos de reperfusão, quando comparadas ao tecido cerebral contralateral (não isquemiado. CONCLUSÕES: Com base nos resultados obtidos, pode-se concluir que o tempo de duração da isquemia foi um fator determinante na alteração da respiração mitocondrial de gatos submetidos à isquemia e reperfusão de curta duração (alterações significativas apenas após 60 minutos de isquemia seguidos de 10 de reperfusão.OBJECTIVE: Brain ischemia is considered a disease difficult to be treated. Despite many other clinical situations, of particular interest for neurosurgery is its occurrence in cerebral vasoespam following subarachnoid hemorrhage, in temporary occlusion of intracranial vessels during neurosurgeries and, in intracranial arterial thrombosis. The cerebral lesion caused by isquemia is time-related and it can aggravated by the reperfusion of the ischemic site. Many clinical and experimental studies have been

  20. Xenon and sevoflurane provide analgesia during labor and fetal brain protection in a perinatal rat model of hypoxia-ischemia.

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    Ting Yang

    Full Text Available It is not possible to identify all pregnancies at risk of neonatal hypoxic-ischemic encephalopathy (HIE. Many women use some form of analgesia during childbirth and some anesthetic agents have been shown to be neuroprotective when used as analgesics at subanesthetic concentrations. In this study we sought to understand the effects of two anesthetic agents with presumptive analgesic activity and known preconditioning-neuroprotective properties (sevoflurane or xenon, in reducing hypoxia-induced brain damage in a model of intrauterine perinatal asphyxia. The analgesic and neuroprotective effects at subanesthetic levels of sevoflurane (0.35% or xenon (35% were tested in a rat model of intrauterine perinatal asphyxia. Analgesic effects were measured by assessing maternal behavior and spinal cord dorsal horn neuronal activation using c-Fos. In separate experiments, intrauterine fetal asphyxia was induced four hours after gas exposure; on post-insult day 3 apoptotic cell death was measured by caspase-3 immunostaining in hippocampal neurons and correlated with the number of viable neurons on postnatal day (PND 7. A separate cohort of pups was nurtured by a surrogate mother for 50 days when cognitive testing with Morris water maze was performed. Both anesthetic agents provided analgesia as reflected by a reduction in the number of stretching movements and decreased c-Fos expression in the dorsal horn of the spinal cord. Both agents also reduced the number of caspase-3 positive (apoptotic neurons and increased cell viability in the hippocampus at PND7. These acute histological changes were mirrored by improved cognitive function measured remotely after birth on PND 50 compared to control group. Subanesthetic doses of sevoflurane or xenon provided both analgesia and neuroprotection in this model of intrauterine perinatal asphyxia. These data suggest that anesthetic agents with neuroprotective properties may be effective in preventing HIE and should be

  1. Tenoxicam exerts a neuroprotective action after cerebral ischemia in rats.

    Science.gov (United States)

    Galvão, Rita I M; Diógenes, João P L; Maia, Graziela C L; Filho, Emídio A S; Vasconcelos, Silvânia M M; de Menezes, Dalgimar B; Cunha, Geanne M A; Viana, Glauce S B

    2005-01-01

    In this study we investigated the effects of Tenoxicam, a type 2 cyclooxygenase (COX-2) inhibitor, on brain damage induced by ischemia-reperfusion. Male Wistar rats (18-month old average) were anesthetized and submitted to ischemia occlusion of both common carotid arteries (BCAO) for 45 min. After 24 h of reperfusion, rats were decapitated and hippocampi removed for further assays. Animals were divided into sham-operated, ischemia, ischemia + Tenoxicam 2.5 mg/kg, and ischemia + Tenoxicam 10 mg/kg groups. Tenoxicam was administered intraperitoneally immediately after BCAO. Histological analyses show that ischemia produced significant striatal as well as hippocampal lesions which were reversed by the Tenoxicam treatment. Tenoxicam also significantly reduced, to control levels, the increased myeloperoxidase activity in hippocampus homogenates observed after ischemia. However, nitrite concentrations showed only a tendency to decrease in the ischemia + Tenoxicam groups, as compared to that of ischemia alone. On the other hand, hippocampal glutamate and aspartate levels were not altered by Tenoxicam. In conclusion, we showed that ischemia is certainly related to inflammation and to increased free radical production, and selective COX-2 inhibitors might be neuroprotective agents of potential benefit in the treatment of cerebral brain ischemia.

  2. Sirt1 in cerebral ischemia

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    Koronowski, Kevin B.; Perez-Pinzon, Miguel A.

    2015-01-01

    Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD+)-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance. PMID:26819971

  3. Sirt1 in cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Kevin B Koronowski

    2015-01-01

    Full Text Available Cerebral ischemia is among the leading causes of death worldwide. It is characterized by a lack of blood flow to the brain that results in cell death and damage, ultimately causing motor, sensory, and cognitive impairments. Today, clinical treatment of cerebral ischemia, mostly stroke and cardiac arrest, is limited and new neuroprotective therapies are desperately needed. The Sirtuin family of oxidized nicotinamide adenine dinucleotide (NAD +-dependent deacylases has been shown to govern several processes within the central nervous system as well as to possess neuroprotective properties in a variety of pathological conditions such as Alzheimer′s Disease, Parkinson′s Disease, and Huntington′s Disease, among others. Recently, Sirt1 in particular has been identified as a mediator of cerebral ischemia, with potential as a possible therapeutic target. To gather studies relevant to this topic, we used PubMed and previous reviews to locate, select, and resynthesize the lines of evidence presented here. In this review, we will first describe some functions of Sirt1 in the brain, mainly neurodevelopment, learning and memory, and metabolic regulation. Second, we will discuss the experimental evidence that has implicated Sirt1 as a key protein in the regulation of cerebral ischemia as well as a potential target for the induction of ischemic tolerance.

  4. Effects of "nourishing liver and kidney" acupuncture therapy on expression of brain derived neurotrophic factor and synaptophysin after cerebral ischemia reperfusion in rats.

    Science.gov (United States)

    Xia, Wen-Guang; Zheng, Chan-Juan; Zhang, Xuan; Wang, Juan

    2017-04-01

    The aim of the present study was to investigate the effect of "nourishing liver and kidney" acupuncture therapy on motor and cognitive deficits, and the underlying mechanism following cerebral ischemia-reperfusion (I/R) via increasing the expression of brain derived neurotrophic factor (BDNF) and synaptophysin (SYN) in the hippocampus. Healthy adult male SD rats were randomly divided into sham operation group (n=51), model group (n=51), acupuncture group (n=51) and acupuncture control group (n=51). The middle cerebral I/R model was established. Acupunctures were performed in the acupuncture group and acupuncture control group at acupoints of Taixi (K103), Taichong (ST09) of both sides, for 30 min once daily every morning. The animals in the sham operation group and model group were conventionally fed in the cage, without any intervention therapy. The rats of each group were assessed with modified neurological severity scores (mNSS). The expression of BDNF and SYN in the hippocampus was detected by immunohistochemical SP method and the synaptic structure in hippocampus area was assessed morphologically and quantitatively at the 3rd, 7th and 14th day. The Morris water Maze (MWM) test was used to evaluate the rats' learning and memory abilities on the 15th day after acupuncture. The animals in the acupuncture control group and sham operation group presented no neurological deficit. In the acupuncture group, the nerve functional recovery was significantly better than that in the model group at the 7th and 14th day after modeling. The average MWM escape latency in the acupuncture group was shorter than that in the model group at the 3rd, 4th and 5th day. The number of crossings of the platform quadrant in the acupuncture group was significantly more than that in the model group. At the each time point, the expression levels of BDNF and SYN in the hippocampal regions increased significantly in the model group as compared with the sham operation group and the acupuncture

  5. Cardiac Arrest-Induced Global Brain Hypoxia-Ischemia during Development Affects Spontaneous Activity Organization in Rat Sensory and Motor Thalamocortical Circuits during Adulthood.

    Science.gov (United States)

    Shoykhet, Michael; Middleton, Jason W

    2016-01-01

    Normal maturation of sensory information processing in the cortex requires patterned synaptic activity during developmentally regulated critical periods. During early development, spontaneous synaptic activity establishes required patterns of synaptic input, and during later development it influences patterns of sensory experience-dependent neuronal firing. Thalamocortical neurons occupy a critical position in regulating the flow of patterned sensory information from the periphery to the cortex. Abnormal thalamocortical inputs may permanently affect the organization and function of cortical neuronal circuits, especially if they occur during a critical developmental window. We examined the effect of cardiac arrest (CA)-associated global brain hypoxia-ischemia in developing rats on spontaneous and evoked firing of somatosensory thalamocortical neurons and on large-scale correlations in the motor thalamocortical circuit. The mean spontaneous and sensory-evoked firing rate activity and variability were higher in CA injured rats. Furthermore, spontaneous and sensory-evoked activity and variability were correlated in uninjured rats, but not correlated in neurons from CA rats. Abnormal activity patterns of ventroposterior medial nucleus (VPm) neurons persisted into adulthood. Additionally, we found that neurons in the entopeduncular nucleus (EPN) in the basal ganglia had lower firing rates yet had higher variability and higher levels of burst firing after injury. Correlated levels of power in local field potentials (LFPs) between the EPN and the motor cortex (MCx) were also disrupted by injury. Our findings indicate that hypoxic-ischemic injury during development leads to abnormal spontaneous and sensory stimulus-evoked input patterns from thalamus to cortex. Abnormal thalamic inputs likely permanently and detrimentally affect the organization of cortical circuitry and processing of sensory information. Hypoxic-ischemic injury also leads to abnormal single neuron and

  6. EFFECTS OF THE SODIUM-CHANNEL BLOCKER TETRODOTOXIN (TTX) ON CELLULAR ION HOMEOSTASIS IN RAT-BRAIN SUBJECTED TO COMPLETE ISCHEMIA

    NARCIS (Netherlands)

    XIE, YX; DENGLER, K; ZACHARIAS, E; WILFFERT, B; TEGTMEIER, F

    1994-01-01

    Anoxic depolarization (AD) and failure of the cellular ion homeostasis are suggested to play a key role in ischemia-induced neuronal death. Recent studies show that the blockade of Na+ influx significantly improved the neuronal outcome. In the present study, we investigated the effects of 10 mu M te

  7. NMDA and non-NMDA receptor gene expression following global brain ischemia in rats: effect of NMDA and non-NMDA receptor antagonists.

    Science.gov (United States)

    Pellegrini-Giampietro, D E; Pulsinelli, W A; Zukin, R S

    1994-03-01

    Transient forebrain or global ischemia in rats induces selective and delayed damage of hippocampal CA1 neurons. In a previous study, we have shown that expression of GluR2, the kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit that governs Ca2+ permeability, is preferentially reduced in CA1 at a time point preceding neuronal degeneration. Postischemic administration of the selective AMPA receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), protects CA1 neurons against delayed death. In this study we examined the effects of NBQX (at a neuroprotective dose) and of MK-801 (a selective NMDA receptor antagonist, not protective in this model) on kainate/AMPA receptor gene expression changes after global ischemia. We also examined the effects of transient forebrain ischemia on expression of the NMDA receptor subunit NMDAR1. In ischemic rats treated with saline, GluR2 and GluR3 mRNAs were markedly reduced in CA1 but were unchanged in CA3 or dentate gyrus. GluR1 and NMDAR1 mRNAs were not significantly changed in any region examined. Administration of NBQX or MK-801 did not alter the ischemia-induced changes in kainate/AMPA receptor gene expression. These findings suggest that NBQX affords neuroprotection by a direct blockade of kainate/AMPA receptors, rather than by a modification of GluR2 expression changes.

  8. The corticosterone synthesis inhibitor metyrapone prevents hypoxia/ischemia-induced loss of synaptic function in the rat hippocampus

    NARCIS (Netherlands)

    Krugers, HJ; Maslam, S; Korf, J; Joëls, M

    2000-01-01

    Background and Purpose-Ischemia is accompanied by abundant corticosterone secretion, which could potentially exacerbate brain damage via activation of glucocorticoid receptors. We addressed whether manipulating steroid levels during ischemia affects hippocampal synaptic function along with neuronal

  9. Acute Mesenteric Ischemia

    Science.gov (United States)

    ... Side Effects Additional Content Medical News Acute Mesenteric Ischemia By Parswa Ansari, MD, Department of Surgery, Lenox ... Abscesses Abdominal Wall Hernias Inguinal Hernia Acute Mesenteric Ischemia Appendicitis Ileus Intestinal Obstruction Ischemic Colitis Perforation of ...

  10. Mesenteric artery ischemia

    Science.gov (United States)

    ... medlineplus.gov/ency/article/001156.htm Mesenteric artery ischemia To use the sharing features on this page, please enable JavaScript. Mesenteric artery ischemia occurs when there is a narrowing or blockage ...

  11. Intestinal ischemia and infarction

    Science.gov (United States)

    ... medlineplus.gov/ency/article/001151.htm Small intestinal ischemia and infarction To use the sharing features on this page, please enable JavaScript. Intestinal ischemia and infarction occurs when there is a narrowing ...

  12. Clinical Neuroimaging of cerebral ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Nakagawara, Jyoji [Nakamura Memorial Hospital, Sapporo (Japan)

    1999-06-01

    Notice points in clinical imaging of cerebral ischemia are reviewed. When cerebral blood flow is determined in acute stage of cerebral embolism (cerebral blood flow SPECT), it is important to find area of ischemic core and ischemic penumbra. When large cortex area is assigned to ischemic penumbra, thrombolytic therapy is positively adapted, but cautious correspondence is necessary when ischemic core is recognized. DWI is superior in the detection of area equivalent to ischemic core of early stage, but, in imaging of area equivalent to ischemic penumbra, perfusion image or distribution image of cerebral blood volume (CBV) by MRI need to be combined. Luxury perfusion detected by cerebral blood flow SPECT in the cases of acute cerebral embolism suggests vascular recanalization, but a comparison with CT/MRI and continuous assessment of cerebral circulation dynamics were necessary in order to predict brain tissue disease (metabolic abnormality). In hemodynamic cerebral ischemia, it is important to find stage 2 equivalent to misery perfusion by quantification of cerebral blood flow SPECT. Degree of diaschisis can indicate seriousness of brain dysfunction for lacuna infarct. Because cerebral circulation reserve ability (perfusion pressure) is normal in all areas of the low cerebral blood flow by diaschisis mechanism, their areas are easily distinguished from those of hemodynamic cerebral ischemia. (K.H.)

  13. Evaluation of the neuroprotective effect of ketoprofen on rats submitted to permanent focal brain ischemia Avaliação do efeito neuroprotetor do cetoprofeno em ratos submetidos à isquemia cerebral focal permanente

    Directory of Open Access Journals (Sweden)

    Manoel Nunes da Silva

    2007-12-01

    Full Text Available OBJECTIVE: To study the neurobehavioral, biochemical and histopathological consequences of permanent focal brain ischemia, and the putative neuroprotective action of ketoprofen. METHOD: One-hundred-and-three Wistar rats divided into groups A and B were respectively submitted to 48 hours and 15 days of ischemia. Each group was divided into 4 subgroups: ischemic not treated, ischemic treated, sham not treated, and sham treated. Ischemic animals had the left middle cerebral artery coagulated. Ketoprofen was administered to treated subgroups 15 minutes before arterial coagulation (manipulation in the sham group. RESULTS: Exploratory activity and defecation were reduced in all ischemic animals in the first postoperative days and constant histopathological changes were observed in each group. The total brain glutamate levels were higher in treated animals 48 hours after surgery. CONCLUSION: No clear parallelism among behavioral, biochemical and histopathological findings was observed. Ketoprofen demonstrated no neuroprotective effect on the behavioral or histopathological aspects of focal permanent brain ischemia.OBJETIVO: Estudar as conseqüências comportamentais, bioquímicas e histopatológicas da isquemia cerebral focal permanente e o possível efeito neuroprotetor do cetoprofeno. MÉTODO: Foram utilizados 103 ratos Wistar, divididos em grupos A e B, submetidos, respectivamente, a 48 horas e a 15 dias de isquemia. Cada grupo foi dividido em 4 subgrupos: isquêmico não tratado; isquêmico tratado; sham não tratado; sham tratado. Nos animais isquêmicos foi coagulada a artéria cerebral média esquerda. Os subgrupos tratados receberam cetoprofeno 15 minutos antes da oclusão ou manipulação arterial. RESULTADOS: Os animais isquêmicos reduziram a atividade exploratória e as evacuações nos primeiros dias pós-operatórios e mostraram alterações histopatológicas constantes em cada grupo. As concentrações do glutamato total 48 horas após a

  14. [Chronic cerebral ischemia associated with Raynaud's syndrome].

    Science.gov (United States)

    Putilina, M V

    2015-01-01

    Over the last years, a number of patients with chronic cerebral ischemia has been increased significantly. Compensatory possibilities of the brain and cerebral circulatory system are so great that even serious disturbances of blood circulation could not cause clinical signs of brain dysfunction for a long time. At the same time, long-term ischemia can lead to peripheral local disturbances of microcirculation that is appears to be a first signal of the problems with homeostasis. Therefore, Raynaud's syndrome may be one of the predictors of standard symptoms of chronic cerebral ischemia (CCI). This phenomenon is explicitly considered as a sign of blood circulation impairment while the pathogenetic mechanism of vascular arterial bed instability is completely ignored. Detailed study of clinical correlations of Raynaud's syndrome in CCI would help to develop a common pharmacotherapeutic approach to its treatment.

  15. [Antioxidant effects of antihypoxic drugs in cerebral ischemia].

    Science.gov (United States)

    Plotnikov, M B; Kobzeva, E A; Plotnikova, T M

    1992-05-01

    Cerebral ischemia in rats (both carotid arteries occlusion) during 30 min, 3 hours and recirculation (1 hour) after ischemia (30 min) stimulated diene conjugates and fluorescent products accumulation in brain tissue. Intraperitoneal injection of sodium hydroxybutyrate (100 mg/kg), bemitil (50 mg/kg), ethomersol (50 mg/kg) reduced brain lipid peroxidation and did not yield in this respect to emoxypin (5 mg/kg). In contrast to emoxypin, sodium hydroxybutyrate, bemitil and ethomersol had no antiradical activity.

  16. Effects of brain focal ischemia or chronic stress on the hippocampus-dependent learning and memory function%脑缺血与慢性应激对依赖海马的学习记忆的影响

    Institute of Scientific and Technical Information of China (English)

    毛琳; 李德强; 罗本燕

    2011-01-01

    目的 对比脑缺血与慢性应激所致认知损害及海马病变的强弱,为临床改善脑卒中后认知障碍(poststroke cognitive impairment,PSCI)提供参考.方法 40只成年雄性SD大鼠平均分为4组:对照组、应激组、缺血组与缺血加应激组,缺血手术采用改良的选择性大脑中动脉栓塞术;应激处理采用连续3周的慢性不可预见性温和应激;Moms水迷宫实验评价依赖海马的学习记忆功能;免疫组织化学染色及半定量RT-PCR观察海马CA3区脑源性神经营养因子(brain-derived neurotrophic factor,BDNF)的表达变化.结果 应激或缺血均可使大鼠学习功能明显下降,表现为与同时点对照组比较,逃避潜伏期显著延长,二者的综合作用更明显.慢性应激对学习功能的影响强于脑缺血损伤.应激或缺血均减弱记忆功能,但二者的作用差异无统计学意义.与对照相比,缺血显著增加海马CA3区BDNF的表达(27.0±2.5与20.1±2.1),应激降低BDNF的表达(15.2±1.8与20.1±2.1),二者综合作用仍显著降低BDNF的表达(8.2±1.5),差异均具有统计学意义(F=52.87,P<0.05).结论 缺血与应激均降低大鼠学习记忆功能,应激对认知功能的损害高于缺血,而缺血与应激的综合作用对认知功能损害与抑制BDNF表达作用更明显,提示进行PSCI的综合治疗时,要重视心理社会应激干预和抑郁状态的改善.%Objective To compare the intensity of cognitive impairment and the level of pathological lesion in hippocampus induced by ischemia or chronic stress for a more valuable guidance in the treatment of post-stroke cognitive impairment(PSCI).Methods Forty male adult SD rats were divided medially into 4 groups:control,stress,ischemia and ischemia plus stress.Animals in 3 treatment groups were subjected respectively to an operation of modified selective middle cerebral artery occlusion or a procedure of continuous 3-week chronic unpredictable mild stress or a combined program of

  17. Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia

    Science.gov (United States)

    Cerebral ischemia is caused by an interruption of blood flow to the brain which generally leads to irreversible brain damage. Ischemic injury is associated with vascular leakage, inflammation, tissue injury, and cell death. Cellular changes associated with ischemia include impairment of metabolism, ...

  18. Neuroprotective effect of melatonin on preterm rat after hypoxia-ischemia brain damage%褪黑素对新生大鼠缺血缺氧后脑损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    乔丽丽; 沈伟勤; 陈国宏

    2012-01-01

    目的 探讨褪黑素对新生大鼠缺氧缺血性脑损伤 (HIBD) 的保护作用.方法 Wistar大鼠 48 只,5日龄时结扎左侧颈总动脉,吸入氧氮混合气体 50 min 制作成HIBD模型,随机分成生理盐水组,褪黑素组,缺血缺氧 (HI)+生理盐水组,HI+褪黑素组.褪黑素腹腔注射共 3 次,每次 5 mg/kg,第 1 次在结扎动脉前,第 2 次在吸入氧氮混合气体前给予,第 3 次在HIBD模型制作 24 h 后给予.大鼠在HIBD模型制作后 72 h 被处死,取脑作免疫组化染色,判断脑灰质 (microtubule-associatedprotein-2,MAP-2)、脑白质 (myelin basic protein,MBP) 损伤;HIBD模型制作后 7 周作Y迷宫记忆功能测试.结果 褪黑素能明显减轻HIBD大鼠脑灰质MAP-2和脑白质MBP损伤,还可提高大鼠的长期记忆能力和运动协调能力.结论 褪黑素对HIBD大鼠大脑损伤有明显的短期和长期保护作用.%Objective To investigate neuroprotective effect of melatonin on newborn rat brain after hypoxia-ischemia brain damage (HIBD). Methods Forty-eight 5-day-old Wistar rats were randomly divided into physiological saline group, melatonin group, hypoxia-ischemia (HI) + saline group and HI + melatonin group. The HIBD rat models were induced by unilateral ligation of the left common carotid artery followed by 50 min inhalation of mixed oxygen and nitrogen. Melatonin was intraperitoneally injected three times with a dose of 5mg/kg before artery ligation, before ischemia and after 24h HI immediately. The rats were sacrified after 72h HI and the immunohistochemical staining was applied to brain tissue. Microtubule-associated protein-2 (MAP-2) and myelin basic protein (MBP) were evaluated as indicators for damages in grey matter and white matter, respectively. The memory abilities of the rats were measured through Y maze test at 7 weeks after HI. Results Melatonin treatment reduced the injury of grey matter and white matter significantly, and improved the long-term memory ability and motor

  19. Prevention of Glutamate Accumulation and Upregulation of Phospho-Akt may Account for Neuroprotection Afforded by Bergamot Essential Oil against Brain Injury Induced by Focal Cerebral Ischemia in Rat.

    Science.gov (United States)

    Amantea, Diana; Fratto, Vincenza; Maida, Simona; Rotiroti, Domenicantonio; Ragusa, Salvatore; Nappi, Giuseppe; Bagetta, Giacinto; Corasaniti, Maria Tiziana

    2009-01-01

    The effects of bergamot essential oil (BEO; Citrus bergamia, Risso) on brain damage caused by permanent focal cerebral ischemia in rat were investigated. Administration of BEO (0.1-0.5 ml/kg but not 1 ml/kg, given intraperitoneally 1 h before occlusion of the middle cerebral artery, MCAo) significantly reduced infarct size after 24 h permanent MCAo. The most effective dose (0.5 ml/kg) resulted in a significant reduction of infarct extension throughout the brain, especially in the medial striatum and the motor cortex as revealed by TTC staining of tissue slices. Microdialysis experiments show that BEO (0.5 ml/kg) did not affect basal amino acid levels, whereas it significantly reduced excitatory amino acid, namely aspartate and glutamate, efflux in the frontoparietal cortex typically observed following MCAo. Western blotting experiments demonstrated that these early effects were associated, 24 h after permanent MCAo, to a significant increase in the phosphorylation and activity of the prosurvival kinase, Akt. Indeed, BEO significantly enhanced the phosphorylation of the deleterious downstream kinase, GSK-3beta, whose activity is negatively regulated via phosphorylation by Akt.

  20. Improvement in Memory and Brain Long-term Potentiation Deficits Due to Permanent Hypoperfusion/Ischemia by Grape Seed Extract in Rats

    Directory of Open Access Journals (Sweden)

    Alireza Sarkaki

    2013-09-01

    Full Text Available   Objective(s: Cerebral hypoperfusion/ischemia (CHI is a neurological disease where impaired hippocampus electrical activity and cognition caused by a serial pathophysiological events. This study aimed to evaluate the effects of chronic oral administration of grape seed extract (GSE on passive avoidance memory and long-term potentiation (LTP after permanent bilateral common carotid arteries occlusion (2CCAO in male adult rats.   Materials and Methods: Thirty-two adult male Wistar rats were randomly divided into: 1 Sham+Veh, 2 Isch+Veh, 3 Sham+GSE, 4 Isch+GSE. In order to make 2CCAO as an animal model of CHI, carotid arteries were ligatured and then cut bilaterally. To evaluation of passive avoidance memory, step-down latency (STL was measured and LTP was recorded from hippocampal dentate gyrus (DG after high frequency stimulation (HFS in all rats. Results: We found that memory was significantly impaired in rats after CHI (P

  1. Migraine and ischemia

    NARCIS (Netherlands)

    van der Wammes-van der Heijden, E.A.

    2009-01-01

    An association between migraine and ischemic events, especially ischemic stroke, has been debated for many years. Whether migraine is a risk factor for ischemic events or ischemia triggers migraine, or both, is still unclear. This thesis explores different relationships between migraine and ischemia

  2. 脑缺血发生后 IP-10趋化 NK 细胞通过血脑屏障%Chemotactic effect of IP-10 to natural killer cells getting through blood brain barrier after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    张瑶; 冯涛; 祝鸿雁; 王广友; 王丹丹; 李呼伦

    2014-01-01

    Objective To research the chemotactic effect of IP-10 on natural killer cells after cerebral ischemia .Methods Experiments in vivo: NK infiltration and IP-10 and CXCR3 ex-pression in pMCAO mouse brain were detected by immunofluorescence;NK infiltration in pM-CAO brains was detected by flowcytometry;IP-10 total expression level in brain were investiga-ted by RT-PCR.Experiments in vitro:Established blood brain barrier ( B.B.B.) in vitro;IP-10 expression of the supernatant from brain microvascular endothclial cell ( BMVEC ) and neu-ral cells after oxygen-gluoose depriuation ( OGD) were detected by ELISA; B.B.B.in vitro were separated into NK , NK+IP-10 blockade two groups , after OGD 6 h, NK cells migration counts were detected by flowcytometry;NK cells were cultured together with IP -10 ( 10 ng/mL), IP-10 (50 ng/mL), IP-10(100 ng/mL), then CXCR3 geomean.MFI value were de-tected by flowcytometry .Results Experiments in vivo:NK cells were found in pMCAO brain section and expressing CXCR 3 and IP-10; NK cells infiltration were higher in ischemia-hemi-sphere , and got a peak at 12 h ( P<0.05 );NK cells had anobviously increase by 12 h at in-filtration frequency (P<0.01 );IP-10 had a highest level at 12 h ( P<0.001 ) .Experiments in vitro:Neural cell had higher expression of IP-10 after OGD than BMVEC ( P <0.001 );Compared with group NK , group NK+IP-10 blockade had lower NK cells migration counts ( P<0.05 ) and permeability ( P<0.001 ) .Conclusion ①NK cells plays an important role dur-ing cerebral ischemia;②IP-10 can absorb NK cells across B .B.B.when ischemia happens by combined with its receptor CXCR 3 and has dose dependent .%目的:探讨脑缺血发生后 IP-10对NK细胞的趋化作用。方法体内实验:免疫荧光染色观察永久性大脑中动脉栓塞小鼠模型( pMCAO)脑组织中NK细胞浸润情况以及IP-10、CXCR3表达情况;流式细胞术检测pMCAO小鼠模型脑中NK细胞浸润数目;RT-PCR

  3. Poly-IC preconditioning protects against cerebral and renal ischemia-reperfusion injury.

    Science.gov (United States)

    Packard, Amy E B; Hedges, Jason C; Bahjat, Frances R; Stevens, Susan L; Conlin, Michael J; Salazar, Andres M; Stenzel-Poore, Mary P

    2012-02-01

    Preconditioning induces ischemic tolerance, which confers robust protection against ischemic damage. We show marked protection with polyinosinic polycytidylic acid (poly-IC) preconditioning in three models of murine ischemia-reperfusion injury. Poly-IC preconditioning induced protection against ischemia modeled in vitro in brain cortical cells and in vivo in models of brain ischemia and renal ischemia. Further, unlike other Toll-like receptor (TLR) ligands, which generally induce significant inflammatory responses, poly-IC elicits only modest systemic inflammation. Results show that poly-IC is a new powerful prophylactic treatment that offers promise as a clinical therapeutic strategy to minimize damage in patient populations at risk of ischemic injury.

  4. 太冲、合谷穴对脑缺血作用机制的研究进展%Mechanisms of Action of Taichong and Hegu Point on Brain Ischemia

    Institute of Scientific and Technical Information of China (English)

    沈俊明; 詹宇豪

    2016-01-01

    With the improvement of living standards and the speedup of social aging,ischemic cerebro-vascular disease has become one of the diseases severely impairing the human health .Treatments of cerebral ischemia are increasingly explored.Taichong and Hegu,as a crucial pair of acupoints,can treat and improve ischemic cerebral vascular disease symptoms throug various ways ,and improve brain blood circulation and pro-mote blood vessel regeneration;improve memory and post-stroke depression.In recent years, the traditional medicine and modern medicine research with regards to the two acupoints,has made significant progress, which provides a strong basis for the further treatment and improve prognosis of cerebral ischemia disease , making the standard more objective and the result more reliable .The current studies are mainly focusing on middle cerebral blood flow,related brain regions and the influence and mechanism of depression after stroke , but further clinical mechanisms are still under exploration .%随着生活水平的提高、社会老龄化的不断加快,缺血性脑血管病逐渐成为危害人类健康的疾病之一. 人们不断寻求治疗脑缺血疾病的方法,太冲、合谷穴作为临床针灸常用的重要穴位,从多种途径治疗和改善缺血性脑血管病的病症,改善脑血流循环,促进血管再生;改善记忆及卒中后抑郁等症状. 近年来太冲、合谷穴在传统医学和现代医学两方面的相关研究有了显著进展,为进一步治疗脑缺血疾病及改善预后提供了有力依据,使标准更加客观,结果更加可靠. 重点对脑缺血疾病中脑血流、相关脑功能区以及脑卒中后抑郁症的影响和作用机制显现出越来越大的优势,但其更深入的临床机制仍处于探索阶段,需进一步研究和阐明.

  5. Minocycline upregulates cyclic AMP response element binding protein and brain-derived neurotrophic factor in the hippocampus of cerebral ischemia rats and improves behavioral deficits

    Directory of Open Access Journals (Sweden)

    Zhao Y

    2015-02-01

    Full Text Available Yu Zhao,1 Ming Xiao,2 Wenbo He,3 Zhiyou Cai3 1Department of Neurology, the Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, People’s Republic of China; 2Department of Anatomy, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 3Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan Renmin Hospital, Shiyan, Hubei Province, People’s Republic of China Background and purpose: The cAMP response element binding protein (CREB plays an important role in the mechanism of cognitive impairment and is also pivotal in the switch from short-term to long-term memory. Brain-derived neurotrophic factor (BDNF seems a promising avenue in the treatment of cerebral ischemia injury since this neurotrophin could stimulate structural plasticity and repair cognitive impairment. Several findings have displayed that the dysregulation of the CREB–BDNF cascade has been involved in cognitive impairment. The aim of this study was to investigate the effect of cerebral ischemia on learning and memory as well as on the levels of CREB, phosphorylated CREB (pCREB, and BDNF, and to determine the effect of minocycline on CREB, pCREB, BDNF, and behavioral functional recovery after cerebral ischemia. Methods: The animal model was established by permanent bilateral occlusion of both common carotid arteries. Behavior was evaluated 5 days before decapitation with Morris water maze and open-field task. Four days after permanent bilateral occlusion of both common carotid arteries, minocycline was administered by douche via the stomach for 4 weeks. CREB and pCREB were examined by Western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry. BDNF was measured by immunohistochemistry and Western blotting. Results: The model rats after minocycline treatment swam shorter distances than control rats before finding the platform (P=0.0007. The number of times the

  6. The oxygen free radicals originating from mitochondrial complex I contribute to oxidative brain injury following hypoxia-ischemia in neonatal mice

    Science.gov (United States)

    Niatsetskaya, Zoya V.; Sosunov, Sergei A.; Matsiukevich, Dzmitry; Utkina-Sosunova, Irina V.; Ratner, Veniamin I.; Starkov, Anatoly A.; Ten, Vadim S.

    2012-01-01

    Oxidative stress and Ca++ toxicity are mechanisms of hypoxic-ischemic (HI) brain injury. This work investigates if partial inhibition of mitochondrial respiratory chain protects HI-brain by limiting generation of oxidative radicals during reperfusion. HI-insult was produced in p10 mice treated with complex-I (C-I) inhibitor, pyridaben (P), or vehicle. Administration of P significantly decreased extent of HI injury. Mitochondria isolated from the ischemic hemisphere in P-treated animals showed reduced H2O2 emission, less oxidative damage to the mitochondrial matrix, and increased tolerance to Ca++ triggered opening of permeability transition pore. Protective effect of P administration was also observed when the reperfusion-driven oxidative stress was augmented by the exposure to 100% O2 which exacerbated brain injury only in V-treated mice. In vitro, intact brain mitochondria dramatically increased H2O2 emission in response to hyperoxia, resulting in substantial loss of Ca++ buffering capacity. However, in the presence of C-I inhibitor, rotenone, or antioxidant, catalase, these effects of hyperoxia were abolished. Our data suggest that the reperfusion-driven recovery of C-I dependent mitochondrial respiration contributes not only to the cellular survival, but also causes an oxidative damage to the mitochondria, potentiating a loss of Ca++ buffering capacity. This highlights a novel neuroprotective strategy against HI-brain injury where the major therapeutic principle is a pharmacological attenuation, rather than an enhancement of mitochondrial oxidative metabolism during early reperfusion. PMID:22378894

  7. Metabolism of biogenic amines in acute cerebral ischemia: Influence of systemic hyperglycemia

    Directory of Open Access Journals (Sweden)

    Milovanović Aleksandar

    2012-01-01

    Full Text Available Dopamine, norepinephrine and serotonin are biogenic amines which are transmitters of the central nervous system. The effects of ischemia on the brain parenchyma depends on many factors, such is the mechanism of blood flow interruption, velocity of the occurring blood flow interruption, duration of an ischemic episode, organization of anatomical structures of the brain blood vessels etc., which all influence the final outcome. During interruption of the brain circulation in experimental or clinical conditions, neurotransmitter metabolism, primarily of biogenic amines, is disturbed. Many researches with various experimental models of complete ischemia reported a decrease in the content of norepinephrine, dopamine and serotonin in the CNS tissue. It was proven that hyperglycemia can drastically increase cerebral injury followed by short-term cerebral ischemia. Considering the fact that biogenic amines (dopamine, norepinephrine and serotonin influence the size of neurologic damage, as well as the fact that in hyperglycemic conditions infarct size (from the morphological aspect is larger relative to normoglycemic status, the intention was to evaluate the role of biogenic amines in occurrence of damage in conditions of hyperglycemia, i.e. in the case of brain apoplexia in diabetics. Analysis of biogenic amines metabolism in states of acute hyperglycemia, as well as analysis of the effects of reversible and irreversible brain ischemia on metabolism of serotonin, dopamine and norepinephrine, showed that acute hyperglycemia slows down serotonin, dopamine and norepinephrine metabolism in the cerebral cortex and n. caudatus. Brain ischemia in normoglycemic animals by itself has no influence on biogenic amines metabolism, but the effect of ischemia becomes apparent during reperfusion. In recirculation, which corresponds to the occurrences in penumbra, release of biogenic amines is uncontrolled and increased. Brain ischemia in acute hyperglycemic animals

  8. Relationship of gelatinases-tight junction proteins and blood-brain barrier permeability in the early stage of cerebral ischemia and reperfusion

    Institute of Scientific and Technical Information of China (English)

    Haolin Xin; Wenzhao Liang; Jing Mang; Lina Lin; Na Guo; Feng Zhang; Zhongxin Xu

    2012-01-01

    Gelatinases matrix metalloproteinase-2 and matrix metalloproteinase-9 have been shown to mediate claudin-5 and occludin degradation, and play an important regulatory role in blood-brain barrier permeability. This study established a rat model of 1.5-hour middle cerebral artery occlusion with reperfusion. Protein expression levels of claudin-5 and occludin gradually decreased in the early stage of reperfusion, which corresponded to the increase of the gelatinolytic activity of matrix metalloproteinase-2 and matrix metalloproteinase-9. In addition, rats that received treatment with matrix metalloproteinase inhibitor N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpenthanoyl]-L- tryptophan methylamide (GM6001) showed a significant reduction in Evans blue leakage and an inhibition of claudin-5 and occludin protein degradation in striatal tissue. These data indicate that matrix metalloproteinase-2 and matrix metalloproteinase-9-mediated claudin-5 and occludin degradation is an important reason for blood-brain barrier leakage in the early stage of reperfusion. The leakage of the blood-brain barrier was present due to gelatinases-mediated degradation of claudin-5 and occludin proteins. We hypothesized that the timely closure of the structural component of the blood-brain barrier (tight junction proteins) is of importance.

  9. Chronic Treatment with a Water-Soluble Extract from the Culture Medium of Ganoderma lucidum Mycelia Prevents Apoptosis and Necroptosis in Hypoxia/Ischemia-Induced Injury of Type 2 Diabetic Mouse Brain

    Directory of Open Access Journals (Sweden)

    Meiyan Xuan

    2015-01-01

    Full Text Available Type 2 diabetes mellitus has been known to increase systemic oxidative stress by chronic hyperglycemia and visceral obesity and aggravate cerebral ischemic injury. On the basis of our previous study regarding a water-soluble extract from the culture medium of Ganoderma lucidum mycelia (designed as MAK, which exerts antioxidative and neuroprotective effects, the present study was conducted to evaluate the preventive effects of MAK on apoptosis and necroptosis (a programmed necrosis induced by hypoxia/ischemia (H/I in type 2 diabetic KKAy mice. H/I was induced by a combination of unilateral common carotid artery ligation with hypoxia (8% O2 for 20 min and subsequent reoxygenation. Pretreatment with MAK (1 g/kg, p.o. for a week significantly reduced H/I-induced neurological deficits and brain infarction volume assessed at 24 h of reoxygenation. Histochemical analysis showed that MAK significantly suppressed superoxide production, neuronal cell death, and vacuolation in the ischemic penumbra, which was accompanied by a decrease in the numbers of TUNEL- or cleaved caspase-3-positive cells. Furthermore, MAK decreased the expression of receptor-interacting protein kinase 3 mRNA and protein, a key molecule for necroptosis. These results suggest that MAK confers resistance to apoptotic and necroptotic cell death and relieves H/I-induced cerebral ischemic injury in type 2 diabetic mice.

  10. 菟丝子醇提液对小鼠脑缺血再灌注损伤的保护作用%Effect of Alcoholic Extraction of Cuscutae Semen on Brain Ischemia-Reperfusion in Mice

    Institute of Scientific and Technical Information of China (English)

    王嘉毅; 杨柳; 郑维兵; 张毅

    2013-01-01

    Objective To study the improvement of alcoholic extraction of cuscutae semen (AECS) on learning and memory impairment induced by cerebral ischemia- reperfusion (I/R) in mice, as well as its effect and mechanism on the the activities of relative enzymes in the liver and brain tissues. Methods AECS was obtained by ultrasonic extraction. Cerebral I/R injury was produced in conscious mice by temporarily obstructing bilateral common carotid arteries. The protective effects of three different doses of AECS on learning and memory impairment in I/R mice were observed using the passive avoidance test and biochemical methods of observing the glutathione peroxidase (GSH-Px) activities in liver and brain. Results The medium and high doses of AECS could decrease the number of error and prolong the latent time in passive avoidance test and increase the activity of GSH-Px in brain and liver tissues. Conclusion AECS shows protective effects on learning and memory impairment of mice induced by cerebral I/R injury. The possible mechanism was argued that AECS can increase the activity of GSH-Px in brain and liver tissues.%  目的探讨菟丝子醇提液(AECS)对脑缺血再灌注(I/R)小鼠学习记忆障碍的改善作用,对肝脑组织中相关酶的作用及其作用机制。方法利用超声提取法制备AECS;采用暂时性阻断两侧颈总动脉的方法制备小鼠脑I/R损伤的模型,进行避暗实验,观察AECS对小鼠学习记忆功能的保护作用;生化方法测定肝脑组织中谷胱甘肽过氧化物酶(GSH-Px)活性。结果AECS中、高剂量可明显减少脑I/R小鼠避暗实验中错误次数,延长潜伏期;AECS中、高剂量能不同程度地提高肝、脑组织中GSH-Px活性。结论AECS对脑I/R所致小鼠记忆功能障碍具有保护作用,其作用机制可能为增强肝、脑组织中GSH-Px活性。

  11. Tamoxifen mediated estrogen receptor activation protects against early impairment of hippocampal neuron excitability in an oxygen/glucose deprivation brain slice ischemia model.

    Science.gov (United States)

    Zhang, Huaqiu; Xie, Minjie; Schools, Gary P; Feustel, Paul F; Wang, Wei; Lei, Ting; Kimelberg, Harold K; Zhou, Min

    2009-01-09

    Pretreatment of ovarectomized rats with estrogen shows long-term protection via activation of the estrogen receptor (ER). However, it remains unknown whether activation of the ER can provide protection against early neuronal damage when given acutely. We simulated ischemic conditions by applying oxygen and glucose deprived (OGD) solution to acute male rat hippocampal slices and examined the neuronal electrophysiological changes. Pyramidal neurons and interneurons showed a time-dependent membrane potential depolarization and reduction in evoked action potential frequency and amplitude over a 10 to 15 min OGD exposure. These changes were largely suppressed by 10 microM TAM. The TAM effect was neuron-specific as the OGD-induced astrocytic membrane potential depolarization was not altered. The TAM effect was mediated through ER activation because it could be simulated by 17beta-estradiol and was completely inhibited by the ER inhibitor ICI 182, 780, and is therefore an example of TAM's selective estrogen receptor modulator (SERM) action. We further show that TAM's effects on OGD-induced impairment of neuronal excitability was largely due to activation of neuroprotective BK channels, as the TAM effect was markedly attenuated by the BK channel inhibitor paxilline at 10 microM. TAM also significantly reduced the frequency and amplitude of AMPA receptor mediated spontaneous excitatory postsynaptic currents (sEPSCs) in pyramidal neurons which is an early consequence of OGD. Altogether, this study demonstrates that both 17beta-estradiol and TAM attenuate neuronal excitability impairment early on in a simulated ischemia model via ER activation mediated potentiation of BK K(+) channels and reduction in enhanced neuronal AMPA/NMDA receptor-mediated excitotoxicity.

  12. Prodigiosin inhibits gp91{sup phox} and iNOS expression to protect mice against the oxidative/nitrosative brain injury induced by hypoxia-ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Chia-Che [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan (China); Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan (China); Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan (China); Wang, Yea-Hwey [Department of Nursing, College of Medicine and Nursing, Hungkuang University, Taichung, Taiwan (China); Chern, Chang-Ming [Division of Neurovascular Disease, Neurological Institute, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei, Taiwan (China); Liou, Kuo-Tong [Department of Chinese Martial Arts, Chinese Culture University, Taipei, Taiwan (China); Hou, Yu-Chang [Department of Chinese Medicine, Taoyuan General Hospital, Department of Health, Taiwan (China); Department of Nursing, Yuanpei University, Hsinchu, Taiwan (China); Department of Bioscience Technology, Chuan-Yuan Christian University, Taoyuan, Taiwan (China); Peng, Yu-Ta [Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China); Shen, Yuh-Chiang, E-mail: yuhcs@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei, Taiwan (China); Institute of Biomedical Sciences, National Chung-Hsing University, Taichung, Taiwan (China)

    2011-11-15

    This study aimed to explore the mechanisms by which prodigiosin protects against hypoxia-induced oxidative/nitrosative brain injury induced by middle cerebral artery occlusion/reperfusion (MCAo/r) injury in mice. Hypoxia in vitro was modeled using oxygen-glucose deprivation (OGD) followed by reoxygenation of BV-2 microglial cells. Our results showed that treatment of mice that have undergone MCAo/r injury with prodigiosin (10 and 100 {mu}g/kg, i.v.) at 1 h after hypoxia ameliorated MCAo/r-induced oxidative/nitrosative stress, brain infarction, and neurological deficits in the mice, and enhanced their survival rate. MCAo/r induced a remarkable production in the mouse brains of reactive oxygen species (ROS) and a significant increase in protein nitrosylation; this primarily resulted from enhanced expression of NADPH oxidase 2 (gp91{sup phox}), inducible nitric oxide synthase (iNOS), and the infiltration of CD11b leukocytes due to breakdown of blood-brain barrier (BBB) by activation of nuclear factor-kappa B (NF-{kappa}B). All these changes were significantly diminished by prodigiosin. In BV-2 cells, OGD induced ROS and nitric oxide production by up-regulating gp91{sup phox} and iNOS via activation of the NF-{kappa}B pathway, and these changes were suppressed by prodigiosin. In conclusion, our results indicate that prodigiosin reduces gp91{sup phox} and iNOS expression possibly by impairing NF-{kappa}B activation. This compromises the activation of microglial and/or inflammatory cells, which then, in turn, mediates prodigiosin's protective effect in the MCAo/r mice. -- Highlights: Black-Right-Pointing-Pointer Prodigiosin ameliorated brain infarction and deficits. Black-Right-Pointing-Pointer Prodigiosin protected against hypoxia/reperfusion-induced brain injury. Black-Right-Pointing-Pointer Prodigiosin diminished oxidative/nitrosativestress and leukocytes infiltration. Black-Right-Pointing-Pointer Prodigiosin reduced BBB breakdown. Black

  13. Silent myocardial ischemia.

    Science.gov (United States)

    Gutterman, David D

    2009-05-01

    Although much progress has been made in reducing mortality from ischemic cardiovascular disease, this condition remains the leading cause of death throughout the world. This might in part be due to the fact that over half of patients have a catastrophic event (heart attack or sudden death) as their initial manifestation of coronary disease. Contributing to this statistic is the observation that the majority of myocardial ischemic episodes are silent, indicating an inability or failure to sense ischemic damage or stress on the heart. This review examines the clinical characteristics of silent myocardial ischemia, and explores mechanisms involved in the generation of angina pectoris. Possible mechanisms for the more common manifestation of injurious reductions in coronary flow; namely, silent ischemia, are also explored. A new theory for the mechanism of silent ischemia is proposed. Finally, the prognostic importance of silent ischemia and potential future directions for research are discussed.

  14. Study of transient ischemia attack by brain single-photon emission CT%短暂性脑缺血发作患者SPECT脑显像的研究

    Institute of Scientific and Technical Information of China (English)

    张翼; 莫颖敏; 韦春英; 杨彭; 陶然

    2011-01-01

    Objective: Study on the clinical value of SPECT, evaluating whether transient ischemia attack (TIA) progressed to cerebral infarction. Methods : We conducted brain SPECT and MRI in 97 transient ischemia attack of internal carotid artery system within 72 hours. Patients were semi-quantitative analyzed from the total counts obtained from each region of interest the asymmetry index (AI) was calculated as follows : 〔( value in unaffected region-value in afected region)/value in unaffected region〕 ×lOO. The patients were divided into 3 groups according to the grade of AI. Clinic assessment of patients were performed at the 6 monhs of the onset of TIA. Analyzing the relationship among brain hypoperfusion,progressing to cerebral infarction, frequency. duration of attacks and history of stroke. Results : 97 TIA patients divided into 3 groups by asymmetry index ( Al). The 3 groups were different in progressing to cerebral infarction, frequency, duration of attacks and history of stroke. 35 patients progressing to cerebral infarction were different from the others in Al,frequency, duration of attacks and history of stroke. Conclusion: SPECT can be used to assess the cerebral blood flow and predict prognosis. The decrement of brain hypoperfusion increase risk of stroke, which should be positive treatment.%目的:探讨SPECT脑血流灌注显像评估短暂性脑缺血发作(TIA)进展为脑梗死的临床应用价值.方法:对97例颈内动脉系统TIA患者发病72h内进行SPECT脑血流灌注显像及磁共振检查.对感兴趣区放射性计数进行半定量分析,按如下公式计算脑血流的不对称指数(AI):[(正常区域放射性计数-感兴趣区放射性计数)/正常区域放射性计数]×100.人组患者根据不对称指数分为轻度(AI≤5)、中度(5<AI≤10=、重度(AI>10)组.发病6个月后对各组患者进行临床评估,分析低灌注程度与是否进展为脑梗死、发作持续时间、发作次数及

  15. THE EFFECT OF ANISODAMINE ON CEREBRAL RESUSCITATION OF RATS IN ACUTE CEREBRAL ISCHEMIA FROM CARDIAC ARREST

    Institute of Scientific and Technical Information of China (English)

    彭新琦; 曹苏谊; 可君

    1995-01-01

    In order to investigate the mechanisms of acute cerebral ischemia,and to look for effective drugs on cerebral resuscitation,we made a model of acute complete global brain ischemia,reperfusion and resuscita-tion on rats according to Garavilla's method.Our results showed that the event of cerebral ischemia and reperfusion injury could result in the in-crease of total brain calcium content,and anisodamine has the same reducing brain calcium contents as dil-tiazem's,while improving neurological outcome and alleviating injury to neurons.

  16. Neuroprotective effects of female sex steroids in cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Drača Sanja

    2013-03-01

    Full Text Available The central and peripheral nervous system are important targets of sex steroids. Sex steroids affect the brain development and differentiation, and influence neuronal functions. Recent evidence emphasizes a striking sex-linked difference in brain damage after experimental stroke, as well as the efficacy of hormones in treating cerebral stroke injury. Several different models of cerebral ischemia have been utilized for hormone neuroprotection studies, including transient or permanent middle cerebral artery occlusion, transient global ischemia, and transient forebrain ischemia. Extensive experimental studies have shown that female sex steroids such as progesterone and 176-estradiol exert neuroprotective effects in the experimental models of stroke, although deleterious effects have also been reported. Also, a significance of numerous factors, including gender and age of experimental animals, localization of brain lesion, duration of ischemia and precise dose of steroids has been pointed out. There are multiple potential mechanisms that might be invoked to explain the beneficial effects of female sex steroids in brain injury, involving neuroprotection, anti-inflammatory properties, effects on vasculature and altered transcriptional regulation. A several clinical trials on the effects of sex hormones to traumatic brain injury have been performed, suggesting that hormone therapy may represent a new therapeutic tool to combat certain diseases, such as traumatic brain injury. Further basic science studies and randomized clinical trials are necessary to reveal a potential application of these molecules as a new therapeutic strategy.

  17. Orally Administrated Ascorbic Acid Suppresses Neuronal Damage and Modifies Expression of SVCT2 and GLUT1 in the Brain of Diabetic Rats with Cerebral Ischemia-Reperfusion

    Directory of Open Access Journals (Sweden)

    Naohiro Iwata

    2014-04-01

    Full Text Available Diabetes mellitus is known to exacerbate cerebral ischemic injury. In the present study, we investigated antiapoptotic and anti-inflammatory effects of oral supplementation of ascorbic acid (AA on cerebral injury caused by middle cerebral artery occlusion and reperfusion (MCAO/Re in rats with streptozotocin-induced diabetes. We also evaluated the effects of AA on expression of sodium-dependent vitamin C transporter 2 (SVCT2 and glucose transporter 1 (GLUT1 after MCAO/Re in the brain. The diabetic state markedly aggravated MCAO/Re-induced cerebral damage, as assessed by infarct volume and edema. Pretreatment with AA (100 mg/kg, p.o. for two weeks significantly suppressed the exacerbation of damage in the brain of diabetic rats. AA also suppressed the production of superoxide radical, activation of caspase-3, and expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-1β in the ischemic penumbra. Immunohistochemical staining revealed that expression of SVCT2 was upregulated primarily in neurons and capillary endothelial cells after MCAO/Re in the nondiabetic cortex, accompanied by an increase in total AA (AA + dehydroascorbic acid in the tissue, and that these responses were suppressed in the diabetic rats. AA supplementation to the diabetic rats restored these responses to the levels of the nondiabetic rats. Furthermore, AA markedly upregulated the basal expression of GLUT1 in endothelial cells of nondiabetic and diabetic cortex, which did not affect total AA levels in the cortex. These results suggest that daily intake of AA attenuates the exacerbation of cerebral ischemic injury in a diabetic state, which may be attributed to anti-apoptotic and anti-inflammatory effects via the improvement of augmented oxidative stress in the brain. AA supplementation may protect endothelial function against the exacerbated ischemic oxidative injury in the diabetic state and improve AA transport through SVCT2 in the cortex.

  18. PNIPAM nanoparticles for targeted and enhanced nose-to-brain delivery of curcuminoids: UPLC/ESI-Q-ToF-MS/MS-based pharmacokinetics and pharmacodynamic evaluation in cerebral ischemia model.

    Science.gov (United States)

    Ahmad, Niyaz; Ahmad, Iqbal; Umar, Sadiq; Iqbal, Zeenat; Samim, Mohd; Ahmad, Farhan Jalees

    2016-09-01

    Stroke is a one of the leading causes of disease and deaths worldwide, which causes irreversible deterioration of the central nervous system. Curcuminoids are reported to have a potential role in the amelioration of cerebral ischemia but they exhibit low serum and tissue levels due to low solubility and poor absorption. Curcumin (CUR), demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC)-loaded PNIPAM nanoparticles (NPs) were prepared by free radical polymerization and characterized for particles size, entrapment efficiency, zeta potential, in vitro release and ex vivo permeation study. Optimized CUR, DMC and BDMC-loaded NPs had the mean size of 92.46 ± 2.8, 91.23 ± 4.2 and 94.28 ± 1.91 nm; zeta potential of -16.2 ± 1.42, -15.6 ± 1.33 and -16.6 ± 1.21 mV; loading capacity of 39.31 ± 3.7, 38.91 ± 3.6 and 40.61 ± 3.6% and entrapment efficiency of 84.63 ± 4.2, 84.71 ± 3.99 and 85.73 ± 4.31%, respectively. Ultra-performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectroscopy based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency and brain drug-targeting potential studies post-intranasal (i.n.) administration which showed enhanced bioavailability of curcuminoids in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) and reduced cytokines levels (TNF-α and IL-1β) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of curcuminoids NPs. Finally, the toxicity study was performed which revealed safe nature of developed NPs.

  19. Granulocyte colony stimulating factor reduces brain injury in a cardiopulmonary bypass-circulatory arrest model of ischemia in a newborn piglet

    Science.gov (United States)

    Pastuszko, Peter; Schears, Gregory J.; Greeley, William J.; Kubin, Joanna; Wilson, David F.; Pastuszko, Anna

    2014-01-01

    Background Ischemic brain injury continues to be of major concern in patients undergoing cardiopulmonary bypass (CPB) surgery for congenital heart disease. Striatum and hippocampus are particularly vulnerable to injury during these processes. Our hypothesis is that the neuronal injury resulting from CPB and the associated circulatory arrest can be at least partly ameliorated by pre-treatment with granulocyte colony stimulating factor (G-CSF). Material and Methods Fourteen male newborn piglets were assigned to three groups: deep hypothermic circulatory arrest (DHCA), DHCA with G-CSF, and sham-operated. The first two groups were placed on CPB, cooled to 18°C, subjected to 60 min of DHCA, re-warmed and recovered for 8-9 hrs. At the end of experiment, the brains were perfused, fixed and cut into 10 μm transverse sections. Apoptotic cells were visualized by in-situ DNA fragmentation assay (TUNEL), with the density of injured cells expressed as a mean number ± SD per mm2. Results The number of injured cells in the striatum and CA1 and CA3 regions of the hippocampus increased significantly following DHCA. In the striatum, the increase was from 0.46±0.37 to 3.67±1.57 (p=0.002); in the CA1, from 0.11±0.19 to 5.16±1.57 (p=0.001), and in the CA3, from 0.28±0.25 to 2.98±1.82 (p=0.040). Injection of G-CSF prior to bypass significantly reduced the number of injured cells in the striatum and CA1 region, by 51% and 37%, respectively. In the CA3 region, injured cell density did not differ between the G-CSF and control group. Conclusion In a model of hypoxic brain insult associated with CPB, G-CSF significantly reduces neuronal injury in brain regions important for cognitive functions, suggesting it can significantly improve neurological outcomes from procedures requiring DHCA. PMID:25082120

  20. 果糖二磷酸钠镁对鼠脑缺血-再灌注损伤的保护作用%Protective Effects of Sodium Magnesium Fructose Diphosphate on Brain Damage of Rats Subjected to Focal Cerebral Ischemia and Reperfusion

    Institute of Scientific and Technical Information of China (English)

    董志; 曾凡新; 周岐新; 傅洁民; 薛春生

    2002-01-01

    目的:三究果糖二磷酸钠镜头(FDPM)对大鼠脑缺备一再灌注引起脑损伤的保护作用.方法:自大鼠颈总动脉插入尼龙线栓栓塞大脑中动脉,造成大脑缺血,拔出线栓实线灌注.脑缺血10 min后给予400 mg·kg-1FDPM,400 mg·kg-1FDP及30mg·kg-1MgSO4,分别于脑缺血1h再灌注2h,5h和23h分别进行神经病学评分,并于脑缺血1h再灌注23h时测定脑梗塞面积及脑组织MDA含量,观察大脑组织病理学变化.结果:FDPM降低脑血一再灌注大鼠神经病学评分,缩小脑梗塞面积,降低脑组织MDA含量,减轻光镜下脑组织的病理改变.其作用强于FDP或MgSO4.结论:FDPM可显著保护大脑缺血再灌注引起的脑损伤,其作用单用FDP或MgSO4.%Objective: To study the effects of sodium magnesiusm fructose diphesphate(FDPM) on brain dsmage of rais after ischemia-reperfusion. Methods: Rats were subjected to cerebral ischemia-reperfusion induced by inserting a nylon thread into internal carotid artery to block the origin of middle cerebral artery and removing the thread later.FDPM (400 mg·kg-1)fructose-l,6-diphosphate(FDP, 400 mg·kg- 1)and magnesium sulfate (MgSO4, 30 mg·kg-1) were administrated 10 min af ter the onset of ischemia. Neurological scale, brain infarct area, Malondialdehyde(MDA) content and histopathological chang es of brain tissue were studied. Results: FDPM decreased neurological scale, diminished brain infarct area, reduced MDA content and relieved histopathologial change of rat brain tissue subjJected to ischemia-repefusion. These effecis were more powerful than that of FDP or MgSO4.Conclusions:It is suggested that FDPM markedly preventad rats against brain damage after cerebral ischmia-reperfusion,and its effect was better than that of FDP or MgSO4.

  1. Oxidative damage following cerebral ischemia depends on reperfusion - a biochemical study in rat

    DEFF Research Database (Denmark)

    Nita, D A; Nita, V; Spulber, S;

    2002-01-01

    The extent of brain injury during reperfusion appears to depend on the experimental pattern of ischemia/reperfusion. The goals of this study were: first, to identify the rate of free radicals generation and the antioxidant activity during ischemia and reperfusion by means of biochemical measureme...

  2. Microglia protect neurons against ischemia by synthesis of tumor necrosis factor

    DEFF Research Database (Denmark)

    Lambertsen, Kate Lykke; Clausen, Bettina Hjelm; Babcock, Alicia Anne;

    2009-01-01

    Microglia and infiltrating leukocytes are considered major producers of tumor necrosis factor (TNF), which is a crucial player in cerebral ischemia and brain inflammation. We have identified a neuroprotective role for microglial-derived TNF in cerebral ischemia in mice. We show that cortical infa...

  3. Hippocampal neurogenesis in the new model of global cerebral ischemia

    Science.gov (United States)

    Kisel, A. A.; Chernysheva, G. A.; Smol'yakova, V. I.; Savchenko, R. R.; Plotnikov, M. B.; Khodanovich, M. Yu.

    2015-11-01

    The study aimed to evaluate the changes of hippocampal neurogenesis in a new model of global transient cerebral ischemia which was performed by the occlusion of the three main vessels (tr. brachiocephalicus, a. subclavia sinistra, and a. carotis communis sinistra) branching from the aortic arch and supplying the brain. Global transitory cerebral ischemia was modeled on male rats (weight = 250-300 g) under chloral hydrate with artificial lung ventilation. Animals after the same surgical operation without vessel occlusion served as sham-operated controls. The number of DCX-positive (doublecortin, the marker of immature neurons) cells in dentate gyrus (DG) and CA1-CA3 fields of hippocampus was counted at the 31st day after ischemia modeling. It was revealed that global cerebral ischemia decreased neurogenesis in dentate gyrus in comparison with the sham-operated group (Pneurogenesis in CA1-CA3 fields was increased as compared to the control (P<0.05).

  4. The role of miR-182 in regulating pineal CLOCK expression after hypoxia-ischemia brain injury in neonatal rats.

    Science.gov (United States)

    Ding, Xin; Sun, Bin; Huang, Jian; Xu, Lixiao; Pan, Jian; Fang, Chen; Tao, Yanfang; Hu, Shukun; Li, Ronghu; Han, Xing; Miao, Po; Wang, Ying; Yu, Jian; Feng, Xing

    2015-03-30

    Circadian rhythm disorder is a common neurological deficit caused by neonatal hypoxic-ischemic brain damage (HIBD). However, little is known about its underlying mechanisms. Our previous studies revealed a significant elevation of clock genes at the protein, but not mRNA, levels in the pineal gland after neonatal HIBD. To investigate the mechanisms of post-transcriptional regulation on clock genes, we screened changes of miRNA levels in the pineal gland after neonatal HIBD using high-throughput arrays. Within the miRNAs whose expression was significantly down-regulated, we identified one miRNA (miR182) that targeted the 3'-untranslated region (3'-UTR) of Clock, a key component of clock genes, and played a crucial role in regulating CLOCK expression after oxygen-glucose deprivation in primarily cultured pinealocytes. Our findings therefore provide new insight on studies of therapeutic targets for circadian rhythm disturbance after neonatal HIBD.

  5. Focal cerebral ischemia induces increased myelin basic protein and growth-associated protein-43 gene transcription in peri-infarct areas in the rat brain

    DEFF Research Database (Denmark)

    Gregersen, R; Christensen, Thomas; Lehrmann, E;

    2001-01-01

    , in peri-infarct areas in adult rat brain after transient middle cerebral artery occlusion (MCAO) and correlated it to the expression of the growth-associated protein-43 (GAP-43), a marker for axonal regeneration and sprouting, using non-radioactive in situ hybridization techniques. Within the infarct, MBP......, corresponding to the appearance of process-bearing MBP and occasional MOG-immunoreactive oligodendrocytes in parallel sections. Quantitative analysis revealed significant increases in the density of oligodendrocytes (up to 7.6-fold) and in the level of MBP mRNA expressed by individual cells. Parallel sections...... showed that increased expression of GAP-43 mRNA in neurons was concomitant to MBP mRNA upregulation in oligodendrocytes. While the mechanisms regulating oligodendrocyte survival and myelination signals are not clear at this point, axonal sprouting could putatively serve as a stimulus for the upregulation...

  6. 陷窝蛋白在脑缺血后血脑屏障破坏中的作用%Role of caveolins in the blood-brain barrier disruption after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    王昭君; 王刘敏; 林颖; 刘亚红

    2016-01-01

    陷窝蛋白是陷窝的主要组成蛋白,也是实现其生理功能的重要蛋白。陷窝蛋白表达于平滑肌细胞、内皮细胞和脂肪细胞。陷窝既参与了细胞的脂肪摄取、胞吞和胞饮等基本生理过程,也对细胞的信号转导以及大分子物质的转运和通透起着非常重要的作用。随着对陷窝蛋白的分子构成和生物化学功能研究的深入,越来越多的研究表明陷窝及其主要成分陷窝蛋白在脑血管病的病理生理学过程起着重要作用。文章就陷窝蛋白在脑缺血后血脑屏障破坏中的作用进行了综述。%Caveolins are the major component proteins of the caveolae, and they are also the essential proteins to carry out the physiological functions of caveolae. Caveolins are expressed in smooth muscle cels, endothelial cels, and adipocytes. Caveolae are not only involved in the basic physiological processes, such as celular fat intake, endocytosis, and pinocytosis, but also play a very important role in cel signal transduction and transport and permeability of macromolecular substance. With the in-depth research on the molecular structure and biochemical function of caveolins, increasing studies have shown that caveolae and their main component caveolins play an important role in the pathophysiological process of cerebrovascular diseases. This article reviews the roles of caveolins in the blood-brain barrier destruction after cerebral ischemia.

  7. Post-Traumatic Late Onset Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Gencer Genc

    2014-03-01

    Full Text Available Artery-to-artery emboli or occlusion of craniocervical arteries mostly due to dissection are the most common causes of ischemia after trauma. A 29 year-old male had been admitted to another hospital with loss of consciousness lasting for about 45 minutes after a hard parachute landing without head trauma three days ago. As his neurological examination and brain CT were normal, he had been discharged after 24 hours of observation. Two days after his discharge, he was admitted to our department with epileptic seizure. His neurological examination revealed left hemianopia. After observing occipital subacute ischemia at right side in brain magnetic resonance imaging (MRI, we performed cerebral angiography and no dissection was observed. Excluding the rheumatologic, cardiologic and vascular events, our final diagnosis was late onset cerebral ischemia. Anti-edema and antiepileptic treatment was initiated. He was discharged with left hemianopia and mild cognitive deficit. We suggest that it will be wise to hospitalize patients for at least 72 hours who has a history of unconsciousness following trauma.

  8. Amniotic cells protect and repair mouse brain cells following ischemia-reperfusion injury%羊膜细胞可保护和修复缺血再灌注损伤小鼠脑组织细胞

    Institute of Scientific and Technical Information of China (English)

    郑彦涛; 刘斌; Robert Lodato; 李奇林; 蓝迪慧; 洪小英; 鲜华

    2014-01-01

    背景:羊膜细胞主要由羊膜上皮细胞和羊膜间充质细胞组成,均具有多分化潜能,可转化为神经元,且还有合成、释放生物活性物质和神经营养因子的功能。作者前期研究证实羊膜细胞移植入脑内后,能明显促进脑内神经元的再生。目的:探索羊膜细胞对小鼠缺血再灌注损伤脑细胞的作用。方法:将Balb/C小鼠通过夹闭双侧颈总动脉方法建立脑缺血再灌注损伤模型后,分离小鼠脑细胞。取孕鼠新鲜胎盘,分离羊膜细胞。将与羊膜细胞共培养的小鼠脑细胞作为实验组,以PBS培养的小鼠脑细胞作为对照组。结果与结论:实验组小鼠脑细胞活性较对照组明显增加(P0.05),而培养48 h后实验组小鼠脑细胞坏死率较对照组明显降低(P0.05);after 48 hours co-culture, however, the necrotic rate of brain cells was significantly lower in the experimental group than the control group (P<0.05). In cellcycle, the experiment group showed increased S phase cells;while, the control group exhibited increased G 1 phase cells and decreased S phase cells. G 2 phase cells had no changes in number in both two groups. Through the above results, amnion cells can be proved to protect and promote the regeneration of brain cells of Balb/C mice with ischemia-reperfusion injury, and inhibit cellnecrosis and apoptosis.

  9. 甲状腺激素转运体MCT8在2VO大鼠脑组织中的表达%Expression of monocarboxylate transporter 8 mRNA in the brain tissue of rats with cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    崔丹; 管玉青; 蒋海山; 汪槿; 席蕾; 王群

    2012-01-01

    目的 探讨2VO大鼠脑组织中甲状腺激素转运体MCT8在不同缺血时间点基因水平的变化规律.方法 25只成年雄性SD大鼠随机分为正常对照组、2VO 3 d组、2VO 2周组和2VO 5周组.采用免疫荧光法观察MCT8在正常大鼠侧脑室中的表达;采用双侧颈总动脉永久性结扎术制备脑缺血模型,术后各组大鼠于实验终点采用荧光定量PCR法测定脑组织中甲状腺激素转运体MCT8 mRNA的表达水平.结果 免疫荧光法观察到MCT8在正常大鼠侧脑室的血管内皮细胞膜上表达丰富;中枢甲状腺激素转运体MCT8 mRNA水平在2VO 3 d组及2VO 2周组与正常组相比较差异无统计学意义(P=-0.909,P=0.694);MCT8 mRNA水平在2VO 5周组较正常组及2VO 3 d组明显增高(P=0.029,P=0.023),与2VO 2周组相比较差异无统计学意义(P=0.065).结论 中枢甲状腺激素转运体MCT8基因水平在脑缺血后呈逐渐代偿性增高趋势.%Objective To investigate the mRNA expression of monocarboxylate transporter 8 (MCT8),a thyroid hormone transport protein,in the lateral ventricle of rats with cerebral ischemia.Methods Immunofluorescence staining was used to observe the expression of MCT8 in the lateral ventricle of 5 normal SD rats.Another 20 adult male SD rats were randomized into 4 groups and subject to permanent ligation of both the common carotid arteries (2-vessel occlusion,2VO) for 3 days,2 weeks,or 5 weeks,or no ligation (control).At the end of the experiment,the transcriptional level of MCT8 in the brain tissue of the rats were detected using fluorescent quantitative PCR.Results MCT8 mRNA levels in 3-day and 2-week 2VO groups were comparable with that in the control group (P=0.909;P=0.694),but increased significantly in 5-week 2VO group compared with that in the control and 3-day 2VO groups (P=0.029;P=0.023).No significance was found in MCT8 mRNA between the 2-week and 5-week 2VO groups (P=0.065).Conclusion Prolonged cerebral ischemia causes

  10. The mechanism of protective effects of melatonin on global ischemia/reperfusion induced brain injury in rats%褪黑激素对大鼠缺血/再灌注所致脑损伤的保护机制

    Institute of Scientific and Technical Information of China (English)

    饶煜; 库宝善

    2001-01-01

    Objective: To study the effects of melatonin(MT) on inducible nitric oxide synthase (iNOS) expression in hippocampal CA1 at 24 hours and TDT-mediated dUPT nick end labling (TUNEL) positive cells in hippocampal CA1 at 48 hours after global ischemia(20 min)/ reperfusion in rats. Methods: MT was injected intraperitoneally at 0 h, 1 h, 2 h and 6 h after ischemia(20 min) induced by the“occlusion of four arteries”, 2.5 mg*kg-1 or 10 mg*kg-1 each time, respectively. Researching the expression of iNOS in hippocampal CA1 with the immunocytochemistry method 24 hours after reperfusion and the number of TUNEL positive cells in hippocampal CA1 48 hours after reperfusion utilizing TUNEL. Results: At these doses, MT could decrease iNOS expression in hippocampal CA1 at 24 h after global ischemia (20 min)/reperfusion and the number of TUNEL cells in hippocampal CA1 at 48h after reperfusion in rats. Conclusion: Decreasing the expression of deleterious iNOS maybe one of the mechanisms involved in protective action of MT on ischemia-vulnerable brain region.%目的:研究褪黑激素(melatonin, MT)对大鼠全脑缺血(20 min)再灌注后24 h海马CA1区诱导型一氧化氮合酶(inducible nitric oxide synthase , iNOS)的蛋白质水平和再灌注后48h海马CA1区TUNEL阳性细胞数的影响。方法:于大鼠“四动脉结扎法”全脑缺血(20 min)/再灌注后第0、1、2、6小时4个时间点分别腹腔注射MT2.5和10 mg*kg-1两个剂量,各组大鼠再灌后24 h后用免疫细胞化学法检测海马CA1区iNOS蛋白水平,用末端脱氧核糖核苷酸转移酶介导的dUTP缺口末端标记法(TDT mediated dUTP nick end labling, TUNEL)计算了各组大鼠再灌后48 h海马CA1区TUNEL阳性细胞数。结果:MT2.5 mg*kg-1和10 mg*kg-1两个剂量于大鼠全脑缺血(20 min)/再灌注后第0、1、2、6小时4个时间点分别腹腔注射可降低再灌注24 h大鼠海马CA1区iNOS的蛋

  11. Curcumin reduces inflammatory reactions following transient cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Jing Zhao; Shanshan Yu; Lan Li; Xuemei Lin; Yong Zhao

    2011-01-01

    Inflammatory reactions are important pathophysiological mechanisms of ischemic brain injury. The present study analyzed the anti-inflammatory characteristics of curcumin via myeloperoxidase activity and nitric oxide content after 2-hour ischemia/24-hour reperfusion in Sprague Dawley rats. In addition, expressions of nuclear factor kappa B, tumor necrosis factor-α and interleukin-1β protein were measured. Curcumin significantly reduced myeloperoxidase and nitric oxide synthase activities and suppressed expressions of nuclear factor kappa B, tumor necrosis factor-a, and interleukin-1β in ischemia/reperfusion brain tissue. Results suggested that the neuroprotective effect of curcumin following cerebral ischemia/reperfusion injury could be associated with inhibition of inflammatory reactions.

  12. Free Radicals and Matrix Metalloproteinases in Blood-Brain Barrier Disruption after Cerebral Ischemia%自由基和基质金属蛋白酶介导脑缺血血脑屏障损伤的研究进展

    Institute of Scientific and Technical Information of China (English)

    戚智锋; 罗玉敏; 刘克建

    2012-01-01

    血脑屏障的破坏是引起脑缺血损伤及继发水肿、出血、炎症的微观原因.缺血缺氧和再灌注过程产生的自由基,以及后续基质金属蛋白酶的激活,是破坏血脑屏障结构和功能的重要分子机制.因而,在脑缺血早期及时抑制自由基产生并清除自由基,抑制基质金属蛋白酶的活性,是降低脑缺血血脑屏障损伤及其并发症的关键环节.本文将从血脑屏障损伤的角度,概述自由基与基质金属蛋白酶在脑缺血损伤过程中的作用.%Cerebral ischemia results in the compromise of blood-brain barrier (BBB) integrity, leading to neurovascular complications, including cerebral hemorrhage, edema, and inflammation. Free radicals and matrix metalloproteinases (MMPs) are critically involved in the mechanism of BBB breakdown following cerebral ischemia and reperfusion. Scavenging free radicals and inhibiting activation of MMPs are potential strategies to protect BBB integrity and reduce ischemia complications. In this review, we will focus on the the role of free radicals and MMPs activation in BBB damages in cerebral ischemia.

  13. 脑缺血后大脑皮质神经生长因子和脑源性神经营养因子的改变%The Change of Nerve Growth Factor and Brain Derived Neurotrophic Factor in Neurons of Cerebral Cortex of Adult Rat Following Local Ischemia

    Institute of Scientific and Technical Information of China (English)

    曾兢; 王廷华; 张晓; 米兰兰; 高礼

    2001-01-01

    【内容摘要】目的探讨脑缺血后大脑皮质神经生长因子(NGF)、脑源性神经营养因子(BDNF)的变化。方法采用免疫组织化学ABC法观察NGF和BDNF的改变。结果 NGF、BDNF样免疫阳性反应物主要分布于大脑皮质第3、5层的神经元。脑缺血1小时后,NGF、BDNF在皮质神经元的表达明显增加。结论 NGF、BDNF与脑缺血后大脑皮质神经细胞的损伤修复有关。%Objective To acquire knowledge about the change of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in neurons of cerebral cortex of adult rat following local ischemia. Methods Using specific antiserums of NGF and BDNF by immunohistochemical ABC method. Results NGF-like and BDNF-like immunoreactions distributed mainly in the neurons of the third and fifth layers in cerebral cortex. After local ischemia, the average gray degrees of NGF and BDNF in neurons of cerebral cortex both decreased on the operated side more than on the un-operated side. Conclusion This experiment demonstrated that the levels of NGF and BDNF in neurons of cerebral cortex following ischemia were upregulated apparently, suggesting that NGF and BDNF may play an important role in the process of neurons' reaction after ischemia.

  14. The neuroprotection of Aspirin on Cerebral Ischemia-Reperfusion rats

    Institute of Scientific and Technical Information of China (English)

    QiuLi-ying; YuJuan; ChenChong-hong; ZhouYu

    2004-01-01

    AIM: Aspirin (aeetylsalicylic acid, ASA as a nonsteroidal anti-inflammatory drug not only has well-established efficacy in anti-thromboxane, but also has direct neuroprotective effect. In this study, we design to investigate its neuroprotective effect on focal cerebral ischemia-reperfusion injury (CIRI rats, and its effect on ATP level from occluded brain tis-

  15. Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury**

    Institute of Scientific and Technical Information of China (English)

    Chunlin Yan; Ji Zhang; Shu Wang; Guiping Xue; Yong Hou

    2013-01-01

    Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia reperfusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 µg/kg carpine were given to mice via intraperitoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutae-carpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neu-rological function fol owing injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice.

  16. Cerebral ischemia produces laddered DNA fragments distinct from cardiac ischemia and archetypal apoptosis.

    Science.gov (United States)

    MacManus, J P; Fliss, H; Preston, E; Rasquinha, I; Tuor, U

    1999-05-01

    The electrophoretic pattern of laddered DNA fragments which has been observed after cerebral ischemia is considered to indicate that neurons are dying by apoptosis. Herein the authors directly demonstrate using ligation-mediated polymerase chain reaction methods that 99% of the DNA fragments produced after either global or focal ischemia in adult rats, or produced after hypoxia-ischemia in neonatal rats, have staggered ends with a 3' recess of approximately 8 to 10 nucleotides. This is in contrast to archetypal apoptosis in which the DNA fragments are blunt ended as seen during developmental programmed cell death in dying cortical neurons, neuroblastoma, or thymic lymphocytes. It is not simply ischemia that results in staggered ends in DNA fragments because ischemic myocardium is similar to archetypal apoptosis with a vast majority of blunt-ended fragments. It is concluded that the endonucleases that produce this staggered fragmentation of the DNA backbone in ischemic brain must be different than those of classic or type I apoptosis.

  17. Effects of intracerebroventricular administration of brain-derived neurotrophic factor at different time intervals on cerebral ischemia-reperfusion injuries in rats%不同时间脑室注射BDNF对大鼠脑缺血再灌注损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    谭永星; 李雪梅; 庾俊雄; 林高翔; 蒋奕红

    2010-01-01

    Objective To observe the effects of intracerebroventricular administration of exogenous brain-derived neurotrophie factor (BDNF) at different intervals on cerebral ischemia-reperfusion(I/R)injuries in rats. Methods A total of 70 adult male Wistar rats,weighring 250-300g,were randomly divided into normal control group(group C,n=10),ischemia-reperfusion group(group I/P,n=10)and BDNF-treatment groups([12 or 6 h before ischemia,at just the moment performing ischemia,60r12 h after ischemia][group A1,A2,A3,A4 and A5],n=10).Focal cerebral I/R model was established in rats by reversible left middle cerebral artery occlusion with filament.BDNF(0.5μg)was microinjected into the left lateral ventricular of the rats in the BDNF-treatment groups.The activities of superoxide dismutase(SOD)in the brain tissue were measured by xanthine oxidase method and the contents of malondialdehyde(MDA)in the brain tissue were determined by thiobarbituric acid method.Neuron apoptosis in the brain cortex was identified by TUNEL.One left brain cortex(1 mmx×1mm)was removed randomly in each group to observe the ultrastructure changes of cerebral tissue under electron microscope. Results Compared with those in the group I/R,the activity of SOD was increased significantly but the content of MDA was decreased significantly in ischemia brain tissue in every BDNF-treatmnent group (P<0.05).The index of apoptotic neuron cells in the BDNF-treatment groups was decreased significantly as compared with that in the group I/R(P<0.05).The activity of SOD in the brain tissue(25.02±2.77,24.01±1.03)was higher and the content of MDA(10.35±1.23,12.29±0.92)and the index of neuron apoptosis(21.77±3.56.23.84±2.63)were lower in the BDNF-treatment groups than those in the other 2 groups at 12 or 6 h before ischemia (P<0.05).The ultrastructure of the cerebral tissue in each BDNF treatment group was improved to different degree,but that in I/R group was seriously damaged. Conclusion Intracerebroventricular

  18. Ischemia-driven angiogenesis.

    Science.gov (United States)

    Dor, Y; Keshet, E

    1997-11-01

    New blood vessels usually develop in places where they are most needed. A prime example of neovascularization representing a positive feedback response to insufficient perfusion is the development of collateral blood vessels in the ischemic myocardium and leg. The recent discoveries of hypoxia-inducible transcription and angiogenic factors have provided important mechanistic links between the metabolic consequences of ischemia and compensatory angiogenesis. Vascular endothelial growth factor (VEGF) has emerged as the key mediator of ischemia-driven angiogenesis. Environmental stresses, including hypoxia, hypoglycemia, and hypoferremia, upregulate VEGF expression at both the transcriptional and posttranscriptional levels. VEGF acts in turn on adjacent vascular beds expressing cognate receptors and induces sprouting and capillary growth toward the ischemic tissue. In addition to expanding the vasculature at sites where existing vessels have been occluded or obliterated, VEGF also functions to match the vascular density according to development and physiologic increases in oxygen consumption. Fine adjustment of the vasculature includes a step of oxygen-regulated vascular pruning mediated by VEGF in its capacity as a survival factor for newly formed vessels. Pathologic settings of ischemia-driven angiogenesis include a major component of stress-induced angiogenesis during tumor neovascularization and abnormal vessel growth associated with retinopathies. The latter represents an excessive angiogenic response to conditions of severe retinal ischemia. Further insights into the mechanism of stress-induced angiogenesis are likely to suggest new ways to augment growth of collateral vessels and to restrain unwarranted neovascularization in tumors and retinopathies. (Trends Cardiovasc Med 1997;7:289-294). © 1997, Elsevier Science Inc.

  19. 不同剂量重组人促红细胞生成素在宫内缺血缺氧环境中透过胎盘屏障及血脑屏障的通透性%Erythropoietin through the Placenta Barrier and Fetal Blood-Brain Barrier with Transient Uteroplacental Ischemia

    Institute of Scientific and Technical Information of China (English)

    马玉姗; 周俊; 柳慧; 杜宇; 林雪梅

    2012-01-01

    目的 探讨不同剂量重组人促红细胞生成素(recombinant human erythropoietin,rhEPO)在宫内缺血缺氧时透过胎盘屏障及胎鼠血脑屏障的通透性.方法 孕19 d(孕晚期)SD大鼠,分为3组:rhEPO治疗组(Treat组)、假手术对照组(Sham组)和生理盐水缺血对照组(I/R组).Treat组和I/R组制备宫内缺血缺氧模型,Sham组只进行开关腹手术.Treat组和Sham组根据注射rhEPO的剂量不同各自再分为3组,分别在宫内缺血缺氧处理或开关腹手术前30 min经孕鼠尾静脉注射125I标记的rhEPO 2500 U/kg、5000 U/kg、7500 U/kg,I/R组在宫内缺血缺氧处理前30 min经尾静脉注入生理盐水.均于缺血缺氧处理或开关腹手术后24 h取胎盘、羊水及胎鼠脑、肝、心、肺和肾,检测并比较各组织中125 I-rhEPO的放射比活性.结果 Treat组和Sham组胎盘、羊水及胎鼠各组织中均能检测到125 I-rhEPO的分布.125 I-rhEPO在胎盘、羊水及胎鼠各组织中的分布均随rhEPO注射剂量的增加而增加.在各剂量组中,Treat组胎鼠各组织中的125I-rhEPO含量均高于Sham组(P<0.05).结论 在宫内缺血缺氧环境下,胎盘屏障及胎鼠血脑屏障对外源性rhEPO的通透性增加.%Objective To observe the permeability of recombinant human erythropoietin through placenta barrier and fetal blood-brain barrier after transient uteroplacental ischemia. Methods Rats on days 19 of pregnancy were divided into rhEPO treated group, ischemia-reperfusion group and sham-operated group. Fetal ischemia in rhEPO treated group and ischemia-reperfusion group was induced by bilateral occlusion of the utero-ovarian artery for 20 minutes. Different dosage of 125I-rhEPO (2500 U/kg,5000 U/kg, 7500 U/kg) was injected into the rats through caudal veins 30 min before injury in rhEPO treated group and sham-operated group. Saline was administered intravenously 30 min before the induction of hypoxic-ischemic injury in ischemia-reperfusion group. The amniotic fluid

  20. Moderate hyperglycemia augments ischemic brain damage: a neuropathologic study in the rat.

    Science.gov (United States)

    Pulsinelli, W A; Waldman, S; Rawlinson, D; Plum, F

    1982-11-01

    We compared the effects of glucose injection with those of saline or mannitol on ischemic brain damage and brain water content in a four-vessel occlusion (4-VO) rat model, which simultaneously causes severe forebrain ischemia and moderate hindbrain ischemia. Glucose given before onset of ischemia was followed by severe brain injury, with necrosis of the majority of neocortical neurons and glia, substantial neuronal damage throughout the remainder of forebrain, and severe brain edema. By comparison, saline injection before forebrain ischemia resulted in only scattered ischemic damage confined to neurons and no change in the brain water content. Mannitol injection before 4-VO or D-glucose injection during or after 4-VO produced no greater forebrain damage than did the saline injection. Morphologic damage in the cerebellum, however, was increased by D-glucose injection given either before or during 4-VO. The results demonstrate that hyperglycemia before severe brain ischemia or during moderate ischemia markedly augments morphologic brain damage.

  1. Effect of total flavonoids of Radix Ilicis pubescentis on cerebral ischemia reperfusion model

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    Xiaoli Yan

    2017-03-01

    Full Text Available This paper aims to observe the effects of total flavonoids of Radix Ilicis pubescentis on mouse model of cerebral ischemia reperfusion. Mice were orally given different doses of total flavonoids of Radix Ilicis pubescentis 10 d, and were administered once daily. On the tenth day after the administration of 1 h in mice after anesthesia, we used needle to hook the bilateral common carotid artery (CCA for 10 min, with 10 min ischemia reperfusion, 10 min ischemia. Then we restored their blood supply, copy the model of cerebral ischemia reperfusion; We then had all mice reperfused for 24 h, and then took their orbital blood samples and measured blood rheology. We quickly removed the brain, with half of the brain having sagittal incision. Then we fixed the brains and sectioned them to observe the pathological changes of brain cells in the hippocampus and cortex. We also measured the other half sample which was made of brain homogenate of NO, NOS, Na+-K+-, ATP enzyme Mg2+-ATPase and Ca2+-ATPase. Acupuncture needle hook occlusion of bilateral common carotid arteries can successfully establish the model of cerebral ischemia reperfusion. After comparing with the model mice, we concluded that Ilex pubescens flavonoids not only reduce damage to the brain nerve cells in the hippocampus and cortex, but also significantly reduce the content of NO in brain homogenate, the activity of nitric oxide synthase (NOS and increases ATP enzyme activity (P < 0.05, P < 0.01. In this way, cerebral ischemia reperfusion injury is improved. Different dosages of Ilex pubescens flavonoids on mouse cerebral ischemia reperfusion model have good effects.

  2. Interleukin-6 receptor expression and localization after transient global ischemia in gerbil hippocampus.

    Science.gov (United States)

    Vollenweider, Florence; Herrmann, Martina; Otten, Uwe; Nitsch, Cordula

    2003-04-24

    Ischemia results in increased interleukin-6 (IL-6) expression in the brain. To prove a connection between IL-6 upregulation and IL-6 receptor (IL-6R) expression following ischemia, we analyzed cell-type specific expression changes of IL-6R using transient global ischemia in the gerbil as a model. In sham operated animals, IL-6R mRNA and protein were mainly detected in hippocampal pyramidal cells and interneurons. After ischemia, IL-6R was expressed in neurons but there was no increase during the peak IL-6 expression. Neuronal IL-6R mRNA and protein decreased in parallel with pyramidal cell death, starting 2 days after ischemia. Double-labeling experiments revealed that in postischemic hippocampus IL-6R was not present in GFAP-reactive astrocytes but that the surviving parvalbumin containing interneurons expressed IL-6R mRNA.

  3. A comparative study of EEG suppressions induced by global cerebral ischemia and anoxia.

    Science.gov (United States)

    Zagrean, L; Vatasescu, R; Oprica, M; Nutiu, O; Ferechide, D

    1995-01-01

    Cerebral ischemia and anoxia induce sequential changes that include ionic redistribution, alteration of enzimatic reactions governing metabolism and intracellular signaling. Despite high technology instrumentation including positron emission, tomography and magnetic resonance imaging used to unravel the intricacies of cerebral blood flow and metabolism, the electroencephalography (EEG) retains a useful place in the evaluation of processes induced by cerebral ischemia, especially in experimental conditions. We have investigated in this study EEG suppression and recovery following global cerebral ischemia, obtained by "four vessel occlusion model", reperfusion and anoxia. Both cerebral ischemia and anoxia have produced a sudden diminution of electrical brain activity and flat line was recorded after 8-10 sec. in the ischemic rats, but after 35-40 sec. in the anoxic rats. After same period of time (2 min) of ischemia and anoxia EEG recovery has been faster in the ischemic rat.

  4. Endogenous Protease Nexin-1 Protects against Cerebral Ischemia

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    Jonathan Thevenet

    2013-08-01

    Full Text Available The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC, leading to tolerance to cerebral ischemia. Here we studied the role of thrombin’s endogenous potent inhibitor, protease nexin-1 (PN-1, in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI exposed to oxygen and glucose deprivation (OGD. We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1−/− mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection.

  5. Endogenous protease nexin-1 protects against cerebral ischemia.

    Science.gov (United States)

    Mirante, Osvaldo; Price, Melanie; Puentes, Wilfredo; Castillo, Ximena; Benakis, Corinne; Thevenet, Jonathan; Monard, Denis; Hirt, Lorenz

    2013-08-14

    The serine protease thrombin plays a role in signalling ischemic neuronal death in the brain. Paradoxically, endogenous neuroprotective mechanisms can be triggered by preconditioning with thrombin (thrombin preconditioning, TPC), leading to tolerance to cerebral ischemia. Here we studied the role of thrombin's endogenous potent inhibitor, protease nexin-1 (PN-1), in ischemia and in tolerance to cerebral ischemia induced by TPC. Cerebral ischemia was modelled in vitro in organotypic hippocampal slice cultures from rats or genetically engineered mice lacking PN-1 or with the reporter gene lacZ knocked into the PN-1 locus PN-1HAPN-1-lacZ/HAPN-1-lacZ (PN-1 KI) exposed to oxygen and glucose deprivation (OGD). We observed increased thrombin enzyme activity in culture homogenates 24 h after OGD. Lack of PN-1 increased neuronal death in the CA1, suggesting that endogenous PN-1 inhibits thrombin-induced neuronal damage after ischemia. OGD enhanced β-galactosidase activity, reflecting PN-1 expression, at one and 24 h, most strikingly in the stratum radiatum, a glial cell layer adjacent to the CA1 layer of ischemia sensitive neurons. TPC, 24 h before OGD, additionally increased PN-1 expression 1 h after OGD, compared to OGD alone. TPC failed to induce tolerance in cultures from PN-1(-/-) mice confirming PN-1 as an important TPC target. PN-1 upregulation after TPC was blocked by the c-Jun N-terminal kinase (JNK) inhibitor, L-JNKI1, known to block TPC. This work suggests that PN-1 is an endogenous neuroprotectant in cerebral ischemia and a potential target for neuroprotection.

  6. Ischemia causes muscle fatigue

    Science.gov (United States)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D. M.

    2001-01-01

    The purpose of this investigation was to determine whether ischemia, which reduces oxygenation in the extensor carpi radialis (ECR) muscle, causes a reduction in muscle force production. In eight subjects, muscle oxygenation (TO2) of the right ECR was measured noninvasively and continuously using near infrared spectroscopy (NIRS) while muscle twitch force was elicited by transcutaneous electrical stimulation (1 Hz, 0.1 ms). Baseline measurements of blood volume, muscle oxygenation and twitch force were recorded continuously, then a tourniquet on the upper arm was inflated to one of five different pressure levels: 20, 40, 60 mm Hg (randomized order) and diastolic (69 +/- 9.8 mm Hg) and systolic (106 +/- 12.8 mm Hg) blood pressures. Each pressure level was maintained for 3-5 min, and was followed by a recovery period sufficient to allow measurements to return to baseline. For each respective tourniquet pressure level, mean TO2 decreased from resting baseline (100% TO2) to 99 +/- 1.2% (SEM), 96 +/- 1.9%, 93 +/- 2.8%, 90 +/- 2.5%, and 86 +/- 2.7%, and mean twitch force decreased from resting baseline (100% force) to 99 +/- 0.7% (SEM), 96 +/- 2.7%, 93 +/- 3.1%, 88 +/- 3.2%, and 86 +/- 2.6%. Muscle oxygenation and twitch force at 60 mm Hg tourniquet compression and above were significantly lower (P ischemia leading to a 7% or greater reduction in muscle oxygenation causes decreased muscle force production in the forearm extensor muscle. Thus, ischemia associated with a modest decline in TO2 causes muscle fatigue.

  7. Ischemia causes muscle fatigue

    Science.gov (United States)

    Murthy, G.; Hargens, A. R.; Lehman, S.; Rempel, D. M.

    2001-01-01

    The purpose of this investigation was to determine whether ischemia, which reduces oxygenation in the extensor carpi radialis (ECR) muscle, causes a reduction in muscle force production. In eight subjects, muscle oxygenation (TO2) of the right ECR was measured noninvasively and continuously using near infrared spectroscopy (NIRS) while muscle twitch force was elicited by transcutaneous electrical stimulation (1 Hz, 0.1 ms). Baseline measurements of blood volume, muscle oxygenation and twitch force were recorded continuously, then a tourniquet on the upper arm was inflated to one of five different pressure levels: 20, 40, 60 mm Hg (randomized order) and diastolic (69 +/- 9.8 mm Hg) and systolic (106 +/- 12.8 mm Hg) blood pressures. Each pressure level was maintained for 3-5 min, and was followed by a recovery period sufficient to allow measurements to return to baseline. For each respective tourniquet pressure level, mean TO2 decreased from resting baseline (100% TO2) to 99 +/- 1.2% (SEM), 96 +/- 1.9%, 93 +/- 2.8%, 90 +/- 2.5%, and 86 +/- 2.7%, and mean twitch force decreased from resting baseline (100% force) to 99 +/- 0.7% (SEM), 96 +/- 2.7%, 93 +/- 3.1%, 88 +/- 3.2%, and 86 +/- 2.6%. Muscle oxygenation and twitch force at 60 mm Hg tourniquet compression and above were significantly lower (P < 0.05) than baseline value. Reduced twitch force was correlated in a dose-dependent manner with reduced muscle oxygenation (r = 0.78, P < 0.001). Although the correlation does not prove causation, the results indicate that ischemia leading to a 7% or greater reduction in muscle oxygenation causes decreased muscle force production in the forearm extensor muscle. Thus, ischemia associated with a modest decline in TO2 causes muscle fatigue.

  8. Evaluation of murine models of permanent focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    席刚明; 汪华侨; 何国厚; 黄朝芬; 魏国耀

    2004-01-01

    Background To date murine models of permanent focal cerebral ischemia have not been well characterized. The purposes of this paper were to compare three different permanent middle cerebral artery occlusion (MCAo) models with or without craniectomy, and to identify an ideal mouse model of permanent focal cerebral ischemia.Methods Experiments were performed on 45 healthy adult male Kunming mice, weighing 28 to 42 g. The animals were randomly assigned to three groups (n=15 in every group) based on surgical procedure: MCAo via the external carotid artery (ECA), MCAo via the common carotid artery (CCA), and direct ligation of the middle cerebral artery (MCA). Each day post-ischemia, the animals were scored using an eight-grade neurological function scale, and mortality was also recorded. Seven days post-ischemia, the brains were removed for lesion size determination using triphenyltetrazolium chloride staining. Correlation analysis of lesion volume and neurological score was carried out. Results Mortality in the group receiving direct MCA ligation was lowest among the three groups, and there was a significant difference between the direct MCA ligation group and the two intraluminal occlusion groups (P0.7, P<0.05), suggesting good reproducibility of lesion volume in the three groups, but the infarct volume was more constant in the direct MCA ligation group. Conclusion The direct ligation model of MCAo provides an optimal means of studying permanent focal cerebral ischemia, and is preferable to the models using intraluminal sutures.

  9. Effect of baicalin on the autophagy and Beclin-1 expression in rats with cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Xiang-Long Hong; Yue-Feng Chen; Ping-Xuan Ma

    2016-01-01

    Objective:To explore the effect of baicalin on the autophagy and Beclin-1 expression in rats with cerebral ischemia, and the role of autophagy in the cerebral ischemia injury. Methods:The healthy male SD rats were randomized into the sham operation group, the ischemia model group, baicalin treatment group (100 mg/kg), and 3MA group (15 mg/kg), with 10 rats in each group. Transient focal cerebral ischemia injury model in rats was induced by occlusion of middle cerebral artery (MCA) for 180 min. The rats were given the corresponding drugs through the tail veins 30 min before molding. Half of the specimens were used for TTC staining to analyze the cerebral infarction volume. The others were used to determine the expression of Beclin-1 in the brain tissues by Western-blot. Results:When compared with the ischemia model group, the cerebral infarction volume in 3MA group was significantly increased, while that in baicalin treatment group was significantly reduced, and the comparison among the groups was statistically significant. When compared with the ischemia model group, Beclin-1 expression level in baicalin treatment group was significantly elevated, while Beclin-1 expression level in 3MA group was significantly higher than that in the sham-operation group but lower than that in the ischemia model group. Conclusions:The autophagy level of brain tissues in normal rats is low. The cerebral ischemia can activate autophagy. The activated autophagy is probably involved in the neuroprotection of cerebral ischemia injury. Application of 3MA to inhibit the occurrence of autophagy can aggravate the cerebral injury. Baicalin can significantly improve the cerebral ischemia injury and promote the occurrence of autophagy, whose mechanism is probably associated with the up-regulation of Beclin-1 expression to promote the activation of type III PI3K signal transduction pathway.

  10. Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome

    Science.gov (United States)

    2016-11-04

    Organic Brain Syndrome, Nonpsychotic; Neurocognitive Disorders; Mental Disorder, Organic; Delirium, Dementia, Amnestic, Cognitive Disorders; Nonpsychotic Organic Brain Syndrome; Organic Mental Disorder; Encephalopathy, Post-Traumatic, Chronic; Encephalopathy, Ischemic; Brain Ischemia

  11. Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats

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    Adem Bozkurt Aras

    2015-01-01

    Full Text Available Daidzein, a plant extract, has antioxidant activity. It is hypothesized, in this study, that daidzein exhibits neuroprotective effects on cerebral ischemia. Rat models of middle cerebral artery occlusion were intraperitoneally administered daidzein. Biochemical and immunohistochemical tests showed that superoxide dismutase and nuclear respiratory factor 1 expression levels in the brain tissue decreased after ischemia and they increased obviously after daidzein administration; malondialdehyde level and apoptosis-related cysteine peptidase caspase-3 and caspase-9 immunoreactivity in the brain tissue increased after ischemia and they decreased obviously after daidzein administration. Hematoxylin-eosin staining and luxol fast blue staining results showed that intraperitoneal administration of daidzein markedly alleviated neuronal damage in the ischemic brain tissue. These findings suggest that daidzein exhibits neuroprotective effects on ischemic brain tissue by decreasing oxygen free radical production, which validates the aforementioned hypothesis

  12. Neuroprotective effects of daidzein on focal cerebral ischemia injury in rats

    Institute of Scientific and Technical Information of China (English)

    Adem Bozkurt Aras; Mustafa Guven; Tark Akman; Adile Ozkan; Halil Murat Sen; Ugur Duz; Yldray Kalkan; Coskun Silan; Murat Cosar

    2015-01-01

    Daidzein, a plant extract, has antioxidant activity. It is hypothesized, in this study, that daidzein exhibits neuroprotective effects on cerebral ischemia. Rat models of middle cerebral artery oc-clusion were intraperitoneally administered daidzein. Biochemical and immunohistochemical tests showed that superoxide dismutase and nuclear respiratory factor 1 expression levels in the brain tissue decreased after ischemia and they increased obviously after daidzein administra-tion; malondialdehyde level and apoptosis-related cysteine peptidase caspase-3 and caspase-9 immunoreactivity in the brain tissue increased after ischemia and they decreased obviously after daidzein administration. Hematoxylin-eosin staining and luxol fast blue staining results showed that intraperitoneal administration of daidzein markedly alleviated neuronal damage in the ischemic brain tissue. These ifndings suggest that daidzein exhibits neuroprotective effects on ischemic brain tissue by decreasing oxygen free radical production, which validates the afore-mentioned hypothesis.

  13. 64 row CT cerebral perfusion applied research of brain ischemia%64排CT脑灌注对脑组织缺血程度的应用研究

    Institute of Scientific and Technical Information of China (English)

    刘贯清; 肖新兰; 李晓; 黄小宁; 李五根

    2015-01-01

    Objective Application of 64 row CT cerebral perfusion brain tissue ischemia. Methods 40 cases of clinical diag-nosis of acute cerebral infarction,patients with unilateral lobe brain perfusion CT perfusion showed abnormal,in combination with MRI to determine infarct,according to the cerebral blood flow group,group A (low perfusion group) and group B (infarction group), respectively,evaluation of two groups of cerebral blood flow perfusion parameters and comparison analysis. Results Of 40 cases, 18 cases of group A,CTP anomaly low perfusion of figure is determined by MTT extend approximately 1.28 (R),decreased CBF mild,CBV basic no change Or moderately reduced,only determined by MTT extension was statistically significant (P<0.01);Infarc-tion group,22 cases of group B,infarction area surrounding IP abnormal perfusion is determined by MTT extend approximately 1. 48(R),CBF significantly decreased approximately 0.45(R),CBV moderately reduced,which extended determined by MTT was sta-tistically significant (P<0.001),decrease CBF was statistically significant (P<0.01);Infarction district performance is determined by MTT extend approximately 1.64(R),CBF significantly decreased approximately 0.36(R),significantly lower CBV (approximately 0. 37)R. Which determined by MTT extension was statistically significant (P<0.001),CBF decline was statistically significant(P<0.01). Conclusion Brain tissue hypoperfusion area with the infarction in central and peripheral IP area the perfusion parameters have significant differences,according to the variation of perfusion parameters characteristics can make the image on the degree of is-chemic infarction assessment,when rCBF<0.5,suggesting infarction risk is extremely high,the clinical guidance for early interven-tion treatment.%目的:探讨应用64排CT脑灌注评价脑组织缺血程度。方法40例临床诊断急性脑梗塞,CT灌注显示单侧脑叶灌注异常患者,结合MRI判断梗塞,根据脑血流量进行分组,A

  14. The protective effects of ethanol extract of Trillium tschonoskii Maxim. on hypoxia-ischemia brain damage in neonatal rats%头顶一颗珠醇提物对新生大鼠缺血/缺氧性脑损伤的保护作用

    Institute of Scientific and Technical Information of China (English)

    邱勇; 李人鹏; 刘粟; 谭志鑫; 陈龙全; 刘红; 吴昊

    2016-01-01

    目的探讨头顶一颗珠醇提物对新生大鼠缺血/缺氧性脑损伤( HIBD )的保护作用及可能机制。方法50只7日龄SD大鼠随机分为假手术组( n=10)、模型组( n=20)、头顶一颗珠治疗组(n=20),各组分别予以3 d相应的生理盐水及头顶一颗珠醇提物腹腔注射。分别通过氯化三苯基四氮唑( TTC)和尼氏染色检测脑缺血及神经细胞死亡情况,通过Western blot检测Bcl-2、Bax蛋白的表达。结果 HIBD模型组可见脑组织稍有肿大,且右侧脑部可见缺血的白色坏死区;治疗组可见大脑形态完好,未见明显肿胀及坏死,TTC染色后,模型组可见右侧脑部出现明显缺血区,经治疗后缺血区域减少。尼氏染色结果提示模型组可见神经元细胞减少,而治疗后神经元细胞增加。 Western blot 显示 HIBD 后Bcl-2表达减少(P<0.01),Bax表达增加(P<0.01),而经过头顶一颗珠治疗后,Bcl-2表达增加(P<0.01),Bax表达降低( P<0.01)。结论头顶一颗珠对HIBD具有保护作用,其机制可能与降低神经元细胞凋亡有关。%Aim To investigate the effect of Trillium tschonoskii Maxim ( TTM ) ethanol extract on hypoxia ischemia brain damage ( HIBD ) in neonatal rats and potential mechanisms. Methods Fifty healthy SD rats of 7 day-old were randomly divided into three groups:the sham operation group ( n=10 ) , the model group ( n=20 ) and TTM treatment group ( n=20 ) , which received 3-day intraperitoneal injection of normal saline or ethanol extract of TTM respectively. TTC staining and Nissl staining were performed to detect the cerebral ischemia area and neuronal death. Western blot was used to detect the expression of Bcl-2 and Bax. Re-sults The brain tissue of model group was slightly swollen, and white necrotic zone induced by ischemia occured on the right side of the brain, while the brain morphology of TTM treatment group was good. After TTC staining, ischemia zone was clearly seen on the right side of the

  15. Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126.

    Science.gov (United States)

    Chen, Fan; Du, Yang; Esposito, Elga; Liu, Yi; Guo, Shuzhen; Wang, Xiaoying; Lo, Eng H; Xing, Changhong; Ji, Xunming

    2015-12-01

    Emerging data suggest that exosomal microRNA (miRNA) may provide potential biomarkers in acute ischemic stroke. However, the effects of ischemia-reperfusion on total versus exosomal miRNA responses in circulating blood remain to be fully defined. Here, we quantified levels of miR-126 in whole serum versus exosomes extracted from serum and compared these temporal profiles against reperfusion and outcomes in a rat model of acute focal cerebral ischemia. First, in vitro experiments confirmed the vascular origin and changes in miR-126 in brain endothelial cultures subjected to oxygen-glucose deprivation. Then in vivo experiments were performed by inducing permanent or transient focal cerebral ischemia in rats, and total serum and exosomal miR-126 levels were quantified, along with measurements of infarction and neurological outcomes. Exosomal levels of miR-126 showed a transient reduction at 3 h post-ischemia that appeared to normalize back close to pre-ischemic baselines after 24 h. There were no detectable differences in exosomal miR-126 responses in permanent or transient ischemia. Serum miR-126 levels appeared to differ in permanent versus transient ischemia. Significant reductions in serum miR-126 were detected at 3 h after permanent ischemia but not transient ischemia. By 24 h, serum miR-126 levels were back close to baseline in both permanent and transient ischemia. Overall, there were no correlations between serum miR-126 and exosomal miR-126. This proof-of-concept study suggests that changes in serum miR-126 may be able to distinguish severe permanent ischemia from milder injury after transient ischemia.

  16. 不同剂量脑醒喷鼻剂对再灌注损伤脑组织自由基及一氧化氮合酶变化的干预%Changes of free radicals and nitric oxide synthase in rat brain following ischemia-reperfusion injury due to different dosage brain-awakening nasal sprayer intervention

    Institute of Scientific and Technical Information of China (English)

    李荣; 吴伟; 陈宏珪; 黄衍寿; 刘煜德; 杨开清

    2005-01-01

    BACKGROUND: Brain-awakening nasal sprayer is composed of many herbs,such as Chuanxiong and Shichangpu, which were regarded by "Shennong Bencaojing" as having the function of "preventing stroke in the brain".OBJECTIVE: To observe the changes of free radicals and nitric oxide synthase in rat brain following focal ischemic-reperfusional injury due to brain-awakening nasal sprayer intervention and compare with that due to classical nimodipine.DESIGN: A randomized controlled study.SETTING: Department of internal medicine of a hospital affiliated to a traditional Chinese medical university.MATERIALS: Seventy adult male Wistar rats of clean grade, were randomly divided into seven groups: brain-awakening nasal sprayer of higher dosage group, moderate dosage group, lower dosage group, nimodipine intraperitoneal injection group, physical saline nasal sprayer group, menstruum nasal sprayer group, and sham operation group with 10 rats in each.METHODS: Focal brain ischemia-reperfusion model was established by blocking the left cerebral middle artery in rats of all the groups except sham operation group. Three days before model establishment and during reperfusion, rats were given different dosages of brain-awakening nasal sprayer composed of Chuanxiongqin and Shichangpu of 5.4, 2.7, 1.08 mg/(kg · d) and 1.35, 0. 54, 0.27 g/(kg· d), respectively, three times a day; which was replaced by physical saline and menstruum nasal sprayer of 0. 18 mL/ (kg · d),three times a day in physical saline nasal sprayer group and menstruum nasal sprayer group; rats in nimodipine intraperitoneal injection group received intraperitoneal injection of nimodipine by 0. 8 mg/(kg · d) twice a day. Rats in sham operation group were routinely raised. The content of prodialdehyde, superoxide dismutase and nitric oxide synthase were measured with colorimetric method.MAIN OUTCOME MEASURES: ① The changes of prodialdehyde content, superoxide dismutase and nitric oxide synthase activity in rat brain

  17. Effect of Morphine Withdrawal Syndrome on Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Mohammad Allahtavakoli

    2011-01-01

    Full Text Available Objective(sOpioid abuse is still remained a major mental health problem, a criminal legal issue and may cause ischemic brain changes including stroke and brain edema. In the present study, we investigated whether spontaneously withdrawal syndrome might affect stroke outcomes.Materials and MethodsAddiction was induced by progressive incremental doses of morphine over 7 days. Behavioral signs of withdrawal were observed 24, 48 and 72 hr after morphine deprivation and total withdrawal score was determined. Cerebral ischemia was induced 18-22 hr after the last morphine injection by placing a natural clot into the middle cerebral artery (MCA. Neurological deficits were evaluated at 2, 24 and 48 hr after ischemia induction, and infarct size and brain edema were determined at 48 hr after stroke.ResultsMorphine withdrawal animals showed a significant increase in total withdrawal score and decrease of weight gain during the 72 hr after the last morphine injection. Compared to the addicted and control animals, infarct volume and brain edema were significantly increased in the morphine deprived animals (P< 0.05 at 48 hr after cerebral ischemia. Also, neurological deficits were higher in the morphine-withdrawn rats at 48 hr after stroke (P< 0.05. ConclusionOur data indicates that spontaneous withdrawal syndrome may worsen stroke outcomes. Further investigations are necessary to elucidate mechanisms of opiate withdrawal syndrome on stroke.

  18. [Neuroprotection of herbs promoting EPO on cerebral ischemia].

    Science.gov (United States)

    Li, Xu; Bai, Zhen-ya; Zhang, Fei-yan; Xu, Xiao-yu

    2015-06-01

    Amounts of researches show that EPO is characterized with neurotrophic and neuroprotective manner, especially in brain stroke, which attracts a large numbers of researchers to study it. With the accumulating researches on its neuroprotection, many related mechanisms were revealed, such as antioxidant, anti-apoptosis, angiogenesis, anti-inflammatory, which suggests a multiple targets role of EPO on brain stroke. However, because of the high risk of thromboembolism in clinical administration of rhEPO and its analogs, the herbs are potential to be a replacer for its less side effects. Many researchers suggested that a larger of herbs were founded having the action of increasing the endogenous EPO in the model of anemia and cerebral ischemia. At the same time, there herbs were also proved that they had the action of against cerebral ischemia while some without considering the role of EPO in the reports. Considering of the action of promoting EPO of these herbs and the neural protection of EPO, this essay mainly summarizes the studies of herbs promoting EPO in the cerebral ischemia and discusses the mechanism of regulating the EPO of these herbs, for the aim of finding the potential drugs against cerebral ischemia.

  19. Aqueous extract of Cordyceps alleviates cerebral ischemia-induced short-term memory impairment in gerbils.

    Science.gov (United States)

    Lee, Sang-Hak; Ko, Il-Gyu; Kim, Sung-Eun; Hwang, Lakkyong; Jin, Jun-Jang; Choi, Hyun-Hee; Kim, Chang-Ju

    2016-04-01

    Cerebral ischemia is caused by reduced cerebral blood flow due to a transient or permanent cerebral artery occlusion. Ischemic injury in the brain leads to neuronal cell death, and eventually causes neurological impairments. Cordyceps, the name given to the fungi on insects, has abundant useful natural products with various biological activities. Cordyceps is known to have nephroprotective, hepatoprotective, anti-inflammatory, antioxidative, and antiapoptotic effects. We investigated the effects of Cordyceps on short-term memory, neuronal apoptosis, and cell proliferation in the hippocampal dentate gyrus following transient global ischemia in gerbils. For this study, a step-down avoidance test, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunohistochemistry for caspase-3 and 5-bromo-2'-de-oxyuridine, and western blot for Bax, Bcl-2, brain-derived neurotrophic factor (BDNF), and tyrosin kinase B were performed. In the present study, Cordyceps alleviated cerebral ischemia-induced short-term memory impairment. Cordyceps showed therapeutic effects through inhibiting cerebral ischemia-induced apoptosis in the hippocampus. Cordyceps suppressed cerebral ischemia-induced cell proliferation in the hippocampal dentate gyrus due to the reduced apoptotic neuronal cell death. Cordyceps treatment also enhanced BDNF and TrkB expressions in the hippocampus of ischemic gerbils. It can be suggested that Cordyceps overcomes cerebral ischemia-induced neuronal apoptosis, thus facilitates recovery following cerebral ischemia injury.

  20. APE/Ref-1蛋白与脑缺血/再灌注神经元损伤%APE/Ref-1 protein and ischemia/reperfusion injury of neurons in the brain

    Institute of Scientific and Technical Information of China (English)

    汪效松; 李智文

    2003-01-01

    Cerebral ischemia and the aftermath of reperfusion form a hypoxic/hyperoxic sequence of events that can trigger DNA damage in neurons of central nervous system.Neuronal apoptosis will happen without immediate DNA repair.APE/Ref-1 is a multifunctional protein involoved in DNA base excision repair pathway and in redox reguiation of DNA-binding activity of AP-1 family members.which may play an important role in protection of postischemic neuronal damage.

  1. Electro-acupuncture could be an effective pretreatment for cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Feng Zhang

    2010-10-01

    Full Text Available "nElectroacupuncture, the integration of traditional Chinese acupuncture and modern electrotherapy, has been used for clinical treatment of cerebral ischemic disease in both eastern and western countries; however, the mechanism underlying its effects is still unknown. It is well known that excessive glutamate results in neuronal excitotoxicity after ischemic stroke. Previous studies have indicated that electro-acupuncture may downregulate the overactivation of glutamate after ischemia, and a recent study implied that electro-acupuncture prior to ischemia could induce brain ischemic tolerance. Based on the present information, we hypothesize that electro-acupuncture could be an effective pretreatment for cerebral ischemia by regulating the glutamatergic system.

  2. Effects of Polysaccharide of Gastrodia Elata Blume and Electro-Acupuncture on Expressions of Brain-Derived Neurotrophic Factor and Stem Cell Factor Protein in Caudate Putamen of Focal Cerebral Ischemia Rats.

    Science.gov (United States)

    Li, Huai-Bin; Wu, Feng; Miao, Hua-Chun; Xiong, Ke-Ren

    2016-12-23

    BACKGROUND The aim of this study was to explore the neural protective effect of polysaccharide of Gastrodia elata Blume (PGB) and electro-acupuncture (EA) on focal cerebral ischemia rats. MATERIAL AND METHODS A total of 40 Sprague-Dawley rats were randomly divided into 5 groups (normal group, model group, PGB group, EA group and PGB+EA group). The model was prepared by middle cerebral artery occlusion (MCAO). Two week after modeling, rats were given PGB, EA, or a combination of the 2 in continuous treatment for 2 successive weeks. 14 days after modeling, expressions of BDNF and SCF protein in the caudate putamen (CPu) were detected by immunohistochemistry. RESULTS Positive expression of BDNF and SCF protein was found in the right caudate putamen of each group of rats. Expressions of BDNF and SCF in the CPu of the model group were higher than normal group (P<0.05). Compared with the model group, the expressions of BDNF and SCF in the CPu of the PGB group, the EA group, and the PGB plus EA group increased significantly (P<0.05). The expressions of BDNF and SCF obviously increased in the PGB plus EA group compared to those of the EA group and the PGB group (P<0.05). CONCLUSIONS PGB and EA up-regulated the expressions of BDNF and SCF protein in the CPu of focal cerebral ischemia rats, and the combination of PGB+EA has a synergistic effect on the recovery from cerebral ischemia.

  3. 大鼠局灶性脑缺血再灌注后内皮细胞对不同缺血时间的耐受性%Endothelial cell endurance to various courses of focal brain ischemia-reperfusional injury in rats

    Institute of Scientific and Technical Information of China (English)

    褚晓凡; 付学军; 亓传洁; 马可夫; 肖学长; 彭健

    2005-01-01

    转化,出血转化多发生于再灌注后的缺血中心区.%BACKGROUND: Endothelial cell structural and functional integrity is importnat decisive fatcor for ischemic time-window and hemorragic transformation follwing brain ischemic injury.OBJECTIVE: To investiagte the endotheliocyt endurance to various course of ischemic injury basing on dynamical observation of morphological and ultrastructural changes of endotheliocyte during IR injury.DESIGN: Randomized controlled experiment.SETTING:Neurological Internal Department of the Second Affiliated Hospital of Jinan University.MATERIALS: This experiment was carried out in the Animal Experimental Laboratory of the Second Affiliated Hospital of Jinan University from March 1998 to March 1999. Totally 53 SD rats were randomly dihours of 6 rats.METHODS: Thread-bolt occlusion method was used to establish focal brain ischemia model on rats. Brain tissue was evenly cut into five coronary segments: namely A, B, C, D and E, segments C underwent TTC staining for marginal region location. segments D was taken for routine dehydration, transparency, envelop, slice and HE staining,optical microscopic observation. Ischemic surrounding area and central brain tissues was obtained from slice B, fixed and enveloped before cutting into ultrathin slices that was observed under transmission electron microscope.the occurring time of hemorrhagic infarction at different ischemic time cell vacuolization degree in foot process layer at different ischemic time points.RESULTS: Totally 53 rats were enrolled in this experiment and all data was entered into results analysis. Under optical microscope: Neuropil loose and small vascular surrounding edema was observed at ischemia 3 hours.Small arterial broken and hemorrhage occurred at ischemia 12 hours reperfusion 3 hours. Under electron microscope: Capillary endothelial nuclear swelling was observed at ischemia 3 hours, with cytoplasmic pinocytosi increasing and vacuolization in foot process layer

  4. A simple and sensitive method to assess ischemia occurrence in the setting of focal cerebral ischemia in rat:A comparative study

    Institute of Scientific and Technical Information of China (English)

    张蓬勃; 刘勇; 李捷; 王莹

    2003-01-01

    Objective:Neurological evaluation is commonly applied to identify ischemia in focal cerebral ischemia model though it might not be sensitive.In present study,we hired sleeping time to assess ischemia occurrence.Methods:Permanent middle cerebral artery occlusion was induced in Sprague-Dawley rats under pentobarbital and ketamine anesthesia respectively.Sleeping time was recorded.Neurological evaluation was conducted by modified Bederson's scoring system at 4 h and histopathological evaluation was performed at 3 d after middle cerebral artery occlusion.Results:Slices of brain stained by TFC,H&E and hoechst 33258 revealed extensive lesion in the two ischemic groups.The sensitivity to identify ischemia by neurological evaluation was 62.5%,but it was 81.3% and 80% respectively when evaluating by sleeping time(pentobarbital:≥90.7 min,ketamine:≥36.1 min).The sensitivity to identify ischemia by sleeping time was significantly higher than that by neurological evaluation(P < 0.05).Conclusion:Our resuits suggested that to identify ischemia by sleeping time is a simple and sensitive method in the setting of focal cerebral ischemia in rat.

  5. CT perfusion during delayed cerebral ischemia after subarachnoid hemorrhage: distinction between reversible ischemia and ischemia progressing to infarction

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    Cremers, Charlotte H.P. [University Medical Center Utrecht, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, PO Box 85500, Utrecht, Utrecht (Netherlands); University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Vos, Pieter C. [University Medical Center Utrecht, Image Sciences Institute, Utrecht (Netherlands); Schaaf, Irene C. van der; Velthuis, Birgitta K.; Dankbaar, Jan Willem [University Medical Center Utrecht, Department of Radiology, Utrecht (Netherlands); Vergouwen, Mervyn D.I.; Rinkel, Gabriel J.E. [University Medical Center Utrecht, Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, PO Box 85500, Utrecht, Utrecht (Netherlands)

    2015-09-15

    Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) can be reversible or progress to cerebral infarction. In patients with a deterioration clinically diagnosed as DCI, we investigated whether CT perfusion (CTP) can distinguish between reversible ischemia and ischemia progressing to cerebral infarction. From a prospectively collected series of aSAH patients, we included those with DCI, CTP on the day of clinical deterioration, and follow-up imaging. In qualitative CTP analyses (visual assessment), we calculated positive and negative predictive value (PPV and NPV) with 95 % confidence intervals (95%CI) of a perfusion deficit for infarction on follow-up imaging. In quantitative analyses, we compared perfusion values of the least perfused brain tissue between patients with and without infarction by using receiver-operator characteristic curves and calculated a threshold value with PPV and NPV for the perfusion parameter with the highest area under the curve. In qualitative analyses of 33 included patients, 15 of 17 patients (88 %) with and 6 of 16 patients (38 %) without infarction on follow-up imaging had a perfusion deficit during clinical deterioration (p = 0.002). Presence of a perfusion deficit had a PPV of 71 % (95%CI: 48-89 %) and NPV of 83 % (95%CI: 52-98 %) for infarction on follow-up. Quantitative analyses showed that an absolute minimal cerebral blood flow (CBF) threshold of 17.7 mL/100 g/min had a PPV of 63 % (95%CI: 41-81 %) and a NPV of 78 % (95%CI: 40-97 %) for infarction. CTP may differ between patients with DCI who develop infarction and those who do not. For this purpose, qualitative evaluation may perform marginally better than quantitative evaluation. (orig.)

  6. Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia.

    Science.gov (United States)

    Khan, Mohammad M; Wakade, Chandramohan; de Sevilla, Liesl; Brann, Darrell W

    2015-02-01

    Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17β-estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia. This article is part of a Special Issue entitled "Sex steroids and brain disorders".

  7. 浸入式金属自显影技术检测游离锌离子在人脑外伤、急性脑缺血、癫痫后神经元中的异常聚集%Abnormal accumulation of free zinc ions in neurons of patients after traumatic brain injury/acute ischemia/epilepsy by immersion autometallography

    Institute of Scientific and Technical Information of China (English)

    朱林; 纪祥军; 王汉东

    2013-01-01

    目的 研究游离锌离子在脑外伤、急性脑缺血和癫痫患者神经元中的分布,为探讨锌离子是否参与上述疾病的神经元损伤提供形态学证据. 方法 于南京军区南京总医院神经外科手术台上直接采集3例脑缺血标本、3例癫痫标本、5例脑外伤标本和5例相对正常新鲜皮层标本,应用浸入式金属自显影方法检测标本中的锌离子分布,应用HE染色观察神经元形态学变化.结果 脑外伤、急性脑缺血和癫痫患者皮层神经元内聚集了大量的锌离子,阳性反应产物主要位于含锌神经元的胞体和轴突终末,胶质细胞中未见明显着色.在正常皮层未见阳性反应产物沉积.进一步的HE染色提示这些富含锌的神经元呈明显损伤样外观. 结论 锌离子可能在脑外伤、急性脑缺血和癫痫的神经元损伤中起重要作用,参与这些疾病的病理生理过程.%Objective To study the distributions of free zinc ions in the neurons of patients after traumatic brain injury/acute ischemia/epilepsy and to provide morphological evidence of involvement of zinc ions in the neuronal injury.Methods Fresh cortex specimens from patients suffered from brain trauma (n=5),acute ischemia (n=3) and epilepsy(n=3) were collected during the surgeries.Immersion autometallography was used to detect the free zinc ions in the neurons,and HE staining was employed to observe the morphological changes of the neurons.Results Pathological zinc accumulation was extensively presented in the neurons of patients after ischemia,epilepsy and mechanical head trauma.Zinc-positive products were predominantly located in the neural bodies and the axon terminals,and could not be seen in the glial cells and the neurons of normal cortex.HE staining indicated that apparently damaged neurons were observed in all of the brain regions with zinc ions labeled neuronal somata.Conclusion zinc ions might play important roles in the neurons of patients after brain

  8. P2X7 receptors in cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Hui-Yu Bai; Ai-Ping Li

    2013-01-01

    Cerebral ischemia is one of the most common diseases resulting in death and disability in aged people.It leads immediately to rapid energy failure,ATP depletion,and ionic imbalance,which increase extracellular ATP levels and accordingly activate P2X7 receptors.These receptors are ATP-gated cation channels and widely distributed in nerve cells,especially in the immunocompetent cells of the brain.Currently,interest in the roles of P2X7 receptors in ischemic brain injury is growing.In this review,we discuss recent research progress on the actions of P2X7 receptors,their possible mechanisms in cerebral ischemia,and the potential therapeutic value of P2X7 receptor antagonists which may provide a new target both for clinical and for research purposes.

  9. Progesterone is neuroprotective by inhibiting cerebral edema after ischemia

    Institute of Scientific and Technical Information of China (English)

    Yuan-zheng Zhao; Min Zhang; Heng-fang Liu; Jian-ping Wang

    2015-01-01

    Ischemic edema can alter the structure and permeability of the blood-brain barrier. Recent stud-ies have reported that progesterone reduces cerebral edema after cerebral ischemia. However, the underlying mechanism of this effect has not yet been elucidated. In the present study, pro-gesterone effectively reduced Evans blue extravasation in the ischemic penumbra, but not in the ischemic core, 48 hours after cerebral ischemia in rats. Progesterone also inhibited the down-reg-ulation of gene and protein levels of occludin and zonula occludens-1 in the penumbra. These results indicate that progesterone may effectively inhibit the down-regulation of tight junctions, thereby maintaining the integrity of the blood-brain barrier and reducing cerebral edema.

  10. Protective effects and potential mechanisms of Pien Tze Huang on cerebral chronic ischemia and hypertensive stroke

    Directory of Open Access Journals (Sweden)

    Kwong Wing

    2010-10-01

    Full Text Available Abstract Background Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH, a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats. Methods The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR and stroke prone SHR (SHRsp were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA and immunostaining. Results Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCR2 in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS damage and possibly subsequent cell death (caspase 3 assay as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum. Conclusion Pien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria.

  11. Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

    Science.gov (United States)

    Gulati, Anil

    2016-01-01

    Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ETB receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest. Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant. Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ETA and ETB). In the central nervous system (CNS) ETA receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ETA receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ETA receptors. On the other hand, blocking ETB receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ETB receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ETB receptor stimulation on mitochondrial functions in the CNS following cerebral ischemia. Conclusion: The findings of this

  12. 3'-甲氧基葛根素对缺血再灌注大鼠脑内氨基酸动态变化的实验研究%Study on 3'-methoxy puerarin to dynamic changes of amino acids in rat brain ischemia-reperfusion

    Institute of Scientific and Technical Information of China (English)

    韩进; 万海同; 李金辉; 葛立军

    2012-01-01

    Objective: To study the effect of 3'-methoxy puerarin on cerebral ischemic glutamic acid, aspartic acid, taurine and y-aminobutyric acid inhibitory of rats and investigate the protective mechanisms of cerebral ischemia-reperfusion. Method: Using middle cerebral artery occlusion rat model, to collect extracellular fluid in rat striatal amino acid neurotransmitters by brain microdialys-is and HPLC techniques with fluorescence detection before and after 3'-methoxy puerarin treatment four kinds of amino acids changes. Result: 3'-methoxy puerarin reduced concentrations of excitatory amino acid (EAA) Asp and Clu, while Tau and GABA inhibitory amino acids were significantly reduced. Conclusion: 3'-methoxy puerarin reduce ischemia-induced brain EAA toxicity against EAA neurotoxicity, regulate the brain neurotransmitter amino acid content, improve the excitatory and inhibitory amino acid balance is one of the mechanisms that to improve and protect the important acute cerebral infarction in rat brain nuclei.%目的:研究脑缺血时3’-甲氧基葛根素对谷氨酸、天门冬氨酸、牛磺酸和γ-氨基丁酸的抑制作用,探讨脑缺血损伤再灌注过程中其对神经损伤的保护机制.方法:制作大鼠大脑中动脉阻塞模型,利用脑微透析技术收集大鼠纹状体细胞外液中的氨基酸类神经递质,并3’-甲氧基葛根索灌胃治疗;HPLC荧光检测用药前后4种氨基酸的含量变化.结果:3’-甲氧基葛根素可降低缺血时脑组织中兴奋性氨基酸Asp,Glu的浓度,同时使抑制性氨基酸Tau,GABA含量明显降低.结论:3’-甲氧基葛根素能降低缺血引起的脑内兴奋性氨基酸的毒性,调节脑内兴奋性氨基酸的含量.因此,该药改善脑内氨基酸的变化状态是改善和保护急性期脑梗死大鼠脑内神经保护作用机制之一.

  13. In vivo Dynamic Studies of Brain Metabolism

    Institute of Scientific and Technical Information of China (English)

    LUO Xuechun; JIANG Yufeng; ZHANG Riqing

    2005-01-01

    Nuclear magnetic resonance (NMR) can noninvasively monitor intracellular concentrations and kinetic properties of numerous inorganic and organic compounds. A 31P NMR surface coil was used in vivo to dynamically measure phosphocreatine (PCr), adenosine triphosphate (ATP), and intracellular inorganic phosphate (Pi) levels in mouse brain during ischemia-reperfusion to study the damage of cerebral tissues caused by ischemia and effects of herbs on cerebral energy metabolism during ischemia-reperfusion. The study provides dynamic brain energy metabolism data during different periods. The data show that some herbs more rapidly increase the PCr level during the recovery phase than in the control group.

  14. Effect of minocycline on cerebral ischemia- reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Yuanyin Zheng; Lijuan Xu; Jinbao Yin; Zhichao Zhong; Hongling Fan; Xi Li; Quanzhong Chang

    2013-01-01

    Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-reperfusion (22.5 mg/kg, initially 45 mg/kg) at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein expression.

  15. Na(+)/Ca(2+) exchanger 2 is neuroprotective by exporting Ca(2+) during a transient focal cerebral ischemia in the mouse.

    Science.gov (United States)

    Jeon, Daejong; Chu, Kon; Jung, Keun-Hwa; Kim, Manho; Yoon, Byung-Woo; Lee, C Justin; Oh, Uhtaek; Shin, Hee-Sup

    2008-05-01

    Na(+)/Ca(2+) exchanger (NCX), by mediating Na(+) and Ca(2+) fluxes bi-directionally, assumes a role in controlling the Ca(2+) homeostasis in the ischemic brain. It has been suggested that the three isoforms of NCX (NCX1, 2 and 3) may be differentially involved in permanent cerebral ischemia. However, the role of NCX2 has not been defined in ischemic reperfusion injury after a transient focal cerebral ischemia. Furthermore, it is not known whether NCX2 imports or exports intracellular Ca(2+) ([Ca(2+)](i)) following ischemia and reperfusion. To define the role of NCX2 in ischemia and reperfusion, we examined mice lacking NCX2, in vivo and in vitro. After an in vitro ischemia, a significantly slower recovery in population spike amplitudes, a sustained elevation of [Ca(2+)](i) and an increased membrane depolarization were developed in the NCX2-deficient hippocampus. Moreover, a transient focal cerebral ischemia in vivo produced a larger infarction and more cell death in the NCX2-deficient mouse brain. In particular, in the wild type brain, NCX2-expressing neurons were largely spared from cell death after ischemia. Our results suggest that NCX2 exports Ca(2+) in ischemia and thus protects neuronal cells from death by reducing [Ca(2+)](i) in the adult mouse brain.

  16. Effect of electroacupuncture on brain cells apoptosis and nerve function recovery after focal cerebral ischemia-reperfusion in rats%电针对局灶性脑缺血再灌注大鼠脑细胞凋亡及神经功能恢复的影响

    Institute of Scientific and Technical Information of China (English)

    王海英; 张秋玲; 李金国; 陈京; 白波

    2010-01-01

    目的 观察针刺干预对于大鼠局灶性脑缺血再灌注脑细胞内游离钙、Caspase-3 mRNA及大鼠双前肢抓力的影响.方法 145只成年雄性SD大鼠随机分成对照组(sham)、缺血再灌注组(1/R)和针刺组(I/R+EA).选用Longa改良线拴法制备大鼠局灶性脑缺血再灌注模型(MCAO).实验大鼠处死后取材制成单细胞悬液,经Fluo-3/AM标记,用激光扫描共聚焦显微镜检测脑细胞[Ca2+]i浓度.应用RT-PCR技术检测大鼠大脑皮层和纹状体内Caspase-3 mRNA表达的变化.大鼠双前肢抓力试验检测大鼠神经功能重建情况.结果 ①针刺干预6h后[Ca2+]i为10.96±1.18,针刺12h后为20.9±4.73,与缺血再灌注组[16.87±3.56,34.10±1.06]比较显著降低,差异有统计学意义(P<0.01).②I/R组大脑皮层及纹状体Caspase-3 mRNA表达增强;电针干预后Caspase-3 mRNA表达与I/R组比较明显下调.③针刺7d、14d大鼠抓力明显高于脑缺血再灌注7d、14d,针刺30d、60d、90d大鼠抓力与脑缺血再灌注30d、60d、90d组大鼠抓力无明显差异.采用单因素方差分析,I/R+EA与sham及I/R组比较(P<0.05),差异有统计学意义.结论 缺血急性期针刺干预显著降低大鼠局灶性脑缺血再灌注脑细胞内游离钙的浓度及Caspase-3 mRNA的表达;并有效促进大鼠神经功能的恢复.%Objective To investigate the influence of acpuncture on free calcium in rat brain cells after focal cerebral ischemia reperfusion.Methods 145 adult male SD rats were randomly divided into control group,simple ischemia reperfusion group and acupuncture with ischemia reperfusion group.The middle cerebral artery occlusion/reperfusion (MCAO/R) rat model was established by the modified Longa occlusion method. ①The part of free calcium in rat brain cells,focal cevebral ischemia model of rats were made by thread locking up the blood vessel for 15 min.30 min later after reperfusion, the Baihui and Shuigou Point in Du meridian were acupunctured electrically

  17. Effects of Estradiol on Spontaneous Depressive-like Behaviors and Brain-derived Neurotrophic Expression after Focal Ischemia in Rat%雌激素对大鼠脑缺血后自发抑郁行为及缺血半暗带纹状体内脑源性神经生长因子的影响

    Institute of Scientific and Technical Information of China (English)

    程一帆; 邵蓓; 金坤林; 程建华; 苏巧尔; 王柳清; 林真珍

    2012-01-01

    目的:探讨雌激素对大鼠脑缺血后自发性抑郁行为的作用及对缺血半暗带纹状体内脑源性神经营养因子(BDNF)表达的影响.方法:应用大脑中动脉线栓术建立大鼠脑缺血模型.脑缺血模型大鼠随机分为对照组,脑卒中组,雌激素干预(皮下注射17β-雌二醇大豆油0.1 mL,×2周)组.观察脑缺血后及雌激素干预后抑郁行为学改变,检测缺血半暗带纹状体内BDNF表达.结果:脑缺血后,大鼠强迫游泳不动时间延长.雌激素组不动时间缩短,缺血半暗带BDNF阳性细胞数明显高于脑卒中组.结论:大鼠脑缺血后可以自发产生抑郁样症状,雌激素治疗可以改善这些症状,提高缺血半暗带BDNF表达可能为其治疗机制之一.%Aim: To determine the effects of estradiol on endogenous depressive-like behaviors and BDNF expression in the penumbra region after focal ischemia in rat. Methods: Focal ischemia was generated by transient occlusion of middle cerebral artery (MCA). Rats were randomly divided into control group, stroke group and estradiol treatment group. Forced swimming test were performed to assess endogenous depression-like behavior after focal ischemia and estradiol treatment. Brain-derived neurotrophic factor (BDNF) expression in the penumbra regions was examined by immunohistochemistry. Results: Ischemic rats were found to develop significantly depressive-like behavioral 3 weeks after MCAO, compared with the sham-operated control rats. Ischemia-induced depressive-like behaviors were significantly improved after estradiol administration for 14 days. A significant regulation of BDNF protein levels in the penumbra regions of striatum were also observed in MCAO animals treated with estradiol, compared with the ischemic rats treated with vehicle. Conclusion: The findings of this study provided the evidence that spontaneous post-stroke depression(PSD) can be found in rat after focal ischemia. Estradiol can improve endogenous depressive

  18. Metabolic crisis in severely head-injured patients: is ischemia just the tip of the iceberg?

    Science.gov (United States)

    Carre, Emilie; Ogier, Michael; Boret, Henry; Montcriol, Ambroise; Bourdon, Lionel; Jean-Jacques, Risso

    2013-10-11

    Ischemia and metabolic crisis are frequent post-traumatic secondary brain insults that negatively influence outcome. Clinicians commonly mix up these two types of insults, mainly because high lactate/pyruvate ratio (LPR) is the common marker for both ischemia and metabolic crisis. However, LPR elevations during ischemia and metabolic crisis reflect two different energetic imbalances: ischemia (Type 1 LPR elevations with low oxygenation) is characterized by a drastic deprivation of energetic substrates, whereas metabolic crisis (Type 2 LPR elevations with normal or high oxygenation) is associated with profound mitochondrial dysfunction but normal supply of energetic substrates. The discrimination between ischemia and metabolic crisis is crucial because conventional recommendations against ischemia may be detrimental for patients with metabolic crisis. Multimodal monitoring, including microdialysis and brain tissue oxygen monitoring, allows such discrimination, but these techniques are not easily accessible to all head-injured patients. Thus, a new "gold standard" and adapted medical education are required to optimize the management of patients with metabolic crisis.

  19. Comparative assessment of the effectiveness of modern neuroprotectors in conditions of experimental chronic cerebral ischemia

    Directory of Open Access Journals (Sweden)

    A. V. Demchenko

    2015-04-01

    Full Text Available Modern pharmacological influence on the pathological changes in cerebral ischemia is actual task of the modern neurology. Aim. To make a comparative assessment of the effectiveness of modern neuroprotectors in conditions of experimental chronic cerebral ischemia. Methods and results. Experimental study of the neuroprotective effects of the citicoline, cortexin and tiocetam on the cognitive functions on the model of the chronic cerebral ischemia was conducted on 75 white rats. Biochemical, immunoassay, pharmacological, statistical methods were used. Conclusion. Obtained results showed citicoline, cortexin and tiocetam ability to positively influence on the molecular-biochemical changes in the brain cortex with ischemia. This resulted in the glutathione-dependent enzymes activity increase, recover of the thiol-disulfide system balance, nitrotyrosine concentration decrease, improvement of the cognitive function in the experimental animals.

  20. Comprehensive regional and temporal gene expression profiling of the rat brain during the first 24 h after experimental stroke identifies dynamic ischemia-induced gene expression patterns, and reveals a biphasic activation of genes in surviving tissue

    DEFF Research Database (Denmark)

    Rickhag, Karl Mattias; Wieloch, Tadeusz; Gidö, Gunilla

    2006-01-01

    In order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large-scale cDNA array analysis of three peri-infarct brain regions at eight time points during the first 24 h of reperfusion following......-dehydrogenase1, and Choline kinase) or cell death-regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up-regulation of the brain-derived neurotrophic factor (BDNF)-G-protein coupled receptor (GPCR)-mitogen-activated protein (MAP) kinase signaling pathways occurs in surviving...... tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity....

  1. Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

    Science.gov (United States)

    Himeda, Toshiki; Hayakawa, Natsumi; Tounai, Hiroko; Sakuma, Mio; Kato, Hiroyuki; Araki, Tsutomu

    2005-11-01

    We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can

  2. ARGININE VASOPRESSIN GENE EXPRESSION IN SUPRAOPTIC NUCLEUS AND PARAVENTRICULAR NUCLEUS OF HYPOTHALAMOUS FOLLOWING CEREBRAL ISCHEMIA AND REPERFUSION

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Background. Our previous studies indicated that the increased arginine vasopressin(AVP) in ischemic brain regions of gerbils could exacerbate the ischemic brain edema. This experiments is further clarify the relation between AVP and cerebral ischemia at the molecular level. Methods. The contents of AVP, AVP mRNA, AVP immunoreactive(ir) neurons in supraoptic nucleus(SON)and paraventricular nucleus(PVN) after cerebral ischemia and reperfusion were respectively determined by radioim-munoassay(RIA), immunocytochemistry( Ⅱ C), situ hybridization and computed image pattem analysis. Results. The contents of AVP in SON, PVN were increased, and the AVP ir positive neurons in SON and PVN were also significantly increased as compared with the controls after ischemia and reperfusion. And there were very light staining of AVP ir positive neurons in the other brain areas such as suprachiasmatic nucleus (SC) and periven-tricular hypothalamic nucleus (PE), but these have no significant changes as compared with the controls. During dif-ferent periods of cerebral ischemia (30~ 120 min) and reperfusion (30 min), AVP mRNA expression in SON and PVN were more markedly increased than the controls. Condusions. The transcription of AVP gene elevated, then promoting synthesis and release of AVP in SON,PVN. Under the specific condition of cerebral ischemia and repeffusion, the activity and contents of central AVP in-creased abnormally is one of the important factors which causes ischemia brain damage.

  3. Responses of CA1 pyramidal neurons in rat hippocampus to transient forebrain ischemia: an in vivo intracellular recording study.

    Science.gov (United States)

    Xu, Z C; Pulsinelli, W A

    1994-04-25

    The electrophysiological responses of CA1 pyramidal neurons to 5 min forebrain ischemia were studied with intracellular recording and staining techniques in vivo. The baseline membrane potential rapidly depolarized to approximately -20 mV about 3 min after the onset of ischemia and began to repolarize 1-3 min after recirculation. The amplitude of this ischemic depolarization (ID) was related directly to the severity of ischemia and its latency of onset was inversely related to brain temperature. Spontaneous synaptic activity ceased shortly after ischemia onset while the evoke synaptic potentials lasted until shortly before the onset of ID. Inhibitory postsynaptic potentials (IPSPs) disappeared earlier than excitatory postsynaptic potentials (EPSPs) and the membrane input resistance of CA1 neurons increased after the onset of ischemia.

  4. 高血糖加重全脑缺血再灌注后缺血不敏感区神经元损伤%Hyperglycemia increases neuron injury in the invulnerable regions under global brain ischemia/reperfusion in rats*

    Institute of Scientific and Technical Information of China (English)

    景丽; 张建忠; 马轶; 郭风英; 王一理

    2011-01-01

    目的:探讨高血糖条件下脑缺血再灌注损伤加重的机制.方法:通过双侧颈总动脉结扎及放血法制备大鼠全脑缺血/再灌注模型,采用组织病理学、组织化学显色和末端脱氧核苷酸转移酶介导的dUTP原位切口末端标记(TUNEL)染色,对比观察注射性高血糖和糖尿病性高血糖大鼠神经元变性以及凋亡.结果:缺血敏感区额叶皮质和海马CA1区可见,各实验组在缺血15 min,再灌注1、3、6h各时间点变性和凋亡神经元数量均多于假手术组(P<0.01).但高血糖组、糖尿病组在缺血15 min,再灌注1、3、6h各时间点,变性和凋亡神经元的数目与正常血糖组接近.在缺血耐受区扣带皮质和海马CA3区,高血糖组和糖尿病组在缺血15 min,再灌注1、3、6h各时间点,变性和凋亡神经元的数目多于正常血糖组(P<0.05).在糖尿病组和高血糖组之间,各时间点变性和凋亡神经元数量无差异.结论:不论是急性高血糖还是糖尿病性高血糖,均可加重暂时性全脑缺血再灌注所引起的神经元损伤,特别是在高血糖条件下,大鼠脑缺血不敏感区扣带皮质和海马CA3区变性及凋亡神经元增加.%Objective:To explore the mechanism by which increases brain injury induced by ischemia/reperfusion under hyperglycemia. Methods: Rats with hyperglycemia injected glucose (hyperglycemia group), hyperglycemia with experimental diabetes mellitus (diabetes group) were subjected to 15 min of global brain ischemia, and then reperfused for 1, 3 and 6 hours. Global brain ischemia and reperfusion was induced with the 2-common carotid arteries occlusion model with exsangui-nation and reinfusing the shed blood. The degeneration and apoptosis of neurons in the experimental rats were detected by means of histopathology, histochemistry and TdT-mediated-dUTP nick end labeling (TUNED techniques. Results: In the vulnerable regions of frontal cortex and CA1 sector of hippocampus, the degeneration

  5. Effect of Rosiglitazone Maleate on Inflammation Following Cerebral Ischemia/Reperfusion in Rats

    Institute of Scientific and Technical Information of China (English)

    XIONG Nanxiang; SUN Fan; ZHAO Hongyang; XIANG Jizhou

    2007-01-01

    In order to evaluate the neuroprotective effect of Rosiglitazone Maleate (RSG) against brain ischemic injury, the effects of Rosiglitazone Maleate on the inflammation following cerebral ischemia/reperfusion were investigated. Focal cerebral ischemia was induced by the intraluminal thread for cerebral middle artery (MCA) occlusion. Rosiglitazone Maleate at concentrations of 0.5,2 and 5 mg/kg was infused by intragastric gavage twice immediately and 2 h after MCA occlusion,respectively. The effects of Rosiglitazone Maleate on brain swelling, myeloperoxidase and interleukin-6 mRNA level in brain tissue after MCA occlusion and reperfusion were evaluated. The results showed that as compared with the model control group, RSG (0.5 mg/kg) had no significant influence on brain swelling (P>0.05), but 2 mg/kg and 5 mg/kg RSG could significantly alleviate brain swelling (P<0.05). All different doses of RSG could obviously reduce MPO activity in brain tissue after MCA occlusion and reperfusion in a dose-dependent manner. RSG (0.5 and 2 mg/kg) could decrease the expression levels of IL-6 mRNA in brain tissue after MCA occlusion and reperfusion to varying degrees (P<0.05) with the difference being significant between them. It was concluded that RSG could effectively ameliorate brain ischemic injury after 24 h MCA occlusion and inhibit the inflammatory response after ischemia-reperfusion in this model.

  6. Targeting reactive nitrogen species: a promising therapeutic strategy for cerebral ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Xing-miao CHEN; Han-sen CHEN; Ming-jing XU; Jian-gang SHEN

    2013-01-01

    Ischemic stroke accounts for nearly 80% of stroke cases.Recanalization with thrombolysis is a currently crucial therapeutic strategy for re-building blood supply,but the thrombolytic therapy often companies with cerebral ischemia-reperfusion injury,which are mediated by free radicals.As an important component of free radicals,reactive nitrogen species (RNS),including nitric oxide (NO) and peroxynitrite (ONO0ˉ),play important roles in the process of cerebral ischemia-reperfusion injury.Ischemia-reperfusion results in the production of nitric oxide (NO) and peroxynitrite (ONOOˉ) in ischemic brain,which trigger numerous molecular cascades and lead to disruption of the blood brain barrier and exacerbate brain damage.There are few therapeutic strategies available for saving ischemic brains and preventing the subsequent brain damage.Recent evidence suggests that RNS could be a therapeutic target for the treatment of cerebral ischemia-reperfusion injury.Herein,we reviewed the recent progress regarding the roles of RNS in the process of cerebral ischemic-reperfusion injury and discussed the potentials of drug development that target NO and ONO0ˉ to treat ischemic stroke.We conclude that modulation for RNS level could be an important therapeutic strategy for preventing cerebral ischemiareperfusion injury.

  7. Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats.

    Directory of Open Access Journals (Sweden)

    Jun Li

    Full Text Available BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia. METHODS: Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis. RESULTS: Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+ increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period. CONCLUSIONS: Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+-induced mitochondrial swelling. The mechanism of this swelling may be mediated by

  8. Effects of hypoxic pretreatment on changes in cerebral ultrastructure and free radical content induced by brain hypoxia and ischemia%缺氧预处理对缺血缺氧脑组织超微结构与自由基的影响

    Institute of Scientific and Technical Information of China (English)

    孟凌新; 董有靖; 崔健君; 王忠成

    2001-01-01

    目的观察缺氧预处理对缺血缺氧脑组织超微结构及脑组织自由基的影响.方法将40只小鼠随机分为4组.A组为盐水对照组,B组为缺氧预处理组,IH组为缺血缺氧组,BIH组为缺氧预处理后缺血缺氧组.各组有6只小鼠分别采用黄嘌呤氧化酶法和硫代巴比妥酸法检测脑组织的超氧化物歧化酶(SOD)活性和丙二醛(MDA)含量,另4只小鼠用于透射电镜下脑组织超微结构的观察.结果与A组比较,B组SOD活性增加,IH组MDA含量明显增加,而BIH组SOD活性明显增加的同时,MDA含量较比IH组明显降低.电镜显示B组除部分神经元轻度肿胀外,脑组织超微结构基本同A组,IH组细胞核变形,细胞浆成空泡,严重者满视野几乎找不到正常细胞,无损害的神经元<10%,BIH组细胞结构基本恢复正常,无损伤神经元达63%.结论缺氧预处理对再缺血缺氧引起的神经元损伤有保护作用,内源性抗氧化物质的增加与其有直接关系.%Objective To investigate whether hypoxic pretreatment could ameliorate the cerebral injuries induced by brain hypoxia and ischemia. Methods Forty mice weighting 18-25g were randomly allocated to 4 groups of ten mice each. Group A served as control. In group B animals received hypoxic pretreatment. Mouse was put in a 150ml bottle, then the mouth of the bottle was closed. The mouse was taken out breathing fresh air whenever it developed dyspnea. When it recovered, it was put in the closed bottle again. The process was repeated four times. In group IH animals received ischemia/hypoxia induced by ligation of left common carotid artery and breathing 8% O2 . In group BIH animals received hypoxic pretreatment first and then ischemia/hypoxia. All animals were decapitated at the end of experiment and brain was removed for ultrastrcture examination and determination of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Results In group B SOD activity incrreased significantly as

  9. Changes of monoamine nervous transmitter and free radical met abolism in aged rats with gastrointestinal injury after brain ischemia reper fusion%脑缺血再灌注胃肠损伤老龄大鼠单胺类神经递质 和自由基代谢的变化

    Institute of Scientific and Technical Information of China (English)

    李建生; 赵君玫; 郭盛典; 李建国

    2001-01-01

    Objective: To study the mechanism of gastrointestinal injury after brain ischemia reperfusi on in aged rats from the changes of dopamine(DA),noradrenalin(NE),epinephrine(E) and the injury of free radical.Methods:Young(5months) and aged (20 months or more) rats were divided into young model group (YMG),young control group(YCG),aged model group (AMG),aged control group(ACG).The following items were measured in rats with 60 minute reperfusion after 30 minute brain ischemia:the pathological change of ga strointestinal tract:the activities of super-oxide dismutase(SOD),the contents of MDA,DA,NE,E. Results:The pathological change of gastrointestinal tract was found in the YMG and the AMG.The excitability of sympathetic-adrenal system was enhanced in the YMG and the AMG,this change in the AMG was serious compared w ith that in the YMG.The gastrointestinal MDA/SOD ratio was larger in the ACG and the YMG than that in the YCG.The stomach MDA/SOD ratio was larger in the AMG th an that in the ACG and the YMG.Conclusion: The gastrointestinal injury after brain ischemia rep erfusion in aged rats was correlated with the change of the enhanced excitabilit y of sympathetic-adrenal system and free radical injury.With aging these pathol ogical change were obvious and distinctive compared with that in the young rats.%目的:从多巴胺(DA)、去甲肾上腺素(NE)、肾上腺素(E)变化和自由基损伤方面揭示脑缺血再灌注胃肠损伤的机制。方法:青年(5月龄)和老龄(20月龄以上)大鼠均分为模型组和正常对照组,观察大鼠全脑缺血30 min再灌注60 min后胃肠损伤的病理改变和超氧化物岐化酶(SOD)的活性及丙二醛(MDA)、DA、NE、E含量。结果:青年和老龄模型组胃肠出现明显的病理改变。青年和老龄模型组交感-肾上腺系统兴奋性增强,其中老龄模型组较青年模型组大鼠严重。老龄对照组和青年模型组胃肠组织MDA/SOD比值高于青年对照组,

  10. Method of empirical dependences in estimation and prediction of activity of creatine kinase isoenzymes in cerebral ischemia

    Science.gov (United States)

    Sergeeva, Tatiana F.; Moshkova, Albina N.; Erlykina, Elena I.; Khvatova, Elena M.

    2016-04-01

    Creatine kinase is a key enzyme of energy metabolism in the brain. There are known cytoplasmic and mitochondrial creatine kinase isoenzymes. Mitochondrial creatine kinase exists as a mixture of two oligomeric forms - dimer and octamer. The aim of investigation was to study catalytic properties of cytoplasmic and mitochondrial creatine kinase and using of the method of empirical dependences for the possible prediction of the activity of these enzymes in cerebral ischemia. Ischemia was revealed to be accompanied with the changes of the activity of creatine kinase isoenzymes and oligomeric state of mitochondrial isoform. There were made the models of multiple regression that permit to study the activity of creatine kinase system in cerebral ischemia using a calculating method. Therefore, the mathematical method of empirical dependences can be applied for estimation and prediction of the functional state of the brain by the activity of creatine kinase isoenzymes in cerebral ischemia.

  11. Expressional changes in cerebrovascular receptors after experimental transient forebrain ischemia

    DEFF Research Database (Denmark)

    Johansson, Sara; Povlsen, Gro Klitgaard; Edvinsson, Lars

    2012-01-01

    of vasoconstrictive endothelin and 5-hydroxytryptamine receptors in cerebral arteries. Experimental transient forebrain ischemia of varying durations was induced in male wistar rats, followed by reperfusion for 48 hours. Neurological function was assessed daily by three different tests and cerebrovascular expression......Global ischemic stroke is one of the most prominent consequences of cardiac arrest, since the diminished blood flow to the brain results in cell damage and sometimes permanently impaired neurological function. The post-arrest period is often characterised by cerebral hypoperfusion due to subacute...... the insult, a phenomenon that leads to increased contraction of cerebral arteries, reduced perfusion of the affected area and worsened ischemic damage. Based on these findings, the aim of the present study was to investigate if transient global cerebral ischemia is associated with upregulation...

  12. Minocycline inhibits neuroinflammation and enhances vascular endothelial growth factor expression in a cerebral ischemia/reperfusion rat model

    Institute of Scientific and Technical Information of China (English)

    Zhiyou Cai; Yong Yan; Changyin Yu; Jun Zhang

    2008-01-01

    BACKGROUND: Brain ischemia involves secondary inflammation, which significantly contributes to the outcome of ischemic insults. Vascular endothelial growth factor (VEGF) may play an important role in the vascular response to cerebral ischemia, because ischemia stimulates VEGF expression in the brain, and VEGF promotes formation of new cerebral blood vessels. Minocyclinc, a tetracycline derivative, protects against cerebral ischemia and reduces inflammation, oxidative stress, and apoptosis.OBJECTIVE: To observe the influence of minocycline on VEGE interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) expression in Wistar rats with focal cerebral ischemia/rcperfusion injury, and to study the neuroproteetion mechanism of minocycline against focal cerebral ischemia/rcpeffusion injury.DESIGN, TIME AND SETTING: Randomized, controlled experiment, which was performed in the Chongqing Key Laboratory of Neurology between March 2007 and March 2008.MATERIALS: A total of 36 female, Wistar rats underwent surgery to insert a thread into the left middle cerebral artery. Animals were randomly divided into sham-operation, minocyclinc treatment, and ischemia/reperfusion groups, with 12 rats in each group. Minocycline (Huishi Pharmaceutical Limited Company, China) was dissolved to 0.5 g/L in normal saline.METHODS: A 0.5- 1.0 cm thread was inserted into rats from the sham-operation group. Rats in the ischemia/reperfusion group underwent ischemia and reperfusion. The minocycline group received minocycline (50 mg/kg) 12 and 24 hours following ischemia and reperfusion, whereas the other groups received saline at the corresponding time points.MAIN OUTCOME MEASURES: mRNA and protein expression of IL-1β and TNF-α was measured by reverse transcriptase-polymerasc chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA), respectively. VEGF mRNA and protein expression was examined by RT-PCR, Western blot, and ELISA.RESULTS: Minocycline decreased the focal infarct

  13. Cerebral hypoxia and ischemia in preterm infants

    Directory of Open Access Journals (Sweden)

    Alberto Ravarino

    2014-06-01

    Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

  14. Ischemic postconditioning protects against ischemic brain injury by up-regulation of acid-sensing ion channel 2a

    Institute of Scientific and Technical Information of China (English)

    Wang-sheng Duanmu; Liu Cao; Jing-yu Chen; Hong-fei Ge; Rong Hu; Hua Feng

    2016-01-01

    Ischemic postconditioning renders brain tissue tolerant to brain ischemia, thereby alleviating ischemic brain injury. However, the exact mechanism of action is still unclear. In this study, a rat model of global brain ischemia was subjected to ischemic postconditioning treat-ment using the vessel occlusion method. After 2 hours of ischemia, the bilateral common carotid arteries were blocked immediately for 10 seconds and then perfused for 10 seconds. This procedure was repeated six times. Ischemic postconditioning was found to mitigate hippocampal CA1 neuronal damage in rats with brain ischemia, and up-regulate acid-sensing ion channel 2a expression at the mRNA and protein level. These ifndings suggest that ischemic postconditioning up-regulates acid-sensing ion channel 2a expression in the rat hippo-campus after global brain ischemia, which promotes neuronal tolerance to ischemic brain injury.

  15. Controversies in cardiovascular care: silent myocardial ischemia

    Science.gov (United States)

    Hollenberg, N. K.

    1987-01-01

    The objective evidence of silent myocardial ischemia--ischemia in the absence of classical chest pain--includes ST-segment shifts (usually depression), momentary left ventricular failure, and perfusion defects on scintigraphic studies. Assessment of angina patients with 24-hour ambulatory monitoring may uncover episodes of silent ischemia, the existence of which may give important information regarding prognosis and may help structure a more effective therapeutic regimen. The emerging recognition of silent ischemia as a significant clinical entity may eventually result in an expansion of current therapy--not only to ameliorate chest pain, but to minimize or eliminate ischemia in the absence of chest pain.

  16. Brain damage of cerebral ischemia/reperfusion and expression of TGF-β1 mRNA in diabetic rats%糖尿病大鼠局灶脑缺血/再灌注损伤 与脑组织TGF-β1 mRNA表达

    Institute of Scientific and Technical Information of China (English)

    王桂侠; 李广仁; 欧阳一冰; 杨同书; 王绍

    2001-01-01

    目的:观察糖尿病和对照组鼠脑缺血/再灌注损伤与转化生长因子β1(TGF-β1) mRNA表达的异质性。方法: 采用逆转录聚合酶链式反应(RT-PCR)检测大鼠中脑动脉阻塞(MCAO)后脑内TGF-β1 mRNA表达水平,并且应用组织病理进行损伤程度评定。 结果:糖尿病组大鼠脑缺血及缺血/再灌损伤程度明显重于“相应对照组”。糖尿病及对照组大鼠在MCAO 2 h时TGF-β1 mRNA表达量明显增高,后者增高比前者更为明显。再灌24 h后TGF-β1 mRNA表达量下降,但仍高于假手术组。 结论: 糖尿病加重缺血/再灌性脑损伤;MCAO后TGF-β1 mRNA表达增高可能是机体一种抗损伤反应,糖尿病组抗损伤反应下降。%AIM: To observe the difference of cerebral injury following ischemia/reperfusion and mRNA expression of TGF-β1 between diabetic and non-diabetic rats.METHODS: At first, Wistar rats were divided into two groups,non-diabetes and diabetes, and then two groups followed by sham, middle cerebral artery occlusion(MCAO) 2h and reperfusion 24 h after MCAO 2 h respectively. TGF-β1 mRNA expression was measured by semi-quantitative reverse transcription polymerase chain reaction(RT-PCR); Cerebral damage was evaluated by histopathology.RESULTS: In the same condition of ischemia or ischemia/reperfusion, injuried area enlarged in DM groups; The expression level of TGF-β1 mRNA increased at the time of 2 h after MCAO in non-diabetic group and diabetic group, especialy significantly in non-diabetic group with MCAO 2 h, and decreased at the time of reperfusion 24 h after MCAO 2 h, but still higher than that in the sham group.CONCLUSION: Diabetes mellitus exacerbated brain lesion following ischemia/repefusion, increased TGF-β1 mRNA expresion after MCAO may be an anti-injury reaction,and anti-injury ability is decreased under diabetic condition

  17. Synergistic effects of prostaglandin E1 and lithium in a rat model of cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Rong RAN; Bo GAO; Rui SHENG; Li-sha ZHANG; Hui-lin ZHANG; Zhen-lun GU; Zheng-hong QIN

    2008-01-01

    Aim:Heat shock proteins (HSPs) are important regulators of cellular survival and exert neuroprotective effects against cerebral ischemia.Both prostaglandin El (PGEI) and lithium have been reported to protect neurons against ischemic injury.The present study was undertaken to examine if lithium could potentiate the neuroprotection of PGE 1 against cerebral ischemia,and if the synergetic effects take place at the level of HSPs.Methods:Brain ischemia was induced by a permanent middle cerebral artery occlusion (pMCAO) in rats.Rats were pretreated with subcutaneous injection of lithium for 2 d and a single intravenous administration of PGEI immediately after ischemic insult.Cerebrocortical blood flow of each group was closely monitored prior to onset of ischemia,5 min,15 rain,30 min and 60 min after surgical operation.Body temperature was measured before,5 min,2 h and 24 h after the onset of pMCAO.The infarct volume,brain edema and motor behavior deficits were analyzed 24 h after ischemic insult.Cytoprotective HSP70 and heme oxygenase-1 (HO-1) in the striatum of the ipsilateral hemisphere were detected by immunoblotting.Brain sections from the striatum of the ipsilateral hemisphere were double-labeled with the anti-HSP70 antibody and 4,6-diamidino-2-phenylindole (DAPI).Results:Treatment with PGEI (8 and 16 ~tg/kg,iv) or lithium (0.5 mEq/kg,sc) alone reduced infarct volume,neurological deficits and brain edema induced by focal cerebral ischemia in rats.Moreover,a greater neuroprotection was observed when PGEI and lithium were given together.Co-administration of PGE1 and lithium significantly upregulated cytoprotective HSP70 and HO-1 protein levels.Conclusion:Lithium and PGEI may exert synergistic effects in treatment of cerebral ischemia and thus may have potential clinical value for the treatment of stroke.

  18. Protective effects of mangiferin on cerebral ischemia-reperfusion injury and its mechanisms.

    Science.gov (United States)

    Yang, Zhang; Weian, Chen; Susu, Huang; Hanmin, Wang

    2016-01-15

    The aim of our study was to investigate the protective properties of mangiferin, a natural glucosyl xanthone found in both mango and papaya on the cerebral ischemia-reperfusion injury and the underlying mechanism. Wistar male rats were subjected to middle cerebral artery occlusion for 2h followed by 24h of reperfusion. Mangiferin (25, 50, and 100mg/kg, ig) or 0.5% carboxymethyl cellulose sodium was administered three times before ischemia and once at 2h after the onset of ischemia. Neurological score, infarct volume, and brain water content, some oxidative stress markers and inflammatory cytokines were evaluated after 24h of reperfusion. Treatment with mangiferin significantly ameliorated neurologic deficit, infarct volume and brain water content after cerebral ischemia reperfusion. Mangiferin also reduced the content of malondialdehyde (MDA), IL-1β and TNF-α, and up-regulated the activities of superoxide dismutase (SOD), glutathione (GSH) and IL-10 levels in the brain tissue of rats with the cerebral ischemia-reperfusion injury. Moreover, mangiferin up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream anti-oxidant protein heme oxygenase-1 (HO-1). The results indicate that mangiferin can play a certain protective role in the cerebral ischemia-reperfusion injury, and the protective effect of mangiferin may be related to the improvement on the antioxidant capacity of brain tissue and the inhibition of overproduction of inflammatory cytokines. The mechanisms are associated with enhancing the oxidant defense systems via the activation of Nrf2/HO-1 pathway.

  19. Arachidonic Acid and Cerebral Ischemia Risk: A Systematic Review of Observational Studies

    Directory of Open Access Journals (Sweden)

    Mai Sakai

    2014-11-01

    Full Text Available Background: Arachidonic acid (ARA is a precursor of various lipid mediators. ARA metabolites such as thromboxane A2 cause platelet aggregation and vasoconstriction, thus may lead to atherosclerotic disease. It is unclear whether dietary ARA influences the ARA-derived lipid mediator balance and the risk for atherosclerotic diseases, such as cerebral ischemia. Considering the function of ARA in atherosclerosis, it is reasonable to focus on the atherothrombotic type of cerebral ischemia risk. However, no systematic reviews or meta-analyses have been conducted to evaluate the effect of habitual ARA exposure on cerebral ischemia risk. We aimed to systematically evaluate observational studies available on the relationship between ARA exposure and the atherothrombotic type of cerebral ischemia risk in free-living populations. Summary: The PubMed database was searched for articles registered up to June 24, 2014. We designed a PubMed search formula as follows: key words for humans AND brain ischemia AND study designs AND ARA exposure. Thirty-three articles were reviewed against predefined criteria. There were 695 bibliographies assessed from the articles that included both ARA and cerebral ischemia descriptions. Finally, we identified 11 eligible articles and categorized them according to their reporting and methodological quality. We used the Strengthening the Reporting of Observational Studies in Epidemiology Statement (STROBE checklist to score the reporting quality. The methodological quality was qualitatively assessed based on the following aspects: subject selection, ARA exposure assessment, outcome diagnosis, methods for controlling confounders, and statistical analysis. We did not conduct a meta-analysis due to the heterogeneity among the studies. All eligible studies measured blood ARA levels as an indicator of exposure. Our literature search did not identify any articles that evaluated dietary ARA intake and tissue ARA as assessments of

  20. Prostacyclin infusion may prevent secondary damage in pericontusional brain tissue

    DEFF Research Database (Denmark)

    Reinstrup, Peter; Nordström, Carl-Henrik

    2011-01-01

    Prostacyclin is a potent vasodilator, inhibitor of leukocyte adhesion, and platelet aggregation, and has been suggested as therapy for cerebral ischemia. A case of focal traumatic brain lesion that was monitored using intracerebral microdialysis, and bedside analysis and display is reported here....... When biochemical signs of cerebral ischemia progressed, i.v. infusion of prostacyclin was started....

  1. Ischemia-induced endothelial cell swelling and mitochondrial dysfunction are attenuated by dietary polyphenols in vitro

    Science.gov (United States)

    Polyphenols possess anti-oxidant and anti-inflammatory properties. Oxidative stress (OS) and inflammation have been implicated in the pathogenesis of cytotoxic brain edema in cerebral ischemia. In addition, OS and pro-inflammatory cytokines also damage the endothelial cells and the neurovascular uni...

  2. Characteristics of global cerebral ischemia models constructed by modified four-vessel occlusion in rats

    Institute of Scientific and Technical Information of China (English)

    Jinbao Li; Lai Jiang; Hua Xu; Yuanchang Xiong; Xiaoming Deng

    2006-01-01

    (n =15): ischemia 15 minutes and reperfusion 180 minutes. ② Preparation of the model of global cerebral ischemia: Four-vessel occlusion- induced global cerebral ischemia rat models were modified, I.e. Bilateral vertebral arteries could be electrocauterized and blocked, and bilateral common carotid arteries were enclosed with 10-0 suture loosely. On the second day, keeping the animal awake, the suture was tightened and kept tense to block the blood flow of bilateral common carotid artery. After certain duration of ischemia, the suture was cut off and drawn out, thus the reperfusion of bilateral common carotid artery was resumed. ③Observation of physiological indexes: VSM hemodynamic monitor and temperature monitor (Thermal ert TH-5,U.S.A) were used to record and measure the changes of blood pressure, rectal temperature, brain temperature ,arterial blood gas and other physiological indexes of the rats in the control group before, 5 and 15 minutes after ischemia and 10,30,60,120 and 180 minutes after reperfusion. ④Preparation of brain tissue pathological samples: Except for ischemia control group, rats of other groups were anesthetized and their brain tissues were harvested and subjected to haematoxylin and eosin staining at 72 hours after reperfusion. ⑤ Evaluation of pathological change of brain tissue: The coronal plane of anterior commissure of cerebrum was used to evaluate corpora striatum, and the coronal plane of anterior hippocampus was used to evaluate hippocampal CA1/2 region, CA3 region and CA4 region, subiculum, superior pyramidal lobe and inferior pyramidal lobe of dentate gyrus as well as neocortex. Irreversible neuronal damage included pyknotic cells with eosinophilic cytoplasm and trachychromatic nucleus, homogenous cytoplasm and naked nucleus. Neurons without the above changes were considered to be normal. The number of normal neurons in the above-mentioned brain regions was counted under the microscope. MAIN OUTCOME MEASURES: ① The changes of

  3. 可卡因-苯丙胺调节转录肽在脑缺血中的神经保护机制%Neuroprotective mechanisms of cocaine-and amphetamine-regulated transcript peptides in brain ischemia

    Institute of Scientific and Technical Information of China (English)

    王路娜; 沙杜鹃; 张均

    2013-01-01

    可卡因-苯丙胺调节转录肽(cocaine-and amphetamine-regulated transcript peptides,CART)是一种存在于人和动物的内源性神经肽,参与调节体内多种生理和病理学过程.多项研究提示,CART在中枢神经系统中广泛分布,具有一定的中枢神经保护作用.文章对CART在脑缺血中的神经保护机制进行了综述.%Cocaine-and amphetamine-regulated transcript(CART) peptides are endogenous neurotransmitters with important roles in a number of physiological and pathological processes in vivo.Many studies suggested that CART is widely distributed in the central nervous system,and it has some central protective effects.This article reviews the recent progress in research on the protective effect of CART on cerebral ischemia and its mechanisms.

  4. Inlfammatory response and neuronal necrosis in rats with cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Lingfeng Wu; Kunnan Zhang; Guozhu Hu; Haiyu Yang; Chen Xie; Xiaomu Wu

    2014-01-01

    In the middle cerebral artery occlusion model of ischemic injury, inlfammation primarily occurs in the infarct and peripheral zones. In the ischemic zone, neurons undergo necrosis and apop-tosis, and a large number of reactive microglia are present. In the present study, we investigated the pathological changes in a rat model of middle cerebral artery occlusion. Neuronal necrosis appeared 12 hours after middle cerebral artery occlusion, and the peak of neuronal apoptosis ap-peared 4 to 6 days after middle cerebral artery occlusion. Inlfammatory cytokines and microglia play a role in damage and repair after middle cerebral artery occlusion. Serum intercellular cell adhesion molecule-1 levels were positively correlated with the permeability of the blood-brain barrier. These ifndings indicate that intercellular cell adhesion molecule-1 may be involved in blood-brain barrier injury, microglial activation, and neuronal apoptosis. Inhibiting blood-brain barrier leakage may alleviate neuronal injury following ischemia.

  5. Systematic investigation of transcription factors critical in the protection against cerebral ischemia by Danhong injection

    Science.gov (United States)

    Wei, Junying; Zhang, Yanqiong; Jia, Qiang; Liu, Mingwei; Li, Defeng; Zhang, Yi; Song, Lei; Hu, Yanzhen; Xian, Minghua; Yang, Hongjun; Ding, Chen; Huang, Luqi

    2016-01-01

    Systematic investigations of complex pathological cascades during ischemic brain injury help to elucidate novel therapeutic targets against cerebral ischemia. Although some transcription factors (TFs) involved in cerebral ischemia, systematic surveys of their changes during ischemic brain injury have not been reported. Moreover, some multi-target agents effectively protected against ischemic stroke, but their mechanisms, especially the targets of TFs, are still unclear. Therefore, a comprehensive approach by integrating network pharmacology strategy and a new concatenated tandem array of consensus transcription factor response elements method to systematically investigate the target TFs critical in the protection against cerebral ischemia by a medication was first reported, and then applied to a multi-target drug, Danhong injection (DHI). High-throughput nature and depth of coverage, as well as high quantitative accuracy of the developed approach, make it more suitable for analyzing such multi-target agents. Results indicated that pre-B-cell leukemia transcription factor 1 and cyclic AMP-dependent transcription factor 1, along with six other TFs, are putative target TFs for DHI-mediated protection against cerebral ischemia. This study provides, for the first time, a systematic investigation of the target TFs critical to DHI-mediated protection against cerebral ischemia, as well as reveals more potential therapeutic targets for ischemic stroke. PMID:27431009

  6. Neuroprotective effect of olive oil in the hippocampus CA1 neurons following ischemia: Reperfusion in mice

    Directory of Open Access Journals (Sweden)

    M Zamani

    2013-01-01

    Full Text Available Introduction: Transient global ischemia induces selective, delayed neuronal death of pyramidal neurons in the hippocampal CA1. Oxidative Stress is considered to be involved in a number of human diseases including ischemia. Preliminary studies confirmed reduction of cell death in brain following treatment with antioxidants. Aim: According to this finding, we study the relationship between consumption of olive oil on cell death and memory disorder in brain ischemia. We studied the protective effect of olive oil against ischemia-reperfusion. Material and Methods: Experimental design includes three groups: Intact (n = 8, ischemic control (n = 8 and treatment groups with olive oil (n = 8. The mice treated with olive oil as pre-treatment for a week. Then, ischemia induced by common carotid artery ligation and following the reduction of inflammation [a week after ischemia], the mice post-treated with olive oil. Nissl staining applied for counting necrotic cells in hippocampus CA1. Tunnel kit was used to quantify apoptotic cell death while to short term memory scale, we apply y-maze and shuttle box tests and for detection the rate of apoptotic and treated cell, we used western blotting test for bax and bcl2 proteins. Results: High rate of apoptosis was seen in ischemic group that significantly associated with short-term memory loss. Cell death was significantly lower when mice treated with olive oil. The memory test results were adjusted with cell death results and bax and bcl2 expression in all groups′ comparison. Ischemia for 15 min induced cell death in hippocampus with more potent effect on CA1. Conclusion: Olive oil intake significantly reduced cell death and decreased memory loss.

  7. Effects of ketamine,midazolam,thiopental,and propofol on brain ischemia injury in rat cerebral cortical slices%氯胺酮,咪唑安定,硫喷妥钠和异丙酚对大鼠皮层脑片缺血性损伤的作用

    Institute of Scientific and Technical Information of China (English)

    薛庆生; 于布为; 王泽剑; 陈红专

    2004-01-01

    AIM: To compare the effects of ketamine, midazolam, thiopental, and propofol on brain ischemia by the model of oxygen-glucose deprivation (OGD) in rat cerebral cortical slices. METHODS: Cerebral cortical slices were incubated in 2 % 2,3,5-triphenyltetrazolium chloride (TTC) solution after OGD, the damages and effects of ketamine,midazolam, thiopental, and propofol were quantitativlye evaluated by ELISA reader of absorbance (A) at 490 nm,which indicated the red formazan extracted from slices, lactic dehydrogenase (LDH) releases in the incubated supernate were also measured. RESULTS: Progressive prolongation of OGD resulted in decreases of TTC staining.The percentage of tissue injury had a positive correlation with LDH releases, r=0.9609, P<0.01. Two hours of reincubation aggravated the decrease of TTC staining compared with those slices stained immediately after OGD (P<0.01). These four anesthetics had no effects on the TTC staining of slices. Ketamine completely inhibited the decrease of A value induced by 10 min of OGD injury. High concentrations of midazolam (10 μmol/L) and thiopental (400 μmol/L)partly attenuated this decrease. Propofol at high concentration (100 μmol/L) enhanced the decrease of A value induced by 10 min of OGD injury (P<0.01). CONCLUSION: Ketamine, high concentration of midazolam and thiopental have neuroprotective effects against OGD injury in rat cerebral cortical slices, while high concentration of propofol augments OGD injury in rat cerebral cortical slices.

  8. Glucose metabolism and neurogenesis in the gerbil hippocampus after transient forebrain ischemia

    Institute of Scientific and Technical Information of China (English)

    Dae Young Yoo; Kwon Young Lee; Joon Ha Park; Hyo Young Jung; Jong Whi Kim; Yeo Sung Yoon; Moo-Ho Won; Jung Hoon Choi; In Koo Hwang

    2016-01-01

    Recent evidence exists that glucose transporter 3 (GLUT3) plays an important role in the energy metabo-lism in the brain. Most previous studies have been conducted using focal or hypoxic ischemia models and have focused on changes in GLUT3 expression based on protein and mRNA levels rather than tissue levels. In the present study, we observed change in GLUT3 immunoreactivity in the adult gerbil hippocampus at various time points after 5 minutes of transient forebrain ischemia. In the sham-operated group, GLUT3 immunoreactivity in the hippocampal CA1 region was weak, in the pyramidal cells of the CA1 region in-creased in a time-dependent fashion 24 hours after ischemia, and in the hippocampal CA1 region decreased signiifcantly between 2 and 5 days after ischemia, with high level of GLUT3 immunoreactivity observed in the CA1 region 10 days after ischemia. In a double immunolfuorescence study using GLUT3 and gli-al-ifbrillary acidic protein (GFAP), we observed strong GLUT3 immunoreactivity in the astrocytes. GLUT3 immunoreactivity increased after ischemia and peaked 7 days in the dentate gyrus after ischemia/reperfu-sion. In a double immunolfuorescence study using GLUT3 and doublecortin (DCX), we observed low level of GLUT3 immunoreactivity in the differentiated neuroblasts of the subgranular zone of the dentate gyrus after ischemia. GLUT3 immunoreactivity in the sham-operated group was mainly detected in the subgran-ular zone of the dentate gyrus. These results suggest that the increase in GLUT3 immunoreactivity may be a compensatory mechanism to modulate glucose level in the hippocampal CA1 region and to promote adult neurogenesis in the dentate gyrus.

  9. Glucose metabolism and neurogenesis in the gerbil hippocampus after transient forebrain ischemia

    Science.gov (United States)

    Yoo, Dae Young; Lee, Kwon Young; Park, Joon Ha; Jung, Hyo Young; Kim, Jong Whi; Yoon, Yeo Sung; Won, Moo-Ho; Choi, Jung Hoon; Hwang, In Koo

    2016-01-01

    Recent evidence exists that glucose transporter 3 (GLUT3) plays an important role in the energy metabolism in the brain. Most previous studies have been conducted using focal or hypoxic ischemia models and have focused on changes in GLUT3 expression based on protein and mRNA levels rather than tissue levels. In the present study, we observed change in GLUT3 immunoreactivity in the adult gerbil hippocampus at various time points after 5 minutes of transient forebrain ischemia. In the sham-operated group, GLUT3 immunoreactivity in the hippocampal CA1 region was weak, in the pyramidal cells of the CA1 region increased in a time-dependent fashion 24 hours after ischemia, and in the hippocampal CA1 region decreased significantly between 2 and 5 days after ischemia, with high level of GLUT3 immunoreactivity observed in the CA1 region 10 days after ischemia. In a double immunofluorescence study using GLUT3 and glial-fibrillary acidic protein (GFAP), we observed strong GLUT3 immunoreactivity in the astrocytes. GLUT3 immunoreactivity increased after ischemia and peaked 7 days in the dentate gyrus after ischemia/reperfusion. In a double immunofluorescence study using GLUT3 and doublecortin (DCX), we observed low level of GLUT3 immunoreactivity in the differentiated neuroblasts of the subgranular zone of the dentate gyrus after ischemia. GLUT3 immunoreactivity in the sham-operated group was mainly detected in the subgranular zone of the dentate gyrus. These results suggest that the increase in GLUT3 immunoreactivity may be a compensatory mechanism to modulate glucose level in the hippocampal CA1 region and to promote adult neurogenesis in the dentate gyrus. PMID:27651772

  10. Experimental Focal Cerebral Ischemia

    DEFF Research Database (Denmark)

    Christensen, Thomas

    2007-01-01

    receptor antagonsists MK-801 and NBQX influence expression of Fos protein, a product of the immediate-early gene c-fos, and changes of general protein synthesis and glucose consumption in the penumbra in the acute phase following MCAO. The effect of treatment with ketobemidone, an opioid receptor agonist...... recruitment of penumbra to infarct resulting in mitigation of the final ischemic brain damage. The pathogenetic mechanisms involved in ischemic cell death in the penumbra encompass excitotoxic mechanisms mediated by activation of ionotropic glutamate receptors, loss of cellular calcium homeostasis...... and weak NMDA glutamate receptor antagonist, upon protein synthesis and glucose metabolism in the penumbra and infarct volume was investigated in a fourth study. In the fifth study, transient periinfarct depolarizations were recorded and the effect of treatment with the free radical scavenger α...

  11. Dynamic changes in the distribution and time course of blood-brain barrier-permeative nitroxides in the mouse head with EPR imaging: visualization of blood flow in a mouse model of ischemia.

    Science.gov (United States)

    Emoto, Miho C; Sato-Akaba, Hideo; Hirata, Hiroshi; Fujii, Hirotada G

    2014-09-01

    Electron paramagnetic resonance (EPR) imaging using nitroxides as redox-sensitive probes is a powerful, noninvasive method that can be used under various physiological conditions to visualize changes in redox status that result from oxidative damage. Two blood-brain barrier-permeative nitroxides, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (HMP) and 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy (MCP), have been widely used as redox-sensitive probes in the brains of small animals, but their in vivo distribution and properties have not yet been analyzed in detail. In this study, a custom-made continuous-wave three-dimensional (3D) EPR imager was used to obtain 3D EPR images of mouse heads using MCP or HMP. This EPR imager made it possible to take 3D EPR images reconstructed from data from 181 projections acquired every 60s. Using this improved EPR imager and magnetic resonance imaging, the distribution and reduction time courses of HMP and MCP were examined in mouse heads. EPR images of living mice revealed that HMP and MCP have different distributions and different time courses for entering the brain. Based on the pharmacokinetics of the reduction reactions of HMP and MCP in the mouse head, the half-lives of HMP and MCP were clearly and accurately mapped pixel by pixel. An ischemic mouse model was prepared, and the half-life of MCP was mapped in the mouse head. Compared to the half-life in control mice, the half-life of MCP in the ischemic model mouse brain was significantly increased, suggesting a shift in the redox balance. This in vivo EPR imaging method using BBB-permeative MCP is a useful noninvasive method for assessing changes in the redox status in mouse brains under oxidative stress.

  12. Protective Effects of Dihydrocaffeic Acid, a Coffee Component Metabolite, on a Focal Cerebral Ischemia Rat Model

    Directory of Open Access Journals (Sweden)

    Kyungjin Lee

    2015-06-01

    Full Text Available We recently reported the protective effects of chlorogenic acid (CGA in a transient middle cerebral artery occlusion (tMCAo rat model. The current study further investigated the protective effects of the metabolites of CGA and dihydrocaffeic acid (DHCA was selected for further study after screening using the same tMCAo rat model. In the current study, tMCAo rats (2 h of MCAo followed by 22 h of reperfusion were injected with various doses of DHCA at 0 and 2 h after onset of ischemia. We assessed brain damage, functional deficits, brain edema, and blood-brain barrier damage at 24 h after ischemia. For investigating the mechanism, in vitro zymography and western blotting analysis were performed to determine the expression and activation of matrix metalloproteinase (MMP-2 and -9. DHCA (3, 10, and 30 mg/kg, i.p. dose-dependently reduced brain infarct volume, behavioral deficits, brain water content, and Evans Blue (EB leakage. DHCA inhibited expression and activation of MMP-2 and MMP-9. Therefore, DHCA might be one of the important metabolites of CGA and of natural products, including coffee, with protective effects on ischemia-induced neuronal damage and brain edema.

  13. The effect of ASK1 on vascular permeability and edema formation in cerebral ischemia.

    Science.gov (United States)

    Song, Juhyun; Cheon, So Yeong; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2015-01-21

    Apoptosis signal-regulating kinase-1 (ASK1) is the mitogen-activated protein kinase kinase kinase (MAPKKK) and participates in the various central nervous system (CNS) signaling pathways. In cerebral ischemia, vascular permeability in the brain is an important issue because regulation failure of it results in edema formation and blood-brain barrier (BBB) disruption. To determine the role of ASK1 on vascular permeability and edema formation following cerebral ischemia, we first investigated ASK1-related gene expression using microarray analyses of ischemic brain tissue. We then measured protein levels of ASK1 and vascular endothelial growth factor (VEGF) in brain endothelial cells after hypoxia injury. We also examined protein expression of ASK1 and VEGF, edema formation, and morphological alteration through cresyl violet staining in ischemic brain tissue using ASK1-small interference RNA (ASK1-siRNA). Finally, immunohistochemistry was performed to examine VEGF and aquaporin-1 (AQP-1) expression in ischemic brain injury. Based on our findings, we propose that ASK1 is a regulating factor of vascular permeability and edema formation in cerebral ischemia.

  14. Picroside Ⅱ down-regulates matrix metalloproteinase-9 expression following cerebral ischemia/reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Xiang Li; Xinying Xu; Zhen Li; Yunliang Guo; Qin Li; Xiaodan Li; Zhen Zhou

    2010-01-01

    Studies have shown that Picroside Ⅱ attenuates inflammatory reactions following brain ischemia through the inhibition of the TLR-4-NF-κB signal transduction pathway,and ameliorates cerebral edema through the reduction of aquaporin-4 expression.Matrix metalloproteinase-9(MMP-9),located downstream of the TLR-4-NF-κB signal transduction pathway,can degrade the neurovascular matrix,damage the blood-brain barrier to induce cerebral edema,and directly result in neuronal apoptosis and brain injury.Therefore,the present study further observed MMP-9expression in the brain tissues of rats with cerebral ischemia/reperfusion injury following Picroside Ⅱtreatment.Results demonstrated that Picroside Ⅱ significantly reduced MMP-9 expression in ischemic brain tissues,as well as neuronal apoptosis and brain infarct volume,suggesting PicrosideⅡ exhibits neuroprotection by down-regulating MMP-9 expression and inhibiting cell apoptosis.

  15. Stem cells to regenerate the newborn brain

    NARCIS (Netherlands)

    van Velthoven, C.T.J.

    2011-01-01

    Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury

  16. Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

    Directory of Open Access Journals (Sweden)

    Tang Huiling

    2010-10-01

    Full Text Available Abstract Background Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. Methods The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Results Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Conclusions These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis.

  17. Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

    Science.gov (United States)

    2010-01-01

    Background Ischemic hypoxic brain injury often causes irreversible brain damage. The lack of effective and widely applicable pharmacological treatments for ischemic stroke patients may explain a growing interest in traditional medicines. From the point of view of "self-medication" or "preventive medicine," Cordyceps sinensis was used in the prevention of cerebral ischemia in this paper. Methods The right middle cerebral artery occlusion model was used in the study. The effects of Cordyceps sinensis (Caterpillar fungus) extract on mortality rate, neurobehavior, grip strength, lactate dehydrogenase, glutathione content, Lipid Peroxidation, glutathione peroxidase activity, glutathione reductase activity, catalase activity, Na+K+ATPase activity and glutathione S transferase activity in a rat model were studied respectively. Results Cordyceps sinensis extract significantly improved the outcome in rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. At the same time, supplementation of Cordyceps sinensis extract significantly boosted the defense mechanism against cerebral ischemia by increasing antioxidants activity related to lesion pathogenesis. Restoration of the antioxidant homeostasis in the brain after reperfusion may have helped the brain recover from ischemic injury. Conclusions These experimental results suggest that complement Cordyceps sinensis extract is protective after cerebral ischemia in specific way. The administration of Cordyceps sinensis extract significantly reduced focal cerebral ischemic/reperfusion injury. The defense mechanism against cerebral ischemia was by increasing antioxidants activity related to lesion pathogenesis. PMID:20955613

  18. The non-opioid KOR agonist Salovinorin A reducing brain edema in rats with forebrain ischemia and reperfusion%非阿片类药物KOR激动剂Salvinorin A减轻前脑缺血再灌注大鼠脑水肿的作用

    Institute of Scientific and Technical Information of China (English)

    张燕; 王震虹; 何振洲; 忻纪华

    2015-01-01

    Objective To discuss the mechanism of Kappa opioid receptor (KOR) agonist Salvinorin A (SA) on decreas-ing brain edema after forebrain ischemia-reperfusion (I/R) injury in rats. Methods Male Sprague-Dawley rats were di-vided into 5 groups (n=10): sham operation group, I/R group, DMSO (vehicle) group, SA group and Norbinaltorphimine (nor-BIN, KOR antagonist) +SA group. Forebrain ischemia was performed by low artery pressure with bilateral carotid artery occlusion for 10 minutes. Intervenes (DMSO, SA, nor-BIN+SA) were performed after forebrain ischemia instantly. The animals were sacrificed 24 hours after reperfusion. The hippocampus was taken for pathology, and TdT-mediated dUTP nick end labeling (TUNEL) and immunohistochemical test were used for AQP4 detection. The wet-dry weight method was used to assess brain water content. Results Compared with sham operation group, hippocampus water con-tent increased in I/R group (P< 0.01). Hippocampus water content was significantly lower in SA group than that in I/R group (P<0.01). Hippocampus water content was significantly higher in nor-BIN+SA group than that in SA group (P<0.05). Compared with I/R and DMSO groups, hippocampus neurosis and apoptosis were alleviated significantly with treatment of SA 24 h after forebrain I/R (P<0.01), which effect was blunted by nor-BIN. Compared with sham opera-tion group, AQP4 expressed in hippocampus was promoted by I/R (P < 0.01). Compared with I/R group, AQP4 ex-pressed was depressed in SA group (P< 0.01). The expression of AQP4 increased significantly with treatment of nor-BIN+SA compared with SA (P< 0.05). Conclusion SA can reduce cerebral edema after forebrain ischemia and brain damage by inhibition of AQP4. Its mechanism may be correlated with KOR.%目的:探讨大鼠前脑缺血再灌注(I/R)损伤后,Kappa阿片受体(KOR)激动剂Salvinorin A(SA)减轻脑水肿的机制。方法成年健康雄性Sprague-Dawley(SD)大鼠随机分为5组(n=10):假手术组、I/R组、DMSO

  19. Predictive Modeling of Cardiac Ischemia

    Science.gov (United States)

    Anderson, Gary T.

    1996-01-01

    The goal of the Contextual Alarms Management System (CALMS) project is to develop sophisticated models to predict the onset of clinical cardiac ischemia before it occurs. The system will continuously monitor cardiac patients and set off an alarm when they appear about to suffer an ischemic episode. The models take as inputs information from patient history and combine it with continuously updated information extracted from blood pressure, oxygen saturation and ECG lines. Expert system, statistical, neural network and rough set methodologies are then used to forecast the onset of clinical ischemia before it transpires, thus allowing early intervention aimed at preventing morbid complications from occurring. The models will differ from previous attempts by including combinations of continuous and discrete inputs. A commercial medical instrumentation and software company has invested funds in the project with a goal of commercialization of the technology. The end product will be a system that analyzes physiologic parameters and produces an alarm when myocardial ischemia is present. If proven feasible, a CALMS-based system will be added to existing heart monitoring hardware.

  20. Effects of treadmill training on matrix metalloproteinases-2 and vascular endotheliar growth factor in ischemic brain of rats after cerebral ischemia-reperfusion%跑台训练对大鼠脑缺血再灌注后脑组织基质金属蛋白酶-2和血管内皮生长因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    马跃文; 强琳

    2012-01-01

    Objective: To study the effects of treadmill training on the recovery of neurological function and the expression of MMP-2 and VEGF in ischemic brain of rats after cerebral ischemia-reperfusion. Method: A total of thirty-five male adult Wistar rats were given cerebral ischemia-reperfusion and were randomly divided into sham-operated group, control group and exercise group, with treadmill running. Neurological function was measured at the 24h after the operation, the 3rd, the 7th and the 14th day after the beginning of exercise respectively. RT-PCR was used to detect the expression of MMP-2 and VEGF in the ischemic brain at the 3rd, 7th and 14th day. Result: Compared with those in the control group, the behavior scores in exercise group was much lower at the 7th and 14th day (P < 0.05). MMP-2 expression in exercises group was higher than in the control group at the 7th and 14th day (P<0.05). The expression of VEGF in the exercise group was greater than that in the control group at all points (P < 0.05). Conclusion: The expression of MMP-2 and VEGF in the brain ischemic area can be improved through treadmill training. It can promote recovery of neurological function by developing neurogenesis and promoting vascularization after cerebral infarction.%目的:探讨跑台训练对大鼠脑缺血再灌注神经功能恢复和缺血脑组织中MMP-2和VEGF表达的影响.方法:用线栓法制作Wistar大鼠大脑中动脉梗死再灌注模型,35只大鼠随机分为假手术组、跑台训练组和手术对照组.跑台训练和手术对照组又分为跑3天、跑7天、跑14天3个亚组,各业组及假手术组每组5只大鼠.跑台组于术后第3天开始给予跑台训练,假手术组及手术对照组不予跑台训练.于跑3天、跑7天、跑14天3个时间点进行神经功能评估后处死大鼠.采用RT-PCR技术测定缺血区脑组织中MMP-2及VEGF的水平.结果:跑台训练组在跑7天、跑14天神经功能评分明显低于对照组(P<0.05).

  1. Therapeutic potential of the novel hybrid molecule JM-20 against focal cortical ischemia in rats

    Directory of Open Access Journals (Sweden)

    Yanier Núñez Figueredo

    2016-08-01

    Full Text Available Context: Despite the great mortality and morbidity of stroke, treatment options remain limited. We previously showed that JM-20, a novel synthetic molecule, possessed a strong neuroprotective effect in rats subjected to transient middle cerebral artery occlusion. However, to verify the robustness of the pre-clinical neuroprotective effects of JM-20 to get good prognosis in the translation to the clinic, it is necessary to use other experimental models of brain ischemia. Aims: To evaluate the neuroprotective effects of JM-20 following the onset of permanent focal cerebral ischemia induced in rats by thermocoagulation of blood into pial blood vessels of cerebral cortices. Methods: Ischemic lesion was induced by thermocoagulation of blood into pial blood vessels of primary motor and somatosensory cortices. Behavioral performance was evaluated by the cylinder testing for a period of 2, 3 and 7 days after surgery, and was followed by histopathological study in brain cortex stained with hematoxylin- eosin. Results: Ischemic injury resulted in impaired function of the forelimb evidenced by high asymmetry punctuation, and caused histopathological alterations indicative of tissue damage at cerebral cortex. JM-20 treatment (4 and 8 mg/kg significantly decreased asymmetry scores and histological alterations with a marked preservation of cortical neurons. Conclusions: The effects of permanent brain ischemia were strongly attenuated by JM-20 administration, which expands and improves the current preclinical data of JM-20 as neuroprotector against cerebral ischemia, and strongly support the examination of its translation to the clinic to treat acute ischemic stroke.

  2. Oxygen or cooling, to make a decision after acute ischemia stroke

    Directory of Open Access Journals (Sweden)

    Wen-cao Liu

    2016-01-01

    Full Text Available The presence of a salvageable penumbra, a region of ischemic brain tissue with sufficient energy for short-term survival, has been widely agreed as the premise for thrombolytic therapy with tissue plasminogen activator (tPA, which remains the only United States Food and Drug Administration (FDA approved treatment for acute ischemia stroke. However, the use of tPA has been profoundly constrained due to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic transformation (HT. Blood brain barrier (BBB damage within the thrombolytic time window is an indicator for tPA-induced HT and both normobaric hyperoxia (NBO and hypothermia have been shown to protect the BBB from ischemia/reperfusion injury. Therefore, providing the O2 as soon as possible (NBO treatment, freezing the brain (hypothermia treatment to slow down ischemia-induced BBB damage or their combined use may extend the time window for the treatment of tPA. In this review, we summarize the protective effects of NBO, hypothermia or their use combined with tPA on ischemia stroke, based on which, the combination of NBO and hypothermia may be an ideal early stroke treatment to preserve the ischemic penumbra. Given this, there is an urge for large randomized controlled trials to address the effect.

  3. 层粘连蛋白及基质金属蛋白酶-9在大鼠局灶性脑缺血梗死区周围的表达及意义%Expression of Laminin and Matrix Metalloproteinase-9 around the Infarct Area Following Focal Ischemia in Rat Brains and Its Significance

    Institute of Scientific and Technical Information of China (English)

    胡晓松; 周东; 唐瑜; 刘静; 李娟

    2013-01-01

    Objective To investigate the expression of matrix metalloproteinase-9 (MMP-9) and laminin around the infarct area following focal ischemia in adult rat brains.Methods Using a random number table,45 four-month-old male SD rats were divided into two groups:sham operation group and middle cerebral artery occlusion (MCAO) group.The model of acute reperfusion injury after cerebral ischemia in rats was made by MCAO.The MCAO group was further divided into four subgroups according to different durations of reperfusion,including 6 hours,24 hours,3 days and 7 days.The expression of MMP-9 and Laminin was detected using an imrnunohistochemical approach.Results The number of MMP-9 immunoreactive cells at hour 6 after reperfusion in ischemic side in MCAO group started to increase markedly and presented significant difference compared with the sham group.It peaked at hour 24 and then decreased gradually at day 3 but was still higher than that of the sham group at day 7 after reperfusion.The expression of laminin began to decrease at hour 6 and reached to the minimum.It started to increase slowly 3 days later.Conclusion In the cerebral ischemiareperfusion injury,the change of MMP-9 and laminin expressions may reflect the impaired cerebral blood wall and has close relationship with the cerebral ischemic injury and repair process.[Key words] Laminin; MMP-9; Cerebral ischemia; Rat%目的 观察局灶性脑缺血梗死区周围层粘连蛋白(Laminin)及基质金属蛋白酶(MMP)-9表达,探讨其在脑缺血再灌注损伤发病机制中的作用.方法 将45只体重250~300 g、4个月龄的Sprague Dawley(SD)雄性大鼠随机分为假手术(Sham)组与局灶性缺血再灌注(MCAO)组.MCAO组又分6、24、72 h及7d组,每组各9只.光学显微镜下观察脑组织病理改变,免疫组织化学染色检测各组Laminin及MMP-9的表达情况.结果 再灌注后6h,即有MMP-9表达明显增高,表达高峰出现在再灌注后24 h,3d时有所下降,至7d时

  4. Neuroprotective Effects of Bone Marrow Mesenchymal Stem Cells on Bilateral Common Carotid Arteries Occlusion Model of Cerebral Ischemia in Rat

    Directory of Open Access Journals (Sweden)

    Bagher Pourheydar

    2016-01-01

    Full Text Available Cell therapy is the most advanced treatment of the cerebral ischemia, nowadays. Herein, we discuss the neuroprotective effects of bone marrow mesenchymal stem cells (BMSCs on rat hippocampal cells following intravenous injection of these cells in an ischemia-reperfusion model. Adult male Wistar rats were divided into 5 groups: control, sham (surgery without blockage of common carotid arteries, ischemia (common carotid arteries were blocked for 30 min prior to reperfusion, vehicle (7 days after ischemia PBS was injected via the tail vein, and treatment (injections of BMSC into the tail veins 7 days after ischemia. We performed neuromuscular and vestibulomotor function tests to assess behavioral function and, finally, brains were subjected to hematoxylin and eosin (H&E, anti-Brdu immunohistochemistry, and TUNEL staining. The ischemia group had severe apoptosis. The group treated with BMSCs had a lower mortality rate and also had significant improvement in functional recovery (P<0.001. Ischemia-reperfusion for 30 min causes damage and extensive neuronal death in the hippocampus, especially in CA1 and CA3 regions, leading to several functional and neurological deficits. In conclusion, intravenous injection of BMSCs can significantly decrease the number of apoptotic neurons and significantly improve functional recovery, which may be a beneficial treatment method for ischemic injuries.

  5. Activation and subcellular distribution of ERK1/2 following cerebral ischemia/reperfusion in rat hippocampus

    Institute of Scientific and Technical Information of China (English)

    WANG Rui-min; ZHANG Guang-yi; ZHANG Quan-guang; YANG Fang; MA Wen-dong; LI Qi-jia

    2006-01-01

    Objective:To investigate the activation (phosphorylation) and subcellular localization of extracellular signal-regulated kinase(ERK1/2), as well as the possible mechanism, following cerebral ischemia and ischemia/reperfusion in rat hippocampus. Methods: Transient brain ischemia was induced by the four-vessel occlusion method in Sprague-Dawley rats. Western blot analysis. Results: During cerebral ischemia without reperfusion ERK1/2 activation immediately increased with a peak at 5 min and then decreased in the cytosol fraction, which was paralleled by the increase of ERK1/2 activation in the nucleus fraction. During reperfusion, ERK1/2 was activated with peaks occurring at 10 min in the cytosol and at 30 min in the nucleus, respectively. Under those conditions, the protein expressions had no significant change. In order to clarify the possible mechanism of ERK1/2 activation, the rats were intraperitoneally administrated with N-methyl D aspartate (NMDA) receptor antagonist dextromethorphan(DM), L-type voltage-gated Ca2+ channel (L-VGCC) antagonist nifedipine (ND) 20 min before ischemia, finding that DM and ND markedly prevented ERK1/2 activation of nucleus fraction induced by reperfusion, not by ischemia. Conclusion: These results suggested that the nuclear translocation mainly occurred during is chemia, while ischemia-reperfusion induced ERK1/2 activation both in the cytosol and the nucleus. Two type calcium channels contributed, at least partially, to the activation of ERK1/2.

  6. Cerebral ischemia-induced mitochondrial changes in a global ischemic rat model by AFM.

    Science.gov (United States)

    Park, Eunkuk; Choi, Seok Keun; Kang, Sung Wook; Pak, Youngmi Kim; Lee, Gi-Ja; Chung, Joo-Ho; Park, Hun-Kuk

    2015-04-01

    Mitochondria play a central role in cell survival, and apoptotic cell death is associated with morphological changes in mitochondria. Quantification of the morphological and mechanical property changes in brain mitochondria is useful for evaluating the degree of ischemic injury and the neuroprotective effects of various drugs. This study was performed to investigate the changes in brain mitochondria in an 11-vessel occlusion ischemic model treated with magnesium sulfate (MgSO4), utilizing atomic force microscopy (AFM). Rats were randomly divided into three groups consisting of sham (n=6), global ischemia (GI, n=6), and MgSO4-treated global ischemia (MgSO4, n=6). The biophysical properties of brain mitochondria determined from AFM topographic images and adhesion force from force-distance measurements. The mean perimeter of ischemic mitochondria significantly increased to 2,396±541 nm (vs. 1,006±318 nm in control group, PAFM could be effective for evaluating neuronal injury and drug effects.

  7. 结扎孕鼠双侧子宫动脉复制围产期缺氧缺血性脑损伤动物模型%Reconstructing new animal model of peri-delivery hypoxia-ischemia brain damage by ligaturing bilateral uterine arteries of pregnant mouse

    Institute of Scientific and Technical Information of China (English)

    薄涛; 李巍; 严超英; 霍淑芳

    2001-01-01

    Objective Hypoxia-ischemia brain injury (HIBD) in infants is one of the important factors which induce intelligent defect,cerebral palasy in human beings. Therefore, we produced a new animal model to study HIBD. Method We assigned twenty 19.5-pregnancy-day mice to four groups randomly and had ligated their bilateral uteral arteries for 0,10,20, and 30 minutes respectively before the cesarean sections. Of each group,we observed the mortality,the growth and the brain's pathological changes. Result The longer the uteral arteries were ligated,the higher the mortality was. The slowlier the body weight increased, the more serious the spastic paralysis was .We also found the mice is similar in the brain pathological change to the human beings such as the edema regions,spotted hemorrhage,and local malacosis in the cortex. Conclusion This is a simple and useful model to study HIBD in newborn.%目的 制作一种新型围产期缺氧缺血性脑损伤(HIBD)的动物模型,为进一步深入研究其病理生理机制及治疗方法提供条件。方法 结扎足月妊娠待产(妊娠19.5d)昆明母鼠双侧子宫动脉,不同时间行剖宫产娩出胎鼠,与正常剖宫产娩出的胎鼠相比较,观察实验胎鼠的生长发育及脑部病理改变。结果 随着结扎子宫动脉阻断血供时间的延长,胎鼠的死亡率迅速增高,两者具有直线正相关关系(P<0.05),实验组胎鼠体重增长明显减慢,运动发育迟滞,脑部的病理改变与人类HIBD的改变相一致。结论 通过结扎孕鼠双侧子宫动脉,胎鼠所产生的一系列变化符合人类HIBD的改变,这是一种较理想的、操作较简便的复制HIBD动物模型的方法。

  8. Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation

    Science.gov (United States)

    Cho, Kyu Suk; Jeon, Se Jin; Kwon, Oh Wook; Jang, Dae Sik; Kim, Sun Yeou; Ryu, Jong Hoon; Choi, Ji Woong

    2017-01-01

    Microglial activation and its-driven neuroinflammation are characteristic pathogenetic features of neurodiseases, including focal cerebral ischemia. The Artemisia asiatica (Asteraceae) extract and its active component, eupatilin, are well-known to reduce inflammatory responses. But the therapeutic potential of eupatilin against focal cerebral ischemia is not known, along with its anti-inflammatory activities on activated microglia. In this study, we investigated the neuroprotective effect of eupatilin on focal cerebral ischemia through its anti-inflammation, particularly on activated microglia, employing a transient middle cerebral artery occlusion/reperfusion (tMCAO), combined with lipopolysaccharide-stimulated BV2 microglia. Eupatilin exerted anti-inflammatory responses in activated BV2 microglia, in which it reduced secretion of well-known inflammatory markers, including nitrite, IL-6, TNF-α, and PGE2, in a concentration-dependent manner. These observed in vitro effects of eupatilin led to in vivo neuroprotection against focal cerebral ischemia. Oral administration of eupatilin (10 mg/kg) in a therapeutic paradigm significantly reduced brain infarction and improved neurological functions in tMCAO-challenged mice. The same benefit was also observed when eupatilin was given even within 5 hours after MCAO induction. In addition, the neuroprotective effects of a single administration of eupatilin (10 mg/kg) immediately after tMCAO challenge persisted up to 3 days after tMCAO. Eupatilin administration reduced the number of Iba1-immunopositive cells across ischemic brain and induced their morphological changes from amoeboid into ramified in the ischemic core, which was accompanied with reduced microglial proliferation in ischemic brain. Eupatilin suppressed NF-κB signaling activities in ischemic brain by reducing IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation. Overall, these data indicate that eupatilin is a neuroprotective agent against

  9. Hippocampal mitochondrial cytochrome C oxidase activity and gene expression in a rat model of chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Qing Zhao; Yingli Zhang; Mingming Zhao; Yu Wang; Ming Ma; Xinquan Gu; Xia Cao

    2011-01-01

    The present study established a rat model of chronic cerebral ischemia using bilateral common carotid artery permanent ligation to analyze cytochrome C oxidase activity and mRNA expression in hippocampal mitochondria.Results showed significantly decreased cytochrome C oxidase activity and cytochrome C oxidase II mRNA expression with prolonged ischemia time.Further analysis revealed five mitochondrial cytochrome C oxidase II gene mutations, two newly generated mutations, and four absent mutational sites at 1 month after cerebral ischemia, as well as three mitochondrial cytochrome C oxidase III gene mutations, including two newly generating mutations, and one disappeared mutational site at 1 month after cerebral ischemia.Results demonstrated that decreased cytochrome C oxidase gene expression and mutations, as well as decreased cytochrome C oxidase activity, resulting in energy dysmetabolism, which has been shown to be involved in the pathological process of ischemic brain injury.

  10. Effects of erythropoietin on nestin expression in neural stem cells of neonatal rats with hypoxia-ischemia brain damage%促红细胞生成素干预缺氧缺血性脑损伤新生鼠神经干细胞巢蛋白的表达

    Institute of Scientific and Technical Information of China (English)

    姜红; 许锋; 周春清; 李向红; 舒志荣

    2010-01-01

    背景:巢蛋白是一种存在于神经干细胞的特异性抗原,在神经系统发生病变或损伤引起再生时广泛表达,因此巢蛋白表达常用作判定神经系统发生病变或损伤后能否促进神经再生的一种手段.目的:从神经再生和神经干细胞激活的角度,探讨外源性促红细胞生成素对新生鼠缺氧缺血性脑损伤后神经干细胞巢蛋白表达的影响.方法:结扎大鼠右侧颈总动脉和8%低氧暴露2 h制备新生大鼠缺氧缺血性脑损伤模型.对照组仅游离右侧颈总动脉,不予结扎和缺氧处理.干预组大鼠缺氧缺血后立即腹腔注射重组人促红细胞生成素5 000 IU/kg,1次/d,连用3 d.缺氧缺血性脑损伤组大鼠缺氧缺血后连续腹腔注射等量生理盐水溶液3d.每组随机取8只分别于术后4,7,14d处死.应用免疫组化方法和计算机图像分析技术检测不同时点海马齿状回巢蛋白标记阳性细胞的变化.结果与结论:各时点缺氧缺血性脑损伤组巢蛋白阳性细胞数较对照组增加(P<0.05);各时点干预组巢蛋白阳性细胞较对照组和缺氧缺血性脑损伤组均增加(P<0.05).3组大鼠海马齿状回区巢蛋白阳性细胞数均于术后7 d达高峰.结果提示早期给予重组入促红细胞生成素可促使新生鼠缺氧缺血性脑损伤后海马齿状回区巢蛋白表达增加,促进神经干细胞的增殖再生,在缺氧缺血性脑损伤后神经再生、修复中发挥一定的保护作用.%BACKGROUND: Nestin is a specific antigen of neural stem cells which widely expressed in lesion of nervous system and brain regeneration.Thus,nestin expression is commonly used to assess whether lesion or damage of the nervous system can promote neural regeneration.OBJECTIVE: To investigate the effects of erythropoietin(EPO)on nestin expression in neural stem cells after hypoxia-ischemia brain damage(HIBD)in neonatal rats from the angles of neural regeneration and activation of neural stem cells

  11. Neuroprotective effects of the immunomodulatory drug Setarud on cerebral ischemia in male rats

    Institute of Scientific and Technical Information of China (English)

    Farzaneh Vafaee; Nasser Zangiabadi; Fatemeh Mehdi Pour; Farzaneh Dehghanian; Majid Asadi-Shekaari; Hossein Karimi Afshar

    2012-01-01

    Anti-inflammatory and anti-oxidant agents can alleviate ischemic cerebral injury. The immunomodulary drug Setarud, which is composed of herbal extracts including Rosa canina, Urtica dioica and Tanacetum vulgare, supplemented with selenium exhibits anti-inflammatory and anti-oxidant properties. Therefore, we hypothesized that Setarud will have a neuroprotective effect against ischemic cerebral injury. To validate this hypothesis, rats were intraperitoneally administered with 0.66 mL/kg Setarud for 30 minutes after middle cerebral artery occlusion. Triphenyltetrazolium chloride staining showed that Setarud could reduce cerebral infarct volume of rats subjected to cerebral ischemia. Transmission electron microscopy and hematoxylin-eosin staining results showed that Setarud could alleviate the degenerative changes in cortical neurons of rats with cerebral ischemia. The inclined plate test and prehensile test showed that Setarud could significantly improve the motor function of rats with cerebral ischemia. These findings suggest that Setarud shows neuroprotective effects against ischemic brain injury.

  12. Early Exercise Affects Mitochondrial Transcription Factors Expression after Cerebral Ischemia in Rats

    Directory of Open Access Journals (Sweden)

    Yongshan Hu

    2012-02-01

    Full Text Available Increasing evidence shows that exercise training is neuroprotective after stroke, but the underlying mechanisms are unknown. To clarify this critical issue, the current study investigated the effects of early treadmill exercise on the expression of mitochondrial biogenesis factors. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion followed by reperfusion. Expression of two genes critical for transcriptional regulation of mitochondrial biogenesis, peroxisome proliferator-activated receptor coactivator-1 (PGC-1 and nuclear respiratory factor-1 (NRF-1, were examined by RT-PCR after five days of exercise starting at 24 h after ischemia. Mitochondrial protein cytochrome C oxidase subunit IV (COX IV was detected by Western blot. Neurological status and cerebral infarct volume were evaluated as indices of brain damage. Treadmill training increased levels of PGC-1 and NRF-1 mRNA, indicating that exercise promotes rehabilitation after ischemia via regulation of mitochondrial biogenesis.

  13. Buyang Huanwu decoction enhances cell membrane fluidity in rats with cerebral ischemia/reperfusion

    Institute of Scientific and Technical Information of China (English)

    Chenxu Li

    2012-01-01

    After bilateral carotid artery occlusion for 30 minutes and reperfusion for 2 hours, distinct patho-logical changes presented in the cerebral cortex and cerebellum of rats. Compared with normal rats, nerve cell membrane fluidity significantly decreased in ischemia/reperfusion rats as detected by spin-labeling electron spin resonance, consistent with order parameter S and rotational correlation time TC measurements. Brain nerve cells from rats with ischemia/reperfusion injury were cultured with 1-100 mg/mL Buyang Huanwu decoction. Results showed that Buyang Huanwu decoction gradually increased membrane fluidity dose-dependently to normal levels, and eliminated hydroxide (OH·) and superoxide (O2·) free radicals dose-dependently. These findings suggest that Buyang Huanwu decoction can protect against cell membrane fluidity changes in rats with ischemia/ reper-fusion injury by scavenging free radicals.

  14. Temporal and topographic profiles of tissue hypoxia following transient focal cerebral ischemia in rats.

    Science.gov (United States)

    Noto, Takahisa; Furuichi, Yasuhisa; Ishiye, Masayuki; Matsuoka, Nobuya; Aramori, Ichiro; Mutoh, Seitaro; Yanagihara, Takehiko; Manabe, Noboru

    2006-08-01

    Intravascular accumulation of blood cells after brain ischemia-reperfusion can cause obstruction of cerebral blood flow and tissue hypoxia/ischemia as a consequence. In the present study, we examined temporal and topographic changes of tissue hypoxia/ischemia after occlusion of the middle cerebral artery (MCA) for 60 min in rats with immunohistochemical staining for hypoxia (2-nitroimidazole hypoxia marker: hypoxyprobe-1 adducts). Our results showed that tissue hypoxia expressed as positive staining for hypoxyprobe-1 adducts preceded neuronal degeneration. Platelets and granulocytes were detected close to the hypoxyprobe-1 adducts positive area. These results suggested that the hypoxic environment could persist even after reperfusion of MCA, because of vascular obstruction with accumulation of platelets and granulocytes.

  15. Effect of morphine preconditioning on neuronal apoptosis following cerebral ischemia/reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    He Dong; Xiangyu Ji; Dong Wang; Yueyi Ren; Shiduan Wang; Jianfang Song

    2010-01-01

    Apoptosis,a form of neuronal damage,takes place following cerebral ischemia/reperfusion injury,and caspase-3 plays an important role in apoptosis.Studies have shown that morphine preconditioning influences neuronal apoptosis and related protein expression following cerebral ischemia/reperfusion injury.In the present study,neuronal degeneration was attenuated,and the number of apoptotic cells and caspase-3 expression decreased following morphine preconditioning in a rat model of cerebral ischemia/reperfusion injury.Moreover,pathological changes were attenuated with increasing morphine doses,as well as the number of apoptotic cells and caspase-3 expression.Results from the present study revealed that morphine preconditioning reduced ischemic brain injury and improved cerebral ischemic tolerance in a dose-dependent manner.The anti-apoptotic mechanism of morphine is closely related to Caspase-3.

  16. Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Wang-shu Xu; Xuan Sun; Cheng-guang Song; Xiao-peng Mu; Wen-ping Ma; Xing-hu Zhang; Chuan-sheng Zhao

    2016-01-01

    Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumeta-nide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These ifndings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.

  17. Cofilin Inhibition Restores Neuronal Cell Death in Oxygen-Glucose Deprivation Model of Ischemia.

    Science.gov (United States)

    Madineni, Anusha; Alhadidi, Qasim; Shah, Zahoor A

    2016-03-01

    Ischemia is a condition associated with decreased blood supply to the brain, eventually leading to death of neurons. It is associated with a diverse cascade of responses involving both degenerative and regenerative mechanisms. At the cellular level, the changes are initiated prominently in the neuronal cytoskeleton. Cofilin, a cytoskeletal actin severing protein, is known to be involved in the early stages of apoptotic cell death. Evidence supports its intervention in the progression of disease states like Alzheimer's and ischemic kidney disease. In the present study, we have hypothesized the possible involvement of cofilin in ischemia. Using PC12 cells and mouse primary cultures of cortical neurons, we investigated the potential role of cofilin in ischemia in two different in vitro ischemic models: chemical induced oxidative stress and oxygen-glucose deprivation/reperfusion (OGD/R). The expression profile studies demonstrated a decrease in phosphocofilin levels in all models of ischemia, implying stress-induced cofilin activation. Furthermore, calcineurin and slingshot 1L (SSH) phosphatases were found to be the signaling mediators of the cofilin activation. In primary cultures of cortical neurons, cofilin was found to be significantly activated after 1 h of OGD. To delineate the role of activated cofilin in ischemia, we knocked down cofilin by small interfering RNA (siRNA) technique and tested the impact of cofilin silencing on neuronal viability. Cofilin siRNA-treated neurons showed a significant reduction of cofilin levels in all treatment groups (control, OGD, and OGD/R). Additionally, cofilin siRNA-reduced cofilin mitochondrial translocation and caspase 3 cleavage, with a concomitant increase in neuronal viability. These results strongly support the active role of cofilin in ischemia-induced neuronal degeneration and apoptosis. We believe that targeting this protein mediator has a potential for therapeutic intervention in ischemic brain injury and stroke.

  18. Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Rui SHENG; Li-sha ZHANG; Rong HAN; Bo GAO; Xiao-qian LIU; Zheng-hong QIN

    2011-01-01

    Alm: To examine the effects of a mixed formulation composed of prostaglandin E1 and lithium (PGE1+Li mixture) on brain damage after cerebral ischemia. The effects of the mixture on protein expression of heat shock proteins (HSPs), p53, and Bcl-2 were also determined.Methods: Brain ischemia was induced with a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were treated with a single intravenous administration of PGE1, lithium or a PGE1+Li mixture immediately after the ischemic insult. The infarct volume and motor behavior deficits were analyzed 24 h after the ischemic insult. The protein levels of HSP70, glucose-regulated protein 78 (GRP78), HSP60, Bcl-2, and p53 in the striatum of the ipsilateral hemisphere were examined using immunoblotting.Results: The mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg) reduced infarct volume and neurological deficits induced by focal cerebral ischemia. Moreover, the mixture had a greater neuroprotective effect against cerebral ischemia compared with PGE1 or lithium alone.The mixture was effective even if it was administered 3 h after ischemia. PGE1+Li also significantly upregulated cytoprotective HSP70,GRP78, HSP60, and Bcl-2 protein levels, while decreasing p53 expression.Conclusion: These results demonstrated a PGE1+Li mixture with a therapeutic window of up to 3 h for clinical treatment of cerebral ischemia. The PGE1+Li mixture potentially exerts a protective effect after stroke through the induction of HSPs and Bcl-2 proteins.

  19. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Science.gov (United States)

    Khodanovich, M. Yu.

    2015-11-01

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  20. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    Energy Technology Data Exchange (ETDEWEB)

    Khodanovich, M. Yu., E-mail: khodanovich@mail.tsu.ru [Tomsk State University, Research Institute of Biology and Biophysics, Laboratory of Neurobiology (Russian Federation)

    2015-11-17

    At the present time two main approaches are in the focus of neurobiological studies of brain recovery after a stroke. One of them is concerned with the infusion of stem cells in damaged brain. The second approach is directed at the stimulation of endogenous reparative processes, in particular, adult neurogenesis. This review considers alterations of adult neurogenesis caused by cerebral ischemia and possible pathways of its regulation. Multiple studies on animal models have shown that adult neurogenesis is mostly increased by cerebral ischemia. In spite of increasing proliferation and moving neural progenitors to infarct zone, most newborn neurons die before reaching maturity. Besides, an increase of neurogenesis in pathological conditions is mainly due to recruitment of new stem cells, but not due to an additional precursor-cells division that results in an overall decline of the regeneration capacity. Thus, the endogenous reparative mechanisms are not sufficient, and the search for new targets to promote proliferation, survival, and maturation of new neurons after a stroke is needed. Neurotransmitter systems and anti-inflammatory drugs are considered as potential regulators of post-ischemic neurogenesis growth factors.

  1. Transgenerational effects of neonatal hypoxia-ischemia in progeny.

    Science.gov (United States)

    Infante, Smitha K; Rea, Harriett C; Perez-Polo, J R

    2013-10-01

    Neonatal hypoxia-ischemia (HI) affects 60% of low birth weight infants and up to 40% of preterm births. Cell death and brain injury after HI have been shown to cause long-lasting behavioral deficits. By using a battery of behavioral tests on second generation 3-week-old rodents, we found that neonatal HI is associated with behavioral outcomes in the progeny of HI-affected parents. Our results suggest an epigenetic transfer mechanism of some of the neurological symptoms associated with neonatal HI. Elucidating the transfer of brain injury to the next generation after HI calls attention to the risks associated with HI injury and the need for proper treatment to reverse these effects. Assessing the devastating extent of HI's reach serves as a cautionary tale to the risks associated with neonatal HI, and provides an incentive to create improved therapeutic measures to treat HI.

  2. Role of mito-KATP channel in isoflurane preconditioning lightening brain ischemia-reperfusion injury in gerbils%mito-KATP通道在异氟醚预处理减轻沙土鼠脑缺血-再灌注损伤中的作用

    Institute of Scientific and Technical Information of China (English)

    章放香; 张伟晶; 王世平; 安裕文; 邱冰

    2011-01-01

    目的 观察mito-KATP通道在异氟醚(ISO)预处理脑保护中的作用.方法 健康沙土鼠60只随机均分为六组:对照组(A组)、缺血-再灌注组(B组)、1.5%ISO预处理组(C组)、1.5%ISO预处理+5-羟葵酸(5-HD)5 mg/kg组(D组)、1.5%ISO预处理+5-HD 10 mg/kg组(E组)、1.50% ISO预处理+5-HD 15 mg/kg组(F组).预处理方法为连续5d吸入1.5% ISO1 h/d;末次预处理24 h后行缺血-再灌注,D、E、F组缺血前30 min分别腹腔注射5、10、15 mg/kg 5-HD.48 h后HE染色观察脑组织形态学变化,TUNEL法检测海马神经元凋亡,免疫组化检测Bd-2及Bax在海马神经元的表达.结果 与A组比较,B、C、D、E、F组脑损伤评分、神经细胞凋亡率、Bax表达均明显升高(P<0.05);而C、D、E、F组Bcl-2阳性表达明显升高(P<0.05).与C组比较,E、F组脑损伤评分、神经细胞凋亡率及Bax表达明显升高(P<0.05),而Bcl-2阳性表达降低(P<0.05).结论 mito-KATP通道在ISO预处理脑保护效应中起重要作用.%Objective To investigate the effect of mito-KATP channel in isoflurane preconditioning induced brain protection in gerbils. Methods Sixty healthy Mongolian gerbils were randomly divided into 6 groups: group A was normal control; group B was the reperfusion; group C was 1. 5% isofulurance preconditioning; group D was 1.5% isofulurance preconditioning+5-HD 5 mg/kg; group E was 1.5% isofulurance preconditioning + 5-HD 10 mg/kg; group F was 1.5% isofulurance preconditioning +5-HD 15 mg/kg group. Once daily of 1. 5% isoflurane was given for five days. Ischemia-reperfusion injury was occurred 24 h after the last preconditioning day. Groups of D, E and F were injected with 5-HD 5, 10, 15 mg/kg 30 min before ischemia-reperfusion injury. HE staining was used to observe the injury of cerebrum, and the expressions of Bcl-2 and Bax were detected with immunohistochemistry, and TUNEL was used to analyze the neuronal apoptosis. Results Compared with group A, other five groups

  3. Recipient twin limb ischemia with postnatal onset.

    Science.gov (United States)

    Broadbent, Roland Spencer

    2007-02-01

    After the occurrence of 3 local cases of limb ischemia in newborn twins, we reviewed the literature to investigate this combination systematically. This review reveals a distinct condition: postnatal onset limb ischemia affecting recipient twins in twin-twin transfusion syndrome.

  4. Retinal ischemia and embolism. Causes and outcomes

    NARCIS (Netherlands)

    Wijman, C.A.C.

    2007-01-01

    The ocular fundus allows direct visualization of the retinal vasculature, blood vessels that are part of the cerebral circulation. Unraveling the causes of retinal ischemia may provide further insight in the pathophysiological processes that underlie cerebral ischemia. The primary aim of the studies

  5. Neuroprotective effects of tadalafil on gerbil dopaminergic neurons following cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Kwang Taek Kim; Kyung Jin Chung; Han Sae Lee; Il Gyu Ko; Chang Ju Kim; Yong Gil Na; Khae Hawn Kim

    2013-01-01

    Impairment of dopamine function, which is known to have major effects on behaviors and cognition, is one of the main problems associated with cerebral ischemia. Tadalafil, a long-acting phosphodiesterase type-5 inhibitor, is known to ameliorate neurologic impairment induced by brain injury, but not in dopaminergic regions. We investigated the neuroprotective effects of treatment with tadalafil on cyclic guanosine monophosphate level and dopamine function following cerebral ischemia. Forty adult Mongolian gerbils were randomly and evenly divided into five groups (n = 8 in each group): Sham-operation group, cerebral ischemia-induced and 0, 0.1, 1, and 10 mg/kg tadalafil-treated groups, respectively. Tadalafil dissolved in distilled water was administered orally for 7 consecutive days, starting 1 day after surgery. Cyclic guanosine monophosphate assay and immunohistochemistry were performed for thyrosine hydroxylase expression and western blot analysis for dopamine D2 receptor expression. A decrease in cyclic guanosine monophosphate level following cerebral ischemia was found with an increase in thyrosine hydroxylase activity and a decrease in dopamine D2 receptor expression in the striatum and substantia nigra region. However, treatment with tadalafil increased cyclic guanosine monophosphate expression, suppressed thyrosine hydroxylase expression and increased dopamine D2 receptor expression in the striatum and substantia nigra region in a dose-dependent manner. Tadalafil might ameliorate cerebral ischemia-induced dopaminergic neuron injury. Therefore, tadalafil has the potential as a new neuroprotective treatment strategy for cerebral ischemic injury.

  6. Pretreatment with scutellaria baicalensis stem-leaf total flavonoid prevents cerebral ischemia-reperfusion injury

    Institute of Scientific and Technical Information of China (English)

    Shumin Zhao; Wei Kong; Shufeng Zhang; Meng Chen; Xiaoying Zheng; Xiangyu Kong

    2013-01-01

    Pretreatment with scutel aria baicalensis stem-leaf total flavonoid has protective effects against ischemia and attenuates myocardial ischemia-reperfusion injury. In this study, rats were given scu-tel aria baicalensis stem-leaf total flavonoid intragastrical y at 50, 100, and 200 mg/kg per day for 7 days before focal cerebral ischemia-reperfusion injury models were established using the suture method. We then determined the protective effects of scutel aria baicalensis stem-leaf total flavo-noid pretreatment on focal cerebral ischemia-reperfusion injury. Results showed that neurological deficit scores increased, infarct volumes enlarged, apoptosis increased and Bcl-2 and Bax protein expression were upregulated at 24 hours after reperfusion. Pretreatment with scutel aria baicalensis stem-leaf total flavonoid at any dose lowered the neurological deficit scores, reduced the infarct volume, prevented apoptosis in hippocampal cells, attenuated neuronal and blood-brain barrier damage and upregulated Bcl-2 protein expression but inhibited Bax protein expression. Doses of 100 and 200 mg/kg were the most efficacious. Our findings indicate that pretreatment with scutel a-ria baicalensis stem-leaf total flavonoid at 100 and 200 mg/kg can improve the neurological func-tions and have preventive and protective roles after focal cerebral ischemia-reperfusion injury.

  7. The influence of warm ischemia elimination on kidney injury during transplantation – clinical and molecular study

    Science.gov (United States)

    Kamińska, Dorota; Kościelska-Kasprzak, Katarzyna; Chudoba, Paweł; Hałoń, Agnieszka; Mazanowska, Oktawia; Gomółkiewicz, Agnieszka; Dzięgiel, Piotr; Drulis-Fajdasz, Dominika; Myszka, Marta; Lepiesza, Agnieszka; Polak, Wojciech; Boratyńska, Maria; Klinger, Marian

    2016-01-01

    Kidney surface cooling was used during implantation to assess the effect of warm ischemia elimination on allograft function, histological changes and immune-related gene expression. 23 recipients were randomly assigned to a group operated on with kidney surface cooling during implantation (ice bag technique, IBT group), and the other 23 recipients receiving the contralateral kidney from the same donor were operated on with a standard technique. Three consecutive kidney core biopsies were obtained during the transplantation procedure: after organ recovery, after cold ischemia and after reperfusion. Gene expression levels were determined using low-density arrays (Format 32, TaqMan). The IBT group showed a significantly lower rate of detrimental events (delayed graft function and/or acute rejection, p = 0.015) as well as higher glomerular filtration rate on day 14 (p = 0.026). A greater decrease of MMP9 and LCN2 gene expression was seen in the IBT group during total ischemia (p = 0.003 and p = 0.018). Elimination of second warm ischemia reduced the number of detrimental events after kidney transplantation, and thus had influence on the short-term but not long-term allograft function. Surface cooling of the kidney during vascular anastomosis may reduce some detrimental effects of immune activation resulting from both brain death and ischemia-reperfusion injury. PMID:27808277

  8. Electroacupuncture pretreatment induces tolerance against focal cerebral ischemia through activation of canonical Notch pathway

    Directory of Open Access Journals (Sweden)

    Zhao Yu

    2012-09-01

    Full Text Available Abstract Background Electroacupuncture (EA pretreatment can induce the tolerance against focal cerebral ischemia. However, the underlying mechanisms have not been fully understood. Emerging evidences suggest that canonical Notch signaling may be involved in ischemic brain injury. In the present study, we tested the hypothesis that EA pretreatment-induced tolerance against focal cerebral ischemia is mediated by Notch signaling. Results EA pretreatment significantly enhanced Notch1, Notch4 and Jag1 gene transcriptions in the striatum, except Notch1 intracellular domain level, which could be increased evidently by ischemia. After ischemia and reperfusion, Hes1 mRNA and Notch1 intracellular domain level in ischemic striatum in EA pretreatment group were increased and reached the peak at 2 h and 24 h, respectively, which were both earlier than the peak achieved in control group. Intraventricular injection with the γ-secretase inhibitor MW167 attenuated the neuroprotective effect of EA pretreatment. Conclusions EA pretreatment induces the tolerance against focal cerebral ischemia through activation of canonical Notch pathway.

  9. Effect of Salvia leriifolia Benth. root extracts on ischemia-reperfusion in rat skeletal muscle

    Directory of Open Access Journals (Sweden)

    Nassiri-Asl Marjan

    2007-07-01

    Full Text Available Abstract Background Salvia leriifolia have been shown to decrease ischemia-reperfusion (I/R injury in brain tissues. In this study, the effects of S. leriifolia aqueous and ethanolic extracts were evaluated on an animal model of I/R injury in the rat hind limb. Methods Ischemia was induced using free-flap surgery in skeletal muscle. The aqueous and ethanolic extracts of S. leriifolia (100, 200 and 400 mg/kg root and normal saline (10 ml/kg were administered intraperitoneally 1 h prior reperfusion. During preischemia, ischemia and reperfusion conditions the electromyographic (EMG potentials in the muscles were recorded. The markers of oxidative stress including thiobarbituric acid reactive substances (TBARS, total sulfhydryl (SH groups and antioxidant capacity of muscle (using FRAP assay were measured. Results In peripheral ischemia, the average peak-to-peak amplitude during ischemic-reperfusion was found to be significantly larger in extracts groups in comparison with control group. Following extracts administration, the total SH contents and antioxidant capacity were elevated in muscle flap. The MDA level was also declined significantly in test groups. Conclusion It is concluded that S. leriifolia root extracts have some protective effects on different markers of oxidative damage in muscle tissue injury caused by lower limb ischemia-reperfusion.

  10. Transient myocardial ischemia after myocardial infarction

    DEFF Research Database (Denmark)

    Mickley, H

    1995-01-01

    Ambulatory ST-segment monitoring is a relatively new device in the evaluation of myocardial ischemia. The method is unique in allowing us to continuously examine the patient over an extended period of time in a changing environmental milieu. In survivors of acute myocardial infarction...... the prevalence of ambulatory or transient myocardial ischemia is lower than in patients with chronic, stable coronary artery disease. A greater proportion of ischemic episodes, however, are silent than in other subgroups with ischemic heart disease. Early after the infarction, transient myocardial ischemia...... exhibits a circadian variation with a peak activity occurring in the late evening hours. Patients with non-Q wave infarction have more transient myocardial ischemia, whereas thrombolytic therapy seems to result in less residual ischemia. Exercise testing is more sensitive than ambulatory monitoring...

  11. 缺血后处理对糖尿病大鼠心肌缺血再灌注诱发脑损伤的影响%Effect of ischemic postconditioning on brain injury induced by myocardial ischemia-reperfusion in diabetic rats

    Institute of Scientific and Technical Information of China (English)

    赵博; 夏中元; 高文蔚; 刘敏; 吴洋

    2014-01-01

    目的 评价缺血后处理对糖尿病大鼠心肌缺血再灌注诱发脑损伤的影响.方法 雄性SD大鼠,体重220 ~ 280 g,腹腔注射链脲佐菌素60 mg/kg制备糖尿病模型.取模型制备成功的大鼠30只,采用随机数字表法,将其分为3组(n=10):假手术组(S组)、心肌缺血再灌注组(IR组)和缺血后处理组(P组).IR组和P组采用结扎左冠状动脉前降支的方法制备大鼠心肌缺血再灌注损伤模型.P组于再灌注前进行缺血后处理,再灌注10 s,缺血10 s,共3次.再灌注120 min时,断头处死大鼠取脑组织,光镜下观察病理学结果,采用TUNEL法测定细胞凋亡指数,采用免疫组化法测定IL-6、IL-8和IL-10的表达水平,采用Western blot法测定糖原合酶激酶-3β(GSK-3β)和磷酸化GSK-3β(pGSK-3β)的表达水平.结果 与S组比较,IR组和P组脑组织细胞凋亡指数升高,IL-6和IL-8的表达上调,IL-10和pGSK-3β的表达下调(P<0.01);与IR组比较,P组脑组织细胞凋亡指数降低,IL-6和IL-8的表达下调,IL-10和pGSK-3β的表达上调(P<0.01),病理学损伤减轻;3组间脑组织GSK-3β表达差异无统计学(P>0.05).结论 缺血后处理可减轻糖尿病大鼠心肌缺血再灌注诱发的脑损伤,其机制可能与抑制GSK-3β活性有关.%Objective To evaluate the effects of ischemic postconditioning on brain injury induced by myocardial ischemia-reperfusion (I/R) in diabetic rats.Methods Diabetes mellitus was induced by intraperitoneal streptozotocin 60 mg/kg and confirmed by blood glucose level > 16.7 mmol/L.Thirty male Sprague-Dawley rats,weighing 220-280 g,in which diabetes mellitus was successfully induced,were randomly allocated into 3 groups (n =10 each) using a random number table:group sham operation (group S),group I/R and group ischemic postconditioning (group P).Myocardial I/R was induced by occlusion of the anterior descending branch of the left coronary artery in I/R and P groups.Group P received 3 cycles of 10 s

  12. Improvement of oxygen supply by an artificial carrier in combination with normobaric oxygenation decreases the volume of tissue hypoxia and tissue damage from transient focal cerebral ischemia

    NARCIS (Netherlands)

    Seiffge, David J.; Lapina, Natalia E.; Tsagogiorgas, Charalambos; Theisinger, Bastian; Henning, Robert H.; Schilling, Lothar

    2012-01-01

    Tissue hypoxia may play an important role in the development of ischemic brain damage. In the present study we investigated in a rat model of transient focal brain ischemia the neuroprotective effects of increasing the blood oxygen transport capacity by applying a semifluorinated alkane (SFA)-contai

  13. Expression profiles of microRNAs after focal cerebral ischemia/reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    Fengguo Zhai; Xiuping Zhang; Yue Guan; Xudong Yang; Yang Li; Gaochen Song; Lixin Guan

    2012-01-01

    Rat models of focal cerebral ischemia/reperfusion injury were established by occlusion of the middle cerebral artery. Microarray analysis showed that 24 hours after cerebral ischemia, there were nine up-regulated and 27 down-regulated microRNA genes in cortical tissue. Bioinformatic analysis showed that bcl-2 was the target gene of microRNA-384-5p and microRNA-494, and caspase-3 was the target gene of microRNA-129, microRNA-320 and microRNA-326. Real-time PCR and western blot analyses showed that 24 hours after cerebral ischemia, bcl-2 mRNA and protein levels in brain tissue were significantly decreased, while caspase-3 mRNA and protein levels were significantly increased. This suggests that following cerebral ischemia, differentially expressed microRNA-384-5p, microRNA-494, microRNA-320, microRNA-129 and microRNA-326 can regulate bcl-2 and caspase-3 expression in brain tissue.

  14. Preconditioning of intravenous parecoxib attenuates focal cerebral ischemia/reperfusion injury in rats

    Institute of Scientific and Technical Information of China (English)

    WANG Na; GUO Qu-lian; YE Zhi; XIA Ping-ping; WANG E; YUAN Ya-jing

    2011-01-01

    Background Several studies suggest that oyclooxygenase-2 (COX-2) contributes to the delayed progression of ischemic brain damage. This study was designed to investigate whether COX-2 inhibition with parecoxib reduces focal cerebral ischemia/reperfusion injury in rats.Methods Ninety male Sprague-Dawley rats were randomly assigned to three groups: the sham group, ischemia/reperfusion (I/R) group and parecoxib group. The parecoxib group received 4 mg/kg of parecoxib intravenously via the vena dorsalis penis 15 minutes before ischemia and again at 12 hours after ischemia. The neurological deficit scores (NDSs) were evaluated at 24 and 72 hours after reperfusion. The rats then were euthanized. Brains were removed and processed for hematoxylin and eosin staining, Nissl staining, and measurements of high mobility group Box 1 protein (HMGB1) and tumor necrosis factor-a (TNF-α) levels. Infarct volume was assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining.Results The rats in the I/R group had lower NDSs (P <0.05), larger infarct volume (P <0.05), lower HMGB1 levels (P<0.05), and higher TNF-α levels (P<0.05) compared with those in the sham group. Parecoxib administration significantly improved NDSs, reduced infarct volume, and decreased HMGB1 and TNF-α levels (P <0.05).Conclusions Pretreatment with intravenous parecoxib was neuroprotective. Its effects may be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory mediators.

  15. [Tonic pupil caused by ischemia].

    Science.gov (United States)

    Wilhelm, H

    1989-01-01

    Tonic pupil is usually an idiopathic condition. In some cases, the cause of the ciliary ganglion lesion leading to tonic pupils is obvious. Rarely ischemia causes a lesion of the ciliary ganglion or the short ciliary nerves due to the good blood supply of the ciliary ganglion. Only two cases of tonic pupils in the course of giant cell arteritis are mentioned in the literature, but tonic pupils are probably much more common with this disease. Five cases are demonstrated here. All had associated ischemic optic neuropathy, and stagnation of the blood flow in the supratrochlear artery could be demonstrated in two cases by Doppler sonography. Tonic pupils may also occur when an oclusion of the internal carotid artery resolves, probably because of transient stasis of the orbital blood flow. In another case, tonic pupils were associated with choroidal ischemia (proved by video fluorescent angiography) of unknown origin. The diagnosis of tonic pupils was made by pharmacological testing for cholinergic hypersensitivity with 0.1% pilocarpine.

  16. Metabolic Adaptation to Muscle Ischemia

    Science.gov (United States)

    Cabrera, Marco E.; Coon, Jennifer E.; Kalhan, Satish C.; Radhakrishnan, Krishnan; Saidel, Gerald M.; Stanley, William C.

    2000-01-01

    Although all tissues in the body can adapt to varying physiological/pathological conditions, muscle is the most adaptable. To understand the significance of cellular events and their role in controlling metabolic adaptations in complex physiological systems, it is necessary to link cellular and system levels by means of mechanistic computational models. The main objective of this work is to improve understanding of the regulation of energy metabolism during skeletal/cardiac muscle ischemia by combining in vivo experiments and quantitative models of metabolism. Our main focus is to investigate factors affecting lactate metabolism (e.g., NADH/NAD) and the inter-regulation between carbohydrate and fatty acid metabolism during a reduction in regional blood flow. A mechanistic mathematical model of energy metabolism has been developed to link cellular metabolic processes and their control mechanisms to tissue (skeletal muscle) and organ (heart) physiological responses. We applied this model to simulate the relationship between tissue oxygenation, redox state, and lactate metabolism in skeletal muscle. The model was validated using human data from published occlusion studies. Currently, we are investigating the difference in the responses to sudden vs. gradual onset ischemia in swine by combining in vivo experimental studies with computational models of myocardial energy metabolism during normal and ischemic conditions.

  17. Lettuce glycoside B ameliorates cerebral ischemia reperfusion injury by increasing nerve growth factor and neurotrophin-3 expression of cerebral cortex in rats

    Directory of Open Access Journals (Sweden)

    Heqin Zhan

    2014-01-01

    Full Text Available Aims: The aim of the study was to investigate the effects of LGB on cerebral ischemia-reperfusion (I/R injury in rats and the mechanisms of action of LGB. Materials and Methods: The study involved extracting LGB from P. laciniata, exploring affects of LGB on brain ischemia and action mechanism at the molecular level. The cerebral ischemia reperfusion injury of middle cerebral artery occlusion was established. We measured brain histopathology and brain infarct rate to evaluate the effects of LGB on brain ischemia injury. The expressions of nerve growth factor (NGF and neurotrophin-3 (NT-3 were also measured to investigate the mechanisms of action by the real-time polymerase chain reaction and immunohistochemistry. Statistical analysis: All results were mentioned as mean ± standard deviation. One-way analysis of variance was used to determine statistically significant differences among the groups. Values of P < 0.05 were considered to be statistically significant. Results: Intraperitoneal injection of LGB at the dose of 12, 24, and 48 mg/kg after brain ischemia injury remarkably ameliorated the morphology of neurons and brain infarct rate (P < 0.05 , P < 0.01. LGB significantly increased NGF and NT-3 mRNA (messenger RNA and both protein expression in cerebral cortex at the 24 and 72 h after drug administration (P < 0.05, P < 0.01. Conclusions: LGB has a neuroprotective effect in cerebral I/R injury and this effect might be attributed to its upregulation of NGF and NT-3 expression ability in the brain cortex during the latter phase of brain ischemia.

  18. Acute mesenteric ischemia in young adults.

    Science.gov (United States)

    Ozturk, Gurkan; Aydinli, Bulent; Atamanalp, S Selcuk; Yildirgan, M Ilhan; Ozoğul, Bünyami; Kısaoğlu, Abdullah

    2012-08-01

    Acute mesenteric ischemia is commonly seen in old patients. This study was undertaken to show that mesenteric ischemia might be seen in individuals under 40 years of age and that its diagnosis is challenging. Twenty-six patients with acute mesenteric ischemia under the age of 40 were studied. The main symptom on admission was abdominal pain. Symptom duration varied between 12 h and 5 days. The medical history of the patients revealed that 9 had no previous diseases. Other 17 had predisposing factors in the first evaluation. None of the patients had any history of narcotic or drug abuse. Ten patients presented with signs and symptoms of sepsis and septic shock. Preoperative diagnosis was acute intestinal ischemia only in 6 patients. Preoperatively, all the patients had intestinal or colonic ischemia and necrosis; one had additional ischemia of the liver, stomach, duodenum, and pancreas. Six patients had massive intestinal necrosis. The overall postoperative complication and overall mortality rates were 61.5 and 26.9 %, respectively. Complications and mortality were determined to be associated with previous pulmonary disease, acidosis, presence of septic shock, acute renal failure, extent of the ischemia and extent of resection, second look operations, previous cardiac events, and the kind of affected bowel (colon involvement).

  19. Erythropoietin improves left ventricular function and coronary flow in an experimental model of ischemia-reperfusion injury

    NARCIS (Netherlands)

    van der Meer, P; Lipsic, E; Henning, RH; de Boer, RA; Suurmeijer, AJH; van Veldhuisen, DJ; van Gilst, WH

    2004-01-01

    Recent studies show that erythropoietin (EPO) plays a protective role in brain ischemia. In this condition, administration of EPO protects neurons from ischemic damage. Recently, it has been shown that in patients with chronic heart failure (CHF), EPO treatment improved cardiac function. In the pres

  20. Protective effects of Echium amoenum Fisch. and C.A. Mey. against cerebral ischemia in the rats

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    Leila Safaeian

    2015-01-01

    Conclusion: The anthocyanin rich fraction from E. amoenum was found to have protective effects against some brain damages postischemic reperfusion . However, further researches are required for investigating the exact mechanisms of the effect of this plant in the prevention of cerebral ischemia in human.

  1. Myocardial Ischemia Caused by Subepicardial Hematoma

    Science.gov (United States)

    Grieshaber, Philippe; Nef, Holger; Böning, Andreas; Niemann, Bernd

    2017-01-01

    Background Bleeding from bypass anastomosis leakage occurs early after coronary artery bypass grafting. Later, once the anastomosis is covered by intima, spontaneous bleeding is unlikely. Case Description A 63-year-old male patient developed a pseudoaneurysm-like, subepicardial late-term bleeding resulting in a hematoma that compromised coronary artery flow by increasing extracoronary pressure. This resulted in severe angina pectoris (Canadian Cardiovascular Society IV) and myocardial ischemia within the affected area. After surgical removal of the hematoma and repair of the anastomosis, the patient's symptoms disappeared and no signs of myocardial ischemia were present. Conclusion Surgical removal is an efficient therapy for subepicardial hematoma inducing myocardial ischemia.

  2. Memory deficits and oxidative stress in cerebral ischemia-reperfusion: neuroprotective role of physical exercise and green tea supplementation.

    Science.gov (United States)

    Schimidt, Helen L; Vieira, Aline; Altermann, Caroline; Martins, Alexandre; Sosa, Priscila; Santos, Francielli W; Mello-Carpes, Pâmela B; Izquierdo, Ivan; Carpes, Felipe P

    2014-10-01

    Ischemic stroke is a major cause of morbidity and mortality all over the world. Among impairments observed in survivors there is a significant cognitive learning and memory deficit. Neuroprotective strategies are being investigated to minimize such deficits after an ischemia event. Here we investigated the neuroprotective potential of physical exercise and green tea in an animal model of ischemia-reperfusion. Eighty male rats were divided in 8 groups and submitted to either transient brain ischemia-reperfusion or a sham surgery after 8 weeks of physical exercise and/or green tea supplementation. Ischemia-reperfusion was performed by bilateral occlusion of the common carotid arteries during 30 min. Later, their memory was evaluated in an aversive and in a non-aversive task, and hippocampus and prefrontal cortex were removed for biochemical analyses of possible oxidative stress effects. Ischemia-reperfusion impaired learning and memory. Reactive oxygen species were increased in the hippocampus and prefrontal cortex. Eight weeks of physical exercise and/or green tea supplementation before the ischemia-reperfusion event showed a neuroprotective effect; both treatments in separate or together reduced the cognitive deficits and were able to maintain the functional levels of antioxidant enzymes and glutathione.

  3. An Early Continuous Experimental Study on Magnetic Resonance Diffusion-weighted Image of Focal Cerebral Ischemia and Reperfusion in Rats

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The chronological and spatial rules of changes during focal cerebral ischemia and reperfusion in different brain regions with magnetic resonance diffusion-weighted imaging (DWI) in a model of occlusion of middle cerebral artery (MCAO) and the development of cytotoxic edema in acute phase were explored. Fifteen healthy S-D rats with MCA occluded by thread-emboli were randomly divided into three groups. 15 min after the operation, the serial imaging was scanned on DWI for the three groups. The relative mean signal intensity (RMSI) of the frontal lobe, parietal lobe, lateral cauda-putamen, medial cauda-putamen and the volume of regions of hyperintense signal on DWI were calculated. After the last DWI scanning, T2 WI was performed for the three groups. After 15min ischemia, the rats was presented hyperintense signals on DWI. The regions of hyperintense signal were enlarged with prolonging ischemia time. The regions of hyperintense signal were back to normal after 60 min reperfusion with a small part remaining to show hyperintense signal. The RMSIs of parietal lobe and lateral cauda-putamen were higher than that of the frontal lobe and medial cauda-putamen both in ischemia phase and recanalization phase. The three groups werenormal on T2WI imaging. DWI had good sensitivity to acute cerebral ischemia, which was used to study the chronological and spatial rules of development of early cell edema in ischemia regions.

  4. Changes of evoked potential and expression of nestin in subventricular zones in rats after focal cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    GAO Jie; WANG Yong-tang; WANG Li-li; ZENG Ling; WU Ya-min; SHAO Yang

    2007-01-01

    Objective:To study the characteristics of latency of somatosensory evoked potential (SEP)and motor evoked potential (MEP) and the expression of nestin in subventricular zones (SVZ) after persistent focal cerebral ischemia in rats. Methods: The model of cerebral ischemia in rats was made by middle cerebral artery occlusion (MCAO). All animals of ischemia were sacrificed after 12 h, 1 d, 3 d, 7 d,and 14 d to observe the changes of latency of SEP and MEP and to detect the expression of nestin, with an immunohistochemical approach. Results: The latencies of P1 (positive wave 1), N1 (negative wave 1) and P2 (positive wave 2) in SEP were significantly prolonged after MCAO. The latencies of N1 and N2 waves in MEP were postponed gradually and no statistical difference of latency of N1 wave was found in rats at 7d and 14 d after MCAO. The expression of nestin increased at 12 h, and showed a significant augmentation at 3 d and peaked at 7 d, then declined slightly at 14 d after MCAO. Conclusion: The cerebral ischemia prolonged the latency of EP waves and the expression of nestin was up-regulated and reached the peak at 7d, showing the ischemia induced the proliferation of nervous stem cells. The SEP and MEP may evaluate the proliferation in SVZ after brain ischemia.

  5. Therapeutic time window for the neuroprotective effects of NGF when administered after focal cerebral ischemia.

    Science.gov (United States)

    Yang, Ji-Ping; Liu, Huai-Jun; Yang, Hua; Feng, Ping-Yong

    2011-06-01

    In the present study, we evaluated the neuroprotection time window for nerve growth factor (NGF) after ischemia/reperfusion brain injury in rabbits as related to this anti-apoptosis mechanism. Male New Zealand rabbits were subjected to 2 h of middle cerebral artery occlusion (MCAO), followed by 70 h of reperfusion. NGF was administered after injury to evaluate the time window. Neurological deficits, infarct volume, neural cell apoptosis and expressions of caspase-3 and Bcl-2 were measured. Compared to saline-treated control, NGF treatment at 2, 3 and 5 h after MCAO significantly reduced infarct volume, neural cell apoptosis and expression of caspase-3 (P NGF provides an extended time window of up to 5 h after ischemia/reperfusion brain injury, in part by attenuating the apoptosis.

  6. Role of mixed lineage kinase inhibition in neonatal hypoxia-ischemia.

    Science.gov (United States)

    Carlsson, Ylva; Leverin, Anna-Lena; Hedtjärn, Maj; Wang, Xiaoyang; Mallard, Carina; Hagberg, Henrik

    2009-01-01

    Hypoxic-ischemic brain injury is often delayed and involves both apoptotic and immunoregulatory mechanisms. In this study, we used a neonatal model of hypoxia-ischemia to examine the effect of the mixed lineage kinase (MLK) inhibitor CEP-1347 on brain damage, apoptosis and inflammation. The tissue volume loss was reduced by 28% (p = 0.019) in CEP-1347-treated versus vehicle-treated rats and CEP-1347 significantly attenuated microgliosis at 7 days (p = 0.038). CEP-1347 decreased TUNEL-positive staining as well as cleaved caspase 3 immunoreactivity. CEP-1347 did not affect the expression of pro-inflammatory cytokines IL-1 beta, IL-6 and MCP-1, nor did it affect the expression of OX-42 (CR3) and OX-18 (MHC I) 24 h after the insult. In conclusion, the MLK inhibitor CEP-1347 has protective effects in a neonatal rat model of hypoxia-ischemia, which is mainly related to reduced apoptosis.

  7. Role of Nitric Oxide and Nitric Oxide Synthases in Ischemia-reperfusion Injury in Rat Organotypic Hippocampus Slice

    Institute of Scientific and Technical Information of China (English)

    MENG Xianfang; SHI Jing; LIU Xiaochun; ZHANG Jing; SUN Ning

    2005-01-01

    To investigate the effects of ischemia-reperfusion on the levels of nitric oxide and nitric oxide synthase isoforms (nNOS and iNOS), rat organotypic hippocampus slice were cultured in vitro and subjected to ischemia by oxygen glucose deprivation (OGD) for 30 min and then placed in the normal culture condition. The ischemia-reperfusion produced a time-dependent increase in nitrite levels in the culture medium. Reverse transcriptional-polymerase chain reaction showed augmented levels of mRNA for both nNOS and iNOS when compared with control at 12 h and remained increase at 36 h after OGD (P<0.05). The protein levels of both nitric oxide synthase isoforms increased significantly as determined by Western Blot. OGD also caused neurotoxicity in this model as revealed by the elevated lactate dehydrogenase (LDH) efflux into the incubation solution. The results suggest that organotypic hippocampus slice is a useful model in studying ischemia-reperfusion brain injury. NO and NOS may play a critical role in the ischemia-reperfusion brain damage in vitro.

  8. Are bone marrow regenerative cells ideal seed cells for the treatment of cerebral ischemia?★

    OpenAIRE

    Li, Yi; Hua, Xuming; Hua, Fang; Mao, Wenwei; Wan, Liang; Li, Shiting

    2013-01-01

    Bone marrow cells for the treatment of ischemic brain injury may depend on the secretion of a large number of neurotrophic factors. Bone marrow regenerative cells are capable of increasing the secretion of neurotrophic factors. In this study, after tail vein injection of 5-fluorouracil for 7 days, bone marrow cells and bone marrow regenerative cells were isolated from the tibias and femurs of rats, and then administered intravenously via the tail vein after focal cerebral ischemia. Immunohist...

  9. Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage

    Science.gov (United States)

    Rowland, Matthew J.; Ezra, Martyn; Herigstad, Mari; Hayen, Anja; Sleigh, Jamie W.; Westbrook, Jon; Warnaby, Catherine E.; Pattinson, Kyle T. S.

    2016-01-01

    Objectives: Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed “early brain injury,” with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as α/δ frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia. Design: Unblinded pilot study testing response to drug intervention. Setting: Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Patients: Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41–69 yr]; 11 women). Interventions: IV sodium nitrite (10 μg/kg/min) for 1 hour. Measurements and Main Results: Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to –31%) (p = 0.006, multivariate analysis accounting for major confounds). Conclusions: Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient’s susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage. PMID:27441898

  10. In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Joana Fernandes

    Full Text Available Transient global cerebral ischemia induces profound changes in the transcriptome of brain cells, which is partially associated with the induction or repression of genes that influence the ischemic response. However, the mechanisms responsible for the selective vulnerability of hippocampal neurons to global ischemia remain to be clarified. To identify molecular changes elicited by ischemic insults, we subjected hippocampal primary cultures to oxygen-glucose deprivation (OGD, an in vitro model for global ischemia that resulted in delayed neuronal death with an excitotoxic component. To investigate changes in the transcriptome of hippocampal neurons submitted to OGD, total RNA was extracted at early (7 h and delayed (24 h time points after OGD and used in a whole-genome RNA microarray. We observed that at 7 h after OGD there was a general repression of genes, whereas at 24 h there was a general induction of gene expression. Genes related with functions such as transcription and RNA biosynthesis were highly regulated at both periods of incubation after OGD, confirming that the response to ischemia is a dynamic and coordinated process. Our analysis showed that genes for synaptic proteins, such as those encoding for PICK1, GRIP1, TARPγ3, calsyntenin-2/3, SAPAP2 and SNAP-25, were down-regulated after OGD. Additionally, OGD decreased the mRNA and protein expression levels of the GluA1 AMPA receptor subunit as well as the GluN2A and GluN2B subunits of NMDA receptors, but increased the mRNA expression of the GluN3A subunit, thus altering the composition of ionotropic glutamate receptors in hippocampal neurons. Together, our results present the expression profile elicited by in vitro ischemia in hippocampal neurons, and indicate that OGD activates a transcriptional program leading to down-regulation in the expression of genes coding for synaptic proteins, suggesting that the synaptic proteome may change after ischemia.

  11. Dendritic development of hippocampal CA1 pyramidal cells in a neonatal hypoxia-ischemia injury model.

    Science.gov (United States)

    Zhao, Yan Dong; Ou, Shan; Cheng, Sai Yu; Xiao, Zhi; He, Wen Juan; Zhang, Jin Hai; Ruan, Huai Zhen

    2013-09-01

    It is believed that neonatal hypoxia-ischemia (HI) brain injury causes neuron loss and brain functional defects. However, the effect of HI brain injury on dendritic development of the remaining pyramidal cells of the hippocampus and the reaction of contralateral hippocampal neurons require further studies. The Morris water maze and Golgi-Cox staining were used to evaluate the learning and memory and dendritic morphology of pyramidal cells. The results of Golgi-Cox staining showed CA1 pyramidal neurons of HI injury models with fewer bifurcations and shorter dendrite length than the naive control group. The density of dendritic spines of hippocampal CA1 pyramidal neurons was significantly lower in the HI brain injury group than in controls. With respect to hippocampal function, the HI brain injury group presented cognitive deficits in the reference memory task and probe trail. In the HI group, the pyramidal cells of left hippocampus that did not experienced ischemia but did experience hypoxia had more complex dendrites and higher density of spine than the HI injury side and control. The functional implementation of injured hippocampus might depend mainly on the hypertrophy of contralateral hippocampus after HI brain injury. Corticosterone can partially prevent the hippocampal pyramidal cells from HI injury and reduce the difference of the bilateral hippocampus pyramidal cells, but there was no improvement in learning and memory.

  12. Mitochondrial Targeted Antioxidant in Cerebral Ischemia.

    Science.gov (United States)

    Ahmed, Ejaz; Donovan, Tucker; Yujiao, Lu; Zhang, Quanguang

    There has been much evidence suggesting that reactive oxygen species (ROS) generated in mitochondria during cerebral ischemia play a major role in programming the senescence of organism. Antioxidants dealing with mitochondria slow down the appearance and progression of symptoms in cerebral ischemia and increase the life span of organisms. The mechanisms of mitochondrial targeted antioxidants, such as SKQ1, Coenzyme Q10, MitoQ, and Methylene blue, include increasing adenosine triphosphate (ATP) production, decreasing production of ROS and increasing antioxidant defenses, providing benefits in neuroprotection following cerebral ischemia. A number of studies have shown the neuroprotective role of these mitochondrial targeted antioxidants in cerebral ischemia. Here in this short review we have compiled the literature supporting consequences of mitochondrial dysfunction, and the protective role of mitochondrial targeted antioxidants.

  13. Nitro-Oxidative Stress after Neuronal Ischemia Induces Protein Nitrotyrosination and Cell Death

    Directory of Open Access Journals (Sweden)

    Marta Tajes

    2013-01-01

    Full Text Available Ischemic stroke is an acute vascular event that obstructs blood supply to the brain, producing irreversible damage that affects neurons but also glial and brain vessel cells. Immediately after the stroke, the ischemic tissue produces nitric oxide (NO to recover blood perfusion but also produces superoxide anion. These compounds interact, producing peroxynitrite, which irreversibly nitrates protein tyrosines. The present study measured NO production in a human neuroblastoma (SH-SY5Y, a murine glial (BV2, a human endothelial cell line (HUVEC, and in primary cultures of human cerebral myocytes (HC-VSMCs after experimental ischemia in vitro. Neuronal, endothelial, and inducible NO synthase (NOS expression was also studied up to 24 h after ischemia, showing a different time course depending on the NOS type and the cells studied. Finally, we carried out cell viability experiments on SH-SY5Y cells with H2O2, a prooxidant agent, and with a NO donor to mimic ischemic conditions. We found that both compounds were highly toxic when they interacted, producing peroxynitrite. We obtained similar results when all cells were challenged with peroxynitrite. Our data suggest that peroxynitrite induces cell death and is a very harmful agent in brain ischemia.

  14. Continuous nimodipine treatment attenuates cortical infarction in rats subjected to 24 hours of focal cerebral ischemia.

    Science.gov (United States)

    Jacewicz, M; Brint, S; Tanabe, J; Pulsinelli, W A

    1990-01-01

    Focal cerebral infarction and edema were measured in rats (Wistar, Fisher 344, and spontaneously hypertensive strains) pretreated with nimodipine (2 micrograms/kg/min i.v.) or its vehicle and subjected to the tandem occlusion of the middle cerebral and common carotid arteries. Animals awoke from anesthesia 10-15 min after onset of ischemia and continued to receive treatment over a 24-h survival period. Cortical infarction and edema were quantified by image analysis of frozen brain sections processed for histology. Nimodipine-treated rats developed 20-60% smaller cortical infarct volumes than controls (p less than 0.002). Cortical edema was reduced proportionately to the decrease in infarct volume and constituted approximately 36% of the infarct volume. Nimodipine caused a mild hypotensive response that did not aggravate ischemic brain damage. The results indicate that continuous nimodipine treatment, started before induction of focal cerebral ischemia, can attenuate ischemic brain damage and edema as late as 24 h after the onset of ischemia.

  15. Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia.

    Science.gov (United States)

    Pulsinelli, W A; Levy, D E; Duffy, T E

    1982-05-01

    Progressive brain damage after transient cerebral ischemia may be related to changes in postischemic cerebral blood flow and metabolism. Regional cerebral blood flow (rCBF) and cerebral glucose utilization (rCGU) were measured in adult rats prior to, during (only rCBF), and serially after transient forebrain ischemia. Animals were subjected to 30 minutes of forebrain ischemia by occluding both common carotid arteries 24 hours after cauterizing the vertebral arteries. Regional CBF was measured by the indicator-fractionation technique using 4-iodo-[14C]-antipyrine. Regional CGU was measured by the 2-[14C]deoxyglucose method. The results were correlated with the distribution and progression of ischemic neuronal damage in animals subjected to an identical ischemic insult. Cerebral blood flow to forebrain after 30 minutes of moderate to severe ischemia (less than 10% control CBF) was characterized by 5 to 15 minutes of hyperemia; rCBF then fell below normal and remained low for as long as 24 hours. Post-ischemic glucose utilization in the forebrain, except in the hippocampus, was depressed below control values at 1 hour and either remained low (neocortex, striatum) or gradually rose to normal (white matter) by 48 hours. In the hippocampus, glucose utilization equaled the control value at 1 hour and fell below control between 24 and 48 hours. The appearance of moderate to severe morphological damage in striatum and hippocampus coincided with a late rise of rCBF above normal and with a fall of rCGU; the late depression of rCGU was usually preceded by a period during which metabolism was increased relative to adjacent tissue. Further refinement of these studies may help identify salvageable brain after ischemia and define ways to manipulate CBF and metabolism in the treatment of stroke.

  16. Protective Effects of HDL Against Ischemia/Reperfusion Injury.

    Science.gov (United States)

    Gomaraschi, Monica; Calabresi, Laura; Franceschini, Guido

    2016-01-01

    Several lines of evidence suggest that, besides being a strong independent predictor of the occurrence of primary coronary events, a low plasma high density lipoprotein (HDL) cholesterol level is also associated with short- and long-term unfavorable prognosis in patients, who have recovered from a myocardial infarction, suggesting a direct detrimental effect of low HDL on post-ischemic myocardial function. Experiments performed in ex vivo and in vivo models of myocardial ischemia/reperfusion (I/R) injury have clearly shown that HDL are able to preserve cardiac function when given before ischemia or at reperfusion; the protective effects of HDL against I/R injury have been also confirmed in other tissues and organs, as brain and hind limb. HDL were shown to act on coronary endothelial cells, by limiting the increase of endothelium permeability and promoting vasodilation and neoangiogenesis, on white blood cells, by reducing their infiltration into the ischemic tissue and the release of pro-inflammatory and matrix-degrading molecules, and on cardiomyocytes, by preventing the activation of the apoptotic cascade. Synthetic HDL retains the cardioprotective activity of plasma-derived HDL and may become a useful adjunctive therapy to improve clinical outcomes in patients with acute coronary syndromes or undergoing coronary procedures.

  17. Diffusion-weighted MR imaging (DWI) in spinal cord ischemia

    Energy Technology Data Exchange (ETDEWEB)

    Thurnher, Majda M. [Medical University of Vienna, Department of Radiology, Neuroradiology Section, Vienna (Austria); Bammer, Roland [Stanford University, Lucas MRS/I Center, Department of Radiology, Stanford, CA (United States)

    2006-11-15

    Spinal cord infarction is a rare clinical diagnosis characterized by a sudden onset of paralysis, bowel and bladder dysfunction, and loss of pain and temperature perception, with preservation of proprioception and vibration sense. Magnetic resonance imaging (MRI) usually demonstrates intramedullary hyperintensity on T2-weighted MR images with cord enlargement. However, in approximately 45% of patients, MR shows no abnormality. Diffusion-weighted MR imaging (DWI) has been widely used for the evaluation of a variety of brain disorders, especially for acute stroke. Preliminary data suggest that DWI has the potential to be useful in the early detection of spinal infarction. We performed DWI, using navigated, interleaved, multishot echo planar imaging (IEPI), in a series of six patients with a clinical suspicion of acute spinal cord ischemia. In all patients, high signal was observed on isotropic DWI images with low ADC values (0.23 and 0.86 x 10{sup -3} cm{sup 2}/s), indicative of restricted diffusion. We analyzed the imaging findings from conventional MR sequences and diffusion-weighted MR sequences in six patients with spinal cord infarction, compared the findings with those in published series, and discuss the value of DWI in spinal cord ischemia based on current experience. Although the number of patients with described DWI findings totals only 23, the results of previously published studies and those of our study suggest that DWI has the potential to be a useful and feasible technique for the detection of spinal infarction. (orig.)

  18. Cognitive Status in Patients with Chronic Cerebral Ischemia

    Directory of Open Access Journals (Sweden)

    Yokudhon N. Madjidova

    2013-12-01

    Full Text Available The aim of our study was to examine the cognitive functions in patients with chronic cerebral ischemia (stages I- II of discirculatory encephalopathy of various origins. Systematization of the patients was performed according to EV Schmidt’s classification of the vascular lesions of the brain. All the subjects were categorized into two groups. Group 1 consisted of 115 patients (42 men and 73 women with chronic cerebral ischemia (CCI that had developed, mainly, against the background of arterial hypertension (AH. Group 2 consisted of 122 patients (33 men and 89 women with CCI, which developed, mainly, against the backdrop of atherosclerosis of the cerebral vessels. The mean age was 54.2±0.7 years in Group 1 and 56.8±0.8 years Group 2, respectively. Control group included 30 healthy subjects (mean age: 52.2±0.9 years without any objective manifestations of CCI. The stage of cognitive deficit was determined by employing the MMSE test and the Bourdon test. The “Schulte Tables” technique was used for estimating the stability of attention and rate of sensorimotor reactions. Luria’s Memory Ten-Word Retrieval Test (LMTWRT was applied for estimating attention and memory. The present study indicates that the cognitive deficits detected in patients with CIC were characterized by the greatest severity against the background of AH. AH predominantly damages the subcortical structures, resulting in subcortical angioencephalopathy, which ultimately leads to a deterioration of the intellectual-mental processes.

  19. Tacrolimus (FK506 reduces ischemia-induced hippocampal damage in rats: a 7- and 30-day study

    Directory of Open Access Journals (Sweden)

    F. Giordani

    2003-04-01

    Full Text Available The neuroprotective effect of the immunosuppressant agent FK506 was evaluated in rats after brain ischemia induced for 15 min in the 4-vessel occlusion model. In the first experimental series, single doses of 1.0, 3.0 or 6.0 mg FK506/kg were given intravenously (iv immediately after ischemia. In the second series, FK506 (1.0 mg/kg was given iv at the beginning of reperfusion, followed by doses applied intraperitoneally (ip 6, 24, 48, and 72 h post-ischemia. The same protocol was used in the third series except that all 5 doses were given iv. Damage to the hippocampal field CA1 was assessed 7 or 30 days post-ischemia on three different stereotaxic planes along the septotemporal axis of the hippocampus. Ischemia caused marked neurodegeneration on all planes (P<0.001. FK506 failed to provide neuroprotection to CA1 both when applied iv as a single dose of 1.0, 3.0 or 6.0 mg/kg (experiment 1, and after five iv injections of 1.0 mg/kg (experiment 3. In contrast, the repeated administration of FK506 combining iv plus ip administration reduced CA1 cell death on all stereotaxic planes both 7 and 30 days post-ischemia (experiment 2; P<=0.01. Compared to vehicle alone, FK506 reduced rectal temperature in a dose-dependent manner (P<=0.05; however, this effect did not alter normothermia (37ºC. FK506 reduced ischemic brain damage, an effect sustained over time and apparently dependent on repeated doses and on delivery route. The present data extend previous findings on the rat 4-vessel occlusion model, further supporting the possible use of FK506 in the treatment of ischemic brain damage.

  20. Protein-energy malnutrition alters hippocampal plasticity-associated protein expression following global ischemia in the gerbil.

    Science.gov (United States)

    Prosser-Loose, Erin J; Verge, Valerie M K; Cayabyab, Francisco S; Paterson, Phyllis G

    2010-11-01

    Previously it has been demonstrated that protein-energy malnutrition (PEM) impairs habituation in the open field test following global ischemia. The present study examined the hypothesis that PEM exerts some of its deleterious effects on functional outcome by altering the post-ischemic expression of the plasticity-associated genes brain-derived neurotrophic factor (BDNF), its receptor tropomyosin-related kinase B (trkB), and growth-associated protein-43 (GAP-43). Male, Mongolian gerbils (11-12 wk) were randomized to either control diet (12.5% protein) or PEM (2% protein) for 4 wk, and then underwent 5 min bilateral common carotid artery occlusion or sham surgery. Tympanic temperature was maintained at 36.5 ± 0.5°C during surgery. Brains collected at 1, 3 and 7 d post-surgery were processed by in-situ hybridization or immunofluorescence. BDNF and trkB mRNA expression was increased in hippocampal CA1 neurons after ischemia at all time points and was not significantly influenced by diet. However, increased trkB protein expression after ischemia was exacerbated by PEM at 7 d in the CA1 region. Post-ischemic GAP-43 protein increased at 3 and 7 d in the CA1 region, and PEM intensified this response and extended it to the CA3 and hilar regions. PEM exerted these effects without exacerbating CA1 neuron loss caused by global ischemia. The findings suggest that PEM increases the stress response and/or hyper-excitability in the hippocampus after global ischemia. Nutritional care appears to have robust effects on plasticity mechanisms important to recovery after brain ischemia.

  1. Pharmacological Neuroprotection after Perinatal Hypoxic-Ischemic Brain Injury

    NARCIS (Netherlands)

    Fan, Xiyong; Kavelaars, Annemieke; Heijnen, Cobi J.; Groenendaal, Floris; van Bel, Frank

    2010-01-01

    Perinatal hypoxia-ischemia (HI) is an important cause of neonatal brain injury. Recent progress in the search for neuroprotective compounds has provided us with several promising drugs to reduce perinatal HI-induced brain injury. In the early stage (first 6 hours after birth) therapies are concentra

  2. Effects of immediate and delayed mild hypothermia on endogenous antioxidant enzymes and energy metabolites following global cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    ZHANG Hong; ZHANG Jun-jian; MEI Yuan-wu; SUN Sheng-gang; TONG E-tang

    2011-01-01

    Background The optimal time window for the administration of hypothermia following cerebral ischemia has been studied for decades,with disparity outcomes.In this study,the efficacy of mild brain hypothermia beginning at different time intervals on brain endogenous antioxidant enzyme and energy metabolites was investigated in a model of global cerebral ischemia.Methods Forty-eight male Sprague-Dawley rats were divided into a sham-operated group,a normothermia (37℃-38℃) ischemic group and a mild hypothermic (31℃-32℃) ischemia groups.Rats in the last group were subdivided into four groups:240 minutes of hypothermia,30 minutes of normothermia plus 210 minutes of hypothermia,60 minutes of normothermia plus 180 minutes of hypothermia and 90 minutes of normothermia plus 150 minutes of hypothermia (n=8).Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model for 20minutes and mild hypothermia was applied after 20 minutes of ischemia.Brain.tissue was collected following 20 minutes of cerebral ischemia and 240 minutes of reperfusion,and used to measure the levels of superoxide dismutase (SOD),glutathione peroxidase (GSH-Px),reduced glutathione (GSH) and adenosine triphosphate (ATP).Results Mild hypothermia that was started within 0 to 60 minutes delayed the consumption of SOD,GSH-Px,GSH,and ATP (P <0.05 or P <0.01) in ischemic tissue,as compared to a normothermic ischemia group.In contrast,mild hypothermia beginning at 90 minutes had little effect on the levels of SOD,GSH-Px,GSH,and ATP (P>0.05).Conclusions Postischemic mild brain hypothermia can significantly delay the consumption of endogenous antioxidant enzymes and energy metabolites,which are critical to the process of cerebral protection by mild hypothermia.These results show that mild hypothermia limits ischemic injury if started within 60 minutes,but loses its protective effects when delayed until 90 minutes following cerebral ischemia.

  3. [Comparative evaluation of the neuroprotective activity of phenotropil and piracetam in laboratory animals with experimental cerebral ischemia].

    Science.gov (United States)

    Tiurenkov, I N; Bagmetov, M N; Epishina, V V

    2007-01-01

    The neuroprotective properties of phenotropil and piracetam were studied in Wistar rats with low and high sensitivity with respect to cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in the brain cortex under ischemic injury conditions were studied. Phenotropil and (to a lower extent) piracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions in animals with gravitational cerebral ischemia, increased the survival of experimental animals, and favored the restoration of local cerebral flow upon the occlusion of carotid arteries.

  4. Hippophae salicifolia D.Don berries attenuate cerebral ischemia reperfusion injury in a rat model of middle cerebral artery occlusion