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Sample records for cerebral ischemia detected

  1. Cytochemical detection of superoxide in cerebral inflammation and ischemia in vivo.

    PubMed

    Kontos, C D; Wei, E P; Williams, J I; Kontos, H A; Povlishock, J T

    1992-10-01

    We used a cytochemical technique for the detection of superoxide in cerebral inflammation and ischemia-reperfusion in anesthetized cats. The technique is based on the oxidation of Mn2+ to Mn3+ by superoxide; Mn3+, in turn, oxidizes diaminobenzidine. The oxidized diaminobenzidine forms an osmiophilic electron-dense product that is detected by electron microscopy. The reagents, manganese chloride (2 mM) and diaminobenzidine (2 mg/ml), were placed topically on the brain surface of anesthetized cats equipped with cranial windows. Inflammation was induced by topical carrageenan with or without phorbol 12-myristate 13-acetate to activate leukocytes. In inflammation, superoxide was detected in the plasma membrane and in the phagocytic vacuoles of leukocytes. In ischemia-reperfusion, superoxide was identified in the meninges in association with blood vessels. It was located primarily in the extracellular space and occasionally in endothelial and vascular smooth muscle cells. In both inflammation and ischemia, the reaction product was eliminated by superoxide dismutase or by the omission of either manganese or diaminobenzidine. It was unaffected by sodium azide, which inhibits peroxidases. No superoxide was detected in the brain parenchyma. The findings confirm the generation of superoxide is cerebral ischemia-reperfusion and show that it is produced in cerebral vessels.

  2. Neuroprotection after cerebral ischemia

    PubMed Central

    Namura, Shobu; Ooboshi, Hiroaki; Liu, Jialing; Yenari, Midori A.

    2013-01-01

    Cerebral ischemia, a focal or global insufficiency of blood flow to the brain, can arise through multiple mechanisms, including thrombosis and arterial hemorrhage. Ischemia is a major driver of stroke, one of the leading causes of morbidity and mortality worldwide. While the general etiology of cerebral ischemia and stroke has been known for some time, the conditions have only recently been considered treatable. This report describes current research in this field seeking to fully understand the pathomechanisms underlying stroke; to characterize the brain’s intrinsic injury, survival, and repair mechanisms; to identify putative drug targets as well as cell-based therapies; and to optimize the delivery of therapeutic agents to the damaged cerebral tissue. PMID:23488559

  3. Heart Rate Variability for the Early Detection of Delayed Cerebral Ischemia.

    PubMed

    Schmidt, J Michael

    2016-06-01

    Delayed cerebral ischemia is considered the leading cause of death or major disability in subarachnoid hemorrhage after the impact of the initial event and rebleeding. Waiting to treat patients until they exhibit clinical symptoms of ischemia is too late to prevent cerebral infarction for more than 60% of patients, and transcranial Doppler ultrasonography has not proven to be a reliable screening tool to identify high-risk patients. Continuous heart rate variability monitoring may provide an alternative screening strategy to identify patients at high risk for delayed cerebral ischemia. Heart rate variability is a composite reflection of autonomic outflow, neuroendocrine influences, and autonomic responsiveness. Most importantly, heart rate variability is responsive to changes in systemic inflammation, which evidence suggests is important to the causal pathway of delayed cerebral ischemia. The clinical application of continuous heart rate variability monitoring in critical care is relatively recent despite its existence for more than 50 years. Initial studies suggest promise for heart rate variability monitoring as a delayed cerebral ischemia screening tool, but significant research is still required before this approach may achieve clinical applicability and bring benefit to patients. PMID:27258451

  4. Animal models of cerebral ischemia

    NASA Astrophysics Data System (ADS)

    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.

  5. Detection of cerebral ischemia using the power spectrum of the pulse wave measured by near-infrared spectroscopy.

    PubMed

    Ebihara, Akira; Tanaka, Yuichi; Konno, Takehiko; Kawasaki, Shingo; Fujiwara, Michiyuki; Watanabe, Eiju

    2013-10-01

    The diagnosis and medical treatment of cerebral ischemia are becoming more important due to the increase in the prevalence of cerebrovascular disease. However, conventional methods of evaluating cerebral perfusion have several drawbacks: they are invasive, require physical restraint, and the equipment is not portable, which makes repeated measurements at the bedside difficult. An alternative method is developed using near-infrared spectroscopy (NIRS). NIRS signals are measured at 44 positions (22 on each side) on the fronto-temporal areas in 20 patients with cerebral ischemia. In order to extract the pulse-wave component, the raw total hemoglobin data recorded from each position are band-pass filtered (0.8 to 2.0 Hz) and subjected to a fast Fourier transform to obtain the power spectrum of the pulse wave. The ischemic region is determined by single-photon emission computed tomography. The pulse-wave power in the ischemic region is compared with that in the symmetrical region on the contralateral side. In 17 cases (85%), the pulse-wave power on the ischemic side is significantly lower than that on the contralateral side, which indicates that the transmission of the pulse wave is attenuated in the region with reduced blood flow. Pulse-wave power might be useful as a noninvasive marker of cerebral ischemia.

  6. [The developing profile of cerebral ischemia].

    PubMed

    Martí-Vilalta, J L; Martí-Fábregas, J

    1999-01-01

    Cerebral ischemia, which may be silently manifested as transitory ischemia attacks or cerebral infarction, is not a stable, but rather, a moving process. In cerebral infarctions the initial ischemic area may change or move in a high percentage of patients and may involve a significant volume (mean of 32%) of neuronal tissue. The negative changes of initial cerebral ischemia which produce a worsening of the same may be due to the progression of the thrombus, appearance of new embolisms, cerebral edema, hemorrhage, blood reperfusion and systemias causes. These changes may determine the conversion of the shaded ischemic area into a definitive, irreversible infarction. The negative changes may also be produced some distance from the initial ischemic area, either because of microthromboembolisms or diaschisis. The positive changes of initial cerebral ischemia which produce as improvement of the same, may be due to collateral circulation, lysis or fragmentation of the embolism and a decrease in cerebral edema. Clinical changes with no evident clinical manifestations may also be produced and may be diagnosed with the use of clinical scales, imaging techniques, ultrasound and hematological and biochemical markers. Acknowledgement of these cerebral ischemia changes in the acute phase may determine the salvation of a part of the brain, and thereby modify the future clinical situation of the patient.

  7. Can near-infrared spectroscopy be used for detection of perioperative severe cerebral ischemia?

    NASA Astrophysics Data System (ADS)

    Smielewski, Piotr; Lam, Joseph M. K.; Al-Rawi, Pippa G.; Czosnyka, Marek; Kirkpatrick, Peter J.

    1998-01-01

    Accurate quantification of near-infrared (NIRS) signal changes during monitoring of the adult head is required for regular clinical use. By incorporating NIRS into a multimodal monitoring system, which documents cerebral haemodynamic changes during carotid endarterectomy, we have provided the opportunity for calibration against parameters known to warn of severe cerebral ischaemia (SCI) under controlled anaesthesia. Application of a particular protocol in which clamping of the External Carotid Artery was performed two minutes before the Internal Carotid Artery enabled isolation of the NIRS measurements from the intracranial tissue. This way the most profound problem in adult NIRS, extracranial contamination, has been successfully addressed. In consequence, NIRS derived thresholds for intraoperative cerebral ischaemia showed in a series of 76 patients high agreement with criteria defined using transcranial Doppler and the cerebral function monitor. In contrast, when non-corrected for extracranial components NIRS measurements were used no thresholds for SCI were apparent.

  8. Can near-infrared spectroscopy be used for detection of perioperative severe cerebral ischemia?

    NASA Astrophysics Data System (ADS)

    Smielewski, Piotr; Lam, Joseph M.; Al-Rawi, Pippa; Czosnyka, Marek; Kirkpatrick, Peter J.

    1997-12-01

    Accurate quantification of near-infrared (NIRS) signal changes during monitoring of the adult head is required for regular clinical use. By incorporating NIRS into a multimodal monitoring system, which documents cerebral haemodynamic changes during carotid endarterectomy, we have provided the opportunity for calibration against parameters known to warn of severe cerebral ischaemia (SCI) under controlled anaesthesia. Application of a particular protocol in which clamping of the External Carotid Artery was performed two minutes before the Internal Carotid Artery enabled isolation of the NIRS measurements from the intracranial tissue. This way the most profound problem in adult NIRS, extracranial contamination, has been successfully addressed. In consequence, NIRS derived thresholds for intraoperative cerebral ischaemia showed in a series of 76 patients high agreement with criteria defined using transcranial Doppler and the cerebral function monitor. In contrast, when non-corrected for extracranial components NIRS measurements were used no thresholds for SCI were apparent.

  9. Activation-flow coupling during graded cerebral ischemia.

    PubMed

    Burnett, Mark G; Detre, John A; Greenberg, Joel H

    2005-06-14

    Most functional neuroimaging techniques rely on activation-flow coupling (AFC) to detect changes in regional brain function, but AFC responses may also be altered during pathophysiological conditions such as ischemia. To define the relationship between progressive ischemia and the AFC response, graded levels of cerebral blood flow reduction were produced using a rat compression ischemia model, and the cerebral hemodynamic response to forepaw stimulation was measured. Graded levels of cortical ischemia of the somatosensory cortex were induced in male Sprague-Dawley rats (n = 16) by compressing the intact dura with a 4-mm-diameter cylinder equipped with a laser-Doppler probe, combined with ipsilateral common carotid artery occlusion. At each level of CBF reduction, electric forepaw stimulation was conducted, and signal-averaged laser Doppler and evoked potential responses were recorded. A visible AFC response was present at all levels of CBF reduction (0-90% reduction from baseline), and the temporal characteristics of the response appeared largely preserved. However, the amplitude of the AFC response began to decline at levels of mild ischemia (10% flow reduction) and progressively decreased with further CBF reduction. The amplitude of the evoked response appeared to decrease in concert with the AFC amplitude and appeared to be equally sensitive to ischemia. AFC appears to be a sensitive marker for cerebral ischemia, and alterations in the AFC response occur at CBF reductions above the accepted thresholds for infarction. However, the AFC response is also preserved when flow is reduced below ischemic thresholds. PMID:15893740

  10. Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia

    PubMed Central

    Shamsaei, Nabi; Khaksari, Mehdi; Erfani, Sohaila; Rajabi, Hamid; Aboutaleb, Nahid

    2015-01-01

    Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral ischemic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction through occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic exercise significantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration. PMID:26487851

  11. Effects of cerebral ischemia on neuronal hemoglobin

    PubMed Central

    He, Yangdong; Hua, Ya; Liu, Wenquan; Hu, Haitao; Keep, Richard F.; Xi, Guohua

    2009-01-01

    Summary The present study examined whether or not neuronal hemoglobin (Hb) is present in rats. It then examined whether cerebral ischemia or ischemic preconditioning (IPC) affects neuronal Hb levels in vivo and in vitro. In vivo, male Sprague-Dawley rats were subjected to either 15 minutes of transient middle cerebral artery occlusion with 24 hours of reperfusion, an IPC stimulus, or 24 hours of permanent middle cerebral artery occlusion (pMCAO), or IPC followed three days later by 24 hours of pMCAO. In vitro, primary cultured neurons were exposed to 2 hours of oxygen-glucose deprivation with 22 hours of reoxygenation. Results showed that Hb is widely expressed in rat cerebral neurons but not astrocytes. Hb expression was significantly upregulated in the ipsilateral caudate and the cortical core of the middle cerebral artery territory after IPC. Hb levels also increased in more penumbral cortex and the contralateral hemisphere 24 hours after pMCAO, but expression in the ipsilateral caudate and cortical core area were decreased. Ischemic preconditioning modified pMCAO-induced brain Hb changes. Neuronal Hb levels in vitro were increased by 2 hours of oxygen-glucose deprivation and 22 hours of reoxygenation. These results indicate that Hb is synthesized in neurons and can be upregulated by ischemia. PMID:19066615

  12. Infrared laser hemotherapy in cerebral ischemia modeling

    NASA Astrophysics Data System (ADS)

    Musienko, Julia I.; Nechipurenko, Natalia I.

    2003-10-01

    Use of intravenous laser irradiation of blood (ILIB) is considered to be the most effective method of laser therapy and its application is expedient pathogenetically in the ischemic disturbances. The aim of this study is to investigate ILIB influence with infrared laser (IL) with 860 nm wavelength on hemostasis, acid-base status (ABS) of blood in normal rabbits and after modeling of local ischemia of brain (LIB). Experimental cerebral ischemia is characterized by development of hypercoagulation syndrom and metabolic acidosis. ILIB with infrared radiation of 2.0 mW power provokes hypocoagulation in intact animals. Application of ILIB in rabbits after LIB contributes for hemostasis and acid-base status normalizing compared to operated animals. IL radiation with 8,5 mW power results in marked hemostatic activation in all animals. Therefore, beneficial effect of low power laser radiation (LPLR) manifests in narrow power diapason in experimental brain ischemia.

  13. Short-term memory and cerebral ischemia: pharmacological application.

    PubMed

    Le Poncin-Lafitte, M; Grosdemouge, C; Billon, C R; Duterte, D; Pontrat, P; Lespinasse, P; Rapin, J R

    1981-01-01

    Transient ischemia results in changes in the cerebral blood flow at the level of microinfarcts, enzymatic and metabolic changes and the development of a cerebral edema; all these disorders regress in the week following ischemia. Besides, the observed functional disorders disappear as the cerebral edema regresses. The brain functional activity is protected by the use of treatments which reduce the development of the cerebral edema and/or a quicker regression of the edema. PMID:7262126

  14. Focal embolic cerebral ischemia in the rat

    PubMed Central

    Zhang, Li; Zhang, Rui Lan; Jiang, Quan; Ding, Guangliang; Chopp, Michael; Zhang, Zheng Gang

    2015-01-01

    Animal models of focal cerebral ischemia are well accepted for investigating the pathogenesis and potential treatment strategies for human stroke. Occlusion of the middle cerebral artery (MCA) with an endovascular filament is a widely used model to induce focal cerebral ischemia. However, this model is not amenable to thrombolytic therapies. As thrombolysis with recombinant tissue plasminogen activator (rtPA) is a standard of care within 4.5 hours of human stroke onset, suitable animal models that mimic cellular and molecular mechanisms of thrombosis and thrombolysis of stroke are required. By occluding the MCA with a fibrin-rich allogeneic clot, we have developed an embolic model of MCA occlusion in the rat, which recapitulates the key components of thrombotic development and of thrombolytic therapy of rtPA observed from human ischemic stroke. The surgical procedures of our model can be typically completed within approximately 30 min and are highly adaptable to other strains of rats as well as mice for both genders. Thus, this model provides a powerful tool for translational stroke research. PMID:25741989

  15. Multiple molecular penumbras after focal cerebral ischemia.

    PubMed

    Sharp, F R; Lu, A; Tang, Y; Millhorn, D E

    2000-07-01

    Though the ischemic penumbra has been classically described on the basis of blood flow and physiologic parameters, a variety of ischemic penumbras can be described in molecular terms. Apoptosis-related genes induced after focal ischemia may contribute to cell death in the core and the selective cell death adjacent to an infarct. The HSP70 heat shock protein is induced in glia at the edges of an infarct and in neurons often at some distance from the infarct. HSP70 proteins are induced in cells in response to denatured proteins that occur as a result of temporary energy failure. Hypoxia-inducible factor (HIF) is also induced after focal ischemia in regions that can extend beyond the HSP70 induction. The region of HIF induction is proposed to represent the areas of decreased cerebral blood flow and decreased oxygen delivery. Immediate early genes are induced in cortex, hippocampus, thalamus, and other brain regions. These distant changes in gene expression occur because of ischemia-induced spreading depression or depolarization and could contribute to plastic changes in brain after stroke. PMID:10908035

  16. An Evidence-Based Review of Related Metabolites and Metabolic Network Research on Cerebral Ischemia

    PubMed Central

    Liu, Mengting; Tang, Liying; Liu, Xin; Fang, Jing; Zhan, Hao; Wu, Hongwei; Yang, Hongjun

    2016-01-01

    In recent years, metabolomics analyses have been widely applied to cerebral ischemia research. This paper introduces the latest proceedings of metabolomics research on cerebral ischemia. The main techniques, models, animals, and biomarkers of cerebral ischemia will be discussed. With analysis help from the MBRole website and the KEGG database, the altered metabolites in rat cerebral ischemia were used for metabolic pathway enrichment analyses. Our results identify the main metabolic pathways that are related to cerebral ischemia and further construct a metabolic network. These results will provide useful information for elucidating the pathogenesis of cerebral ischemia, as well as the discovery of cerebral ischemia biomarkers. PMID:27274780

  17. Cerebral blood flow in experimental ischemia assessed by sup 19 F magnetic resonance spectroscopy in cats

    SciTech Connect

    Brunetti, A.; Nagashima, G.; Bizzi, A.; DesPres, D.J. )

    1990-10-01

    We evaluated a 19F magnetic resonance spectroscopic technique that detects Freon-23 washout as a means of measuring cerebral blood flow in halothane-anesthetized adult cats during and after transient cerebral ischemia produced by vascular occlusion. The experiments were performed to test the ability of this recently developed method to detect postischemic flow deficits. Results were consistent with postischemic hypoperfusion. The method also proved valuable for measuring small residual flow during vascular occlusion. Our experiments indicate that this method provides simple, rapid, and repeatable flow measurements that can augment magnetic resonance examinations of cerebral metabolic parameters in the study of ischemia.

  18. Oxytocin mediates social neuroprotection after cerebral ischemia

    PubMed Central

    Karelina, Kate; Stuller, Kathleen A.; Jarrett, Brant; Zhang, Ning; Wells, Jackie; Norman, Greg J.; DeVries, A. Courtney

    2011-01-01

    Background and Purpose The reduced incidence, morbidity and mortality of stroke among humans with strong social support have been well-documented; however, the mechanisms underlying this socially mediated phenomenon remain unknown, but may involve oxytocin (OT), a hormone that modulates some aspects of social behavior in humans and other animals. Methods In the present study, adult male mice were socially isolated (housed individually) or socially paired (housed with an ovariectomized female); social pairing increased hypothalamic OT gene expression. To determine whether a causal relationship exists between increased OT and improved stroke outcome, mice were treated with exogenous OT or OT receptor antagonist (OTA) beginning one week prior to induction of experimental stroke via middle cerebral artery occlusion (MCAO). Results Relative to social isolation, social housing attenuated infarct size, neuroinflammation, and oxidative stress following experimental stroke; the neuroprotective effect of social housing was eliminated by OTA treatment. In contrast, administration of OT to socially isolated mice reproduced the neuroprotection conferred by social housing. We further report evidence for a direct suppressive action of OT on cultured microglia, which is a key instigator in the development of neuroinflammation after cerebral ischemia. Conclusions These findings support the hypothesis that OT mediates the neuroprotective effect of social interaction on stroke outcome. PMID:21960564

  19. Role of Histamine and Its Receptors in Cerebral Ischemia

    PubMed Central

    2012-01-01

    Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application. PMID:22860191

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

    NASA Astrophysics Data System (ADS)

    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 (P<0.05) while neurogenesis in CA1-CA3 fields was increased as compared to the control (P<0.05).

  1. Thrombin exacerbates brain edema in focal cerebral ischemia.

    PubMed

    Hua, Y; Wu, J; Keep, R F; Hoff, J T; Xi, G

    2003-01-01

    Thrombin contributes to edema formation after intracerebral hemorrhage. Recent studies suggest that thrombin may also play a role in ischemic brain damage. In the present study, adult male Sprague-Dawley rats were anesthetized with pentobarbital. Middle cerebral artery (MCA) was occluded using the suture method. We found that brain thrombin activity was elevated after permanent MCA occlusion as was prothrombin messenger RNA expression. Intracerebral injection of a thrombin inhibitor, hirudin, reduced neurological deficits following cerebral ischemia. In contrast, intracerebral administration of exogenous thrombin (at a dose that is non-toxic to normal brain), markedly exacerbated brain edema after transient focal cerebral ischemia. These results indicate that extravascular thrombin inhibition may be a new therapeutic target for cerebral ischemia.

  2. Vascular Protection Following Cerebral Ischemia and Reperfusion

    PubMed Central

    Palomares, Sara Morales; Cipolla, Marilyn J.

    2011-01-01

    Despite considerable research that has contributed to a better understanding of the pathophysiology of stroke, translation of this knowledge into effective therapies has largely failed. The only effective treatment for ischemic stroke is rapid recanalization of an occluded vessel by dissolving the clot with tissue plasminogen activator (tPA). However, stroke adversely affects vascular function as well that can cause secondary brain injury and limit treatment that depends on a patent vasculature. In middle cerebral arteries (MCA), ischemia/reperfusion (I/R) cause loss of myogenic tone, vascular paralysis, and endothelial dysfunction that can lead to loss of autoregulation. In contrast, brain parenchymal arterioles retain considerable tone during I/R that likely contributes to expansion of the infarct into the penumbra. Microvascular dysregulation also occurs during ischemic stroke that causes edema and hemorrhage, exacerbating the primary insult. Ischemic injury of vasculature is progressive with longer duration of I/R. Early postischemic reperfusion has beneficial effects on stroke outcome but can impair vascular function and exacerbate ischemic injury after longer durations of I/R. This review focuses on current knowledge on the effects of I/R on the structure and function of different vascular segments in the brain and highlight some of the more promising targets for vascular protection. PMID:22102980

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

    PubMed

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

    PubMed

    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 < 0.0001). A repeated CTP was performed in 8 patients with a TCD-measured BFV increase > 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.

  5. Endogenous Protease Nexin-1 Protects against Cerebral Ischemia

    PubMed Central

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

    2013-01-01

    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. PMID:23949634

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

    PubMed

    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.

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

    PubMed

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

    2013-01-01

    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. PMID:23949634

  8. Ligustrazine monomer against cerebral ischemia/reperfusion injury.

    PubMed

    Gao, Hai-Jun; Liu, Peng-Fei; Li, Pei-Wen; Huang, Zhuo-Yan; Yu, Feng-Bo; Lei, Ting; Chen, Yong; Cheng, Ye; Mu, Qing-Chun; Huang, Hai-Yan

    2015-05-01

    Ligustrazine (2,3,5,6-tetramethylpyrazine) is a major active ingredient of the Szechwan lovage rhizome and is extensively used in treatment of ischemic cerebrovascular disease. The mechanism of action of ligustrazine use against ischemic cerebrovascular diseases remains unclear at present. This study summarizes its protective effect, the optimum time window of administration, and the most effective mode of administration for clinical treatment of cerebral ischemia/reperfusion injury. We examine the effects of ligustrazine on suppressing excitatory amino acid release, promoting migration, differentiation and proliferation of endogenous neural stem cells. We also looked at its effects on angiogenesis and how it inhibits thrombosis, the inflammatory response, and apoptosis after cerebral ischemia. We consider that ligustrazine gives noticeable protection from cerebral ischemia/reperfusion injury. The time window of ligustrazine administration is limited. The protective effect and time window of a series of derivative monomers of ligustrazine such as 2-[(1,1-dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine, CXC137 and CXC195 after cerebral ischemia were better than ligustrazine. PMID:26109963

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

    PubMed

    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. PMID:26591507

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

    PubMed

    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.

  11. Temporal and topographic profiles of tissue hypoxia following transient focal cerebral ischemia in rats.

    PubMed

    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.

  12. Spreading Depolarizations: A Therapeutic Target Against Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

    PubMed

    Chung, David Y; Oka, Fumiaki; Ayata, Cenk

    2016-06-01

    Delayed cerebral ischemia is the most feared cause of secondary injury progression after subarachnoid hemorrhage. Initially thought to be a direct consequence of large artery spasm and territorial ischemia, recent data suggests that delayed cerebral ischemia represents multiple concurrent and synergistic mechanisms, including microcirculatory dysfunction, inflammation, and microthrombosis. Among these mechanisms, spreading depolarizations (SDs) are arguably the most elusive and underappreciated in the clinical setting. Although SDs have been experimentally detected and examined since the late 1970s, their widespread occurrence in human brain was not unequivocally demonstrated until relatively recently. We now know that SDs occur with very high incidence in human brain after ischemic or hemorrhagic stroke and trauma, and worsen outcomes by increasing metabolic demand, decreasing blood supply, predisposing to seizure activity, and possibly worsening brain edema. In this review, we discuss the causes and consequences of SDs in injured brain. Although much of our mechanistic knowledge comes from experimental models of focal cerebral ischemia, clinical data suggest that the same principles apply regardless of the mode of injury (i.e., ischemia, hemorrhage, or trauma). The hope is that a better fundamental understanding of SDs will lead to novel therapeutic interventions to prevent SD occurrence and its adverse consequences contributing to injury progression in subarachnoid hemorrhage and other forms of acute brain injury. PMID:27258442

  13. Neuroprotective Effects of Pregabalin on Cerebral Ischemia and Reperfusion

    PubMed Central

    Aşcı, Sanem; Demirci, Serpil; Aşcı, Halil; Doğuç, Duygu Kumbul; Onaran, İbrahim

    2016-01-01

    Background: Stroke is one of the most common causes of death and the leading cause of disability in adults. Cerebral ischemia/reperfusion injury causes cerebral edema, hemorrhage, and neuronal death. Aims: In post-ischemic reperfusion, free radical production causes brain tissue damage by oxidative stress. Pregabalin, an antiepileptic agent was shown to have antioxidant effects. The aim of this study was to evaluate the neuroprotective and antioxidant effects of pregabalin on ischemia and reperfusion in rat brain injury. Study Design: Animal experimentation. Methods: Male Wistar rats weighing (250–300 g) were randomly divided into six groups, each consisting of 6 rats: control (C), pregabalin (P), ischemia (I), pregabalin + ischemia (PI), ischemia + reperfusion (IR) and ischemia + reperfusion + pregabalin (PIR). Rats were initially pre-treated with 50 mg/kg/d pregabalin orally for two days. Then, animals that applied ischemia in I, PI, IR and PIR groups were exposed to carotid clamping for 30 minutes and 20 minutes reperfusion was performed in the relevant reperfusion groups. Results: NR2B receptor levels were significantly lower in the PIR group in comparison to the IR group. In the PIR group, Thiobarbituric acid reactive substance (TBARS) level had statistically significant decrease compared with IR group. Glutathione peroxidase (GSH-PX) levels were also significantly increased in the PIR group compared with I, IR and control groups. In the PI and PIR groups, catalase (CAT) levels were also significantly increased compared with I and IR groups (p=0.03 and p=0.07, respectively). Conclusion: Pregabalin may protect the damage of oxidative stress after ischemia + reperfusion. This result would illuminate clinical studies in the future. PMID:27403394

  14. microRNAs: innovative targets for cerebral ischemia and stroke

    PubMed Central

    Ouyang, Yi-Bing; Stary, Creed M.; Yang, Guo-Yuan; Giffard, Rona

    2013-01-01

    Stroke is one of the leading causes of death and disability worldwide. Because stroke is a multifactorial disease with a short therapeutic window many clinical stroke trials have failed and the only currently approved therapy is thrombolysis. MicroRNAs (miRNA) are endogenously expressed noncoding short single-stranded RNAs that play a role in the regulation of gene expression at the post-transcriptional level, via degradation or translational inhibition of their target mRNAs. The study of miRNAs is rapidly growing and recent studies have revealed a significant role of miRNAs in ischemic disease. miRNAs are especially important candidates for stroke therapeutics because of their ability to simultaneously regulate many target genes and since to date targeting single genes for therapeutic intervention has not yet succeeded in the clinic. Although there are already quite a few review articles about miRNA in ischemic heart disease, much less is currently known about miRNAs in cerebral ischemia. This review summarizes current knowledge about miRNAs and cerebral ischemia, focusing on the role of miRNAs in ischemia, both changes in expression and identification of potential targets, as well as the potential of miRNAs as biomarkers and therapeutic targets in cerebral ischemia. PMID:23170800

  15. Focal cerebral ischemia activates neurovascular restorative dynamics in mouse brain.

    PubMed

    Chu, Min; Hu, Xiaoming; Lu, Shiduo; Gan, Yu; Li, Peiying; Guo, Yanling; Zhang, Jia; Chen, Jun; Gao, Yanqin

    2012-01-01

    Cerebral ischemia triggers regeneration of neural stem/progenitor cells (NSCs/NPCs), which are associated with neovascularization and white matter repair in the brain. This study analyzed the dynamics of neurogenesis, neovascularization, and white matter injury/repair after middle cerebral artery occlusion (MCAO) and elucidated their temporal association. Mice were subjected to MCAO for 60 minutes and sacrificed up to 28 days after reperfusion. Neurogenesis and angiogenesis, as measured by double staining of 5-bromo-2-deoxyuridine (BrdU) with DCX or tomato lectin, respectively, were substantially activated soon after ischemia and persisted for 4 weeks. Despite the moderate recovery of functional vessels in infarct margin from 7 days post-ischemia, a significant decrease in vascular density remained over time. Clusters of immature neurons localized proximal to angiogenic blood vessels beginning 14 days after ischemia, suggesting interplay between neurogenesis and revascularization. Progenitors of oligodendrocytes (NG2+) constitutively presented in the normal brain and proliferated soon after ischemia. However, axon damage and the loss of white matter integrity after ischemic stroke were almost irreversible, as revealed by sustained decreases of myelin basic protein (MBP) and neurofilament-200 expression. PMID:22202008

  16. Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography.

    PubMed

    Stöber, Franziska; Baldauf, Kathrin; Ziabreva, Iryna; Harhausen, Denise; Zille, Marietta; Neubert, Jenni; Reymann, Klaus G; Scheich, Henning; Dirnagl, Ulrich; Schröder, Ulrich H; Wunder, Andreas; Goldschmidt, Jürgen

    2014-01-01

    Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K(+)-probe thallium (Tl(+)) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl(+) after crossing the blood-brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl(+) uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl(+) uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl(+) uptake. At 24 hours, the areas of reduced Tl(+)uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of (201)TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K(+) metabolism and prediction of tissue viability in cerebral ischemia.

  17. Mapping tissue chromophore changes in cerebral ischemia: a pilot study

    NASA Astrophysics Data System (ADS)

    Abookasis, David; Mathews, Marlon S.; Lay, Christopher; Cuccia, David J.; Frostig, Ron D.; Linskey, Mark E.; Tromberg, Bruce J.

    2007-02-01

    We describe the projection of spatially modulated light for quantitatively mapping changes in oxyhemoglobin, deoxyhemoglobin, and oxygen saturation in two pilot studies in the rat barrel cortex during both permanent and temporary cerebral ischemia. The approach is based on the projection of spatial modulation of white light onto the brain. The reflected light is captured on a CCD camera, which is then processed to obtain the concentration and distribution of chromophores over a wide field. Preliminary results confirm a measurable and quantifiable increase in tissue molecular concentration of deoxy-hemoglobin and decrease in hemoglobin oxygen concentration in both experimental settings. Our preliminary data from our pilot studies demonstrate that spatial modulation of light can provide quantitative chromophore mapping of the brain and has a potential role in monitoring the course and severity of cerebral ischemia in cerebrovascular disease patients.

  18. Neuroprotective effect of L-kynurenine sulfate administered before focal cerebral ischemia in mice and global cerebral ischemia in gerbils.

    PubMed

    Gigler, Gábor; Szénási, Gábor; Simó, Annamária; Lévay, György; Hársing, László Gábor; Sas, Katalin; Vécsei, László; Toldi, József

    2007-06-14

    Excessive stimulation of N-methyl-D-aspartate (NMDA) receptors during ischemia contributes to apoptotic and excitotoxic nerve cell death. Kynurenic acid is a selective antagonist at the glycine co-agonist site of the NMDA receptor complex at low concentration, and it is a broad-spectrum excitatory amino acid receptor blocker at high concentration. Kynurenic acid provides neuroprotection in animal models of cerebral ischemia only at very high doses as it hardly crosses the blood-brain barrier. The neuroprotective effect of L-kynurenine sulfate, a precursor of kynurenic acid, was therefore studied because L-kynurenine readily crosses the blood-brain barrier. L-kynurenine sulfate was administered 15 min before permanent focal cerebral ischemia produced by electrocoagulation of the distal middle cerebral artery in mice. L-kynurenine sulfate induced a small decrease in the surface area of the brain infarction (10%, P<0.05) at 30 mg/kg i.p., and it caused strong reductions in infarct size (24-25%, P<0.01) at 100 and 300 mg/kg i.p. Treatment of gerbils with L-kynurenine sulfate at 300 mg/kg i.p. 2 h before a 3-min bilateral carotid occlusion decreased (40%, P<0.01) the pyramidal cell loss in the CA1 area of the hippocampus. Furthermore, L-kynurenine sulfate inhibited the ischemia-induced hypermotility (77%, P<0.001), and decreased (50%, P<0.01) the ischemia-induced deterioration of spontaneous alternation, a measure of spatial memory, without altering the rectal temperature. In conclusion, the administration of L-kynurenine can elevate the brain concentration of kynurenic acid to neuroprotective levels, suggesting the potential clinical usefulness of L-kynurenine for the prevention of neuronal loss.

  19. Propofol Prevents Hippocampal Neuronal Loss and Memory Impairment in Cerebral Ischemia Injury Through Promoting PTEN Degradation.

    PubMed

    Chen, Xin; Du, Ye-Mu; Xu, Feng; Liu, Dai; Wang, Yuan-Lin

    2016-09-01

    Neuroprotective effect of propofol against cerebral ischemia injury was widely investigated. However, its mechanisms remain unclear. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is supposed as a cell survival pathway, and phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a negative regulator of AKT phosphorylation. Whether PTEN was involved in the protective effect of propofol against cerebral ischemia injury was not elucidated. In this study, the function of PTEN in the acute phase of cerebral ischemia injury was investigated. Our data showed that propofol promoted the PTEN degradation in the acute phase of cerebral ischemia injury and concurrently activated AKT phosphorylation. The increase of ubiquitinated PTEN caused by cerebral ischemia injury were degraded in propofol-pretreated rats. Moreover, we evidenced that proteasome activity was stimulated in propofol-treated rats. These data pointed that PTEN degradation was facilitated in the acute phase after propofol treatment possibly through activating ubiquitin-proteasome system. Therefore, we applied PTEN inhibitor-bpV before cerebral ischemia injury. Like propofol, bpV pretreatment also mitigated cerebral ischemia injury-induced cell loss in CA1 region and memory impairment. Taken together, our data suggest that PTEN degradation is neuroprotective against cerebral ischemia injury and propofol facilitates PTEN degradation to prevent hippocampal neuronal loss and memory deficit in cerebral ischemia injury.

  20. Propofol Prevents Hippocampal Neuronal Loss and Memory Impairment in Cerebral Ischemia Injury Through Promoting PTEN Degradation.

    PubMed

    Chen, Xin; Du, Ye-Mu; Xu, Feng; Liu, Dai; Wang, Yuan-Lin

    2016-09-01

    Neuroprotective effect of propofol against cerebral ischemia injury was widely investigated. However, its mechanisms remain unclear. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is supposed as a cell survival pathway, and phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a negative regulator of AKT phosphorylation. Whether PTEN was involved in the protective effect of propofol against cerebral ischemia injury was not elucidated. In this study, the function of PTEN in the acute phase of cerebral ischemia injury was investigated. Our data showed that propofol promoted the PTEN degradation in the acute phase of cerebral ischemia injury and concurrently activated AKT phosphorylation. The increase of ubiquitinated PTEN caused by cerebral ischemia injury were degraded in propofol-pretreated rats. Moreover, we evidenced that proteasome activity was stimulated in propofol-treated rats. These data pointed that PTEN degradation was facilitated in the acute phase after propofol treatment possibly through activating ubiquitin-proteasome system. Therefore, we applied PTEN inhibitor-bpV before cerebral ischemia injury. Like propofol, bpV pretreatment also mitigated cerebral ischemia injury-induced cell loss in CA1 region and memory impairment. Taken together, our data suggest that PTEN degradation is neuroprotective against cerebral ischemia injury and propofol facilitates PTEN degradation to prevent hippocampal neuronal loss and memory deficit in cerebral ischemia injury. PMID:27480093

  1. Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia.

    PubMed

    Zheng, Yong-Qiu; Liu, Jian-Xun; Wang, Jan-Nong; Xu, Li

    2007-03-23

    This paper studied the effects of crocin, a pharmacologically active component of Crocus sativus L., on ischemia/reperfusion (I/R) injury in mice cerebral microvessels. Transient global cerebral ischemia (20 min), followed by 24 h of reperfusion, significantly promoted the generation of nitric oxide (NO) and malondialdehyde (MDA) in cortical microvascular homogenates, as well as markedly reduced the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) and promoted the activity of nitric oxide synthase (NOs). Reperfusion for 24 h led to serous edema with substantial microvilli loss, vacuolation, membrane damage and mitochondrial injuries in cortical microvascular endothelial cells (CMEC). Furthermore, enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and decreased expression of matrix metalloproteinase-9 (MMP-9) were detected in cortical microvessels after I (20 min)/R (24 h). Reperfusion for 24 h also induced membrane (functional) G protein-coupled receptor kinase 2 (GRK2) expression, while it reduced cytosol GRK2 expression. Pretreatment with crocin markedly inhibited oxidizing reactions and modulated the ultrastructure of CMEC in mice with 20 min of bilateral common carotid artery occlusion (BCCAO) followed by 24 h of reperfusion in vivo. Furthermore, crocin inhibited GRK2 translocation from the cytosol to the membrane and reduced ERK1/2 phosphorylation and MMP-9 expression in cortical microvessels. We propose that crocin protects the brain against excessive oxidative stress and constitutes a potential therapeutic candidate in transient global cerebral ischemia.

  2. Relationship between cerebral sodium-glucose transporter and hyperglycemia in cerebral ischemia.

    PubMed

    Yamazaki, Yui; Harada, Shinichi; Tokuyama, Shogo

    2015-09-14

    Post-ischemic hyperglycemia exacerbates the development of cerebral ischemia. To elucidate this exacerbation mechanism, we focused on sodium-glucose transporter (SGLT) as a mediator that lead hyperglycemia to cerebral ischemia. SGLT transport glucose into the cell, together with sodium ion, using the sodium concentration gradient. We have previously reported that suppression of cerebral SGLT ameliorates cerebral ischemic neuronal damage. However, detail relationship cerebral between SGLT and post-ischemic hyperglycemia remain incompletely defined. Therefore, we examined the involvement of cerebral SGLT on cerebral ischemic neuronal damage with or without hyperglycemic condition. Cell survival rate of primary cultured neurons was assessed by biochemical assay. A mouse model of focal ischemia was generated using a middle cerebral artery occlusion (MCAO). Neuronal damage was assessed with histological and behavioral analyses. Concomitant hydrogen peroxide/glucose treatment exacerbated hydrogen peroxide alone-induced cell death. Although a SGLT family-specific inhibitor, phlorizin had no effect on developed hydrogen peroxide alone-induced cell death, it suppressed cell death induced by concomitant hydrogen peroxide/glucose treatment. α-MG induced a concentration-dependent and significant decrease in neuronal survival. PHZ administered on immediately after reperfusion had no effect, but PHZ given at 6h after reperfusion had an effect. Our in vitro study indicates that SGLT is not involved in neuronal cell death in non-hyperglycemic condition. We have already reported that post-ischemic hyperglycemia begins to develop at 6h after MCAO. Therefore, current our in vivo study show post-ischemic hyperglycemic condition may be necessary for the SGLT-mediated exacerbation of cerebral ischemic neuronal damage.

  3. Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice

    SciTech Connect

    Cao Canxiang; Yang Qingwu . E-mail: yangqwmlys@hotmail.com; Lv Fenglin; Cui Jie; Fu Huabin; Wang Jingzhou

    2007-02-09

    Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-{alpha} and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity.

  4. MRI of Blood–Brain Barrier Permeability in Cerebral Ischemia

    PubMed Central

    Ewing, James R.; Chopp, Michael

    2013-01-01

    Quantitative measurement of blood–brain barrier (BBB) permeability using MRI and its application to cerebral ischemia are reviewed. Measurement of BBB permeability using MRI has been employed to evaluate ischemic damage during acute and subacute phases of stroke and to predict hemorrhagic transformation. There is also an emerging interest on the development and use of MRI to monitor vascular structural changes and angiogenesis during stroke recovery. In this review, we describe MRI BBB permeability and susceptibility-weighted MRI measurements and its applications to evaluate ischemic damage during the acute and subacute phases of stroke and vascular remodeling during stroke recovery. PMID:23997835

  5. Optical coherence tomography reveals in vivo cortical structures of adult rats in response to cerebral ischemia injury

    NASA Astrophysics Data System (ADS)

    Ni, Yi-rong; Guo, Zhou-yi; Shu, So-yun; Bao, Xin-min

    2008-12-01

    Optical coherence tomography(OCT) is a high resolution imaging technique which uses light to directly image living tissue. we investigate the potential use of OCT for structural imaging of the ischemia injury mammalian cerebral cortex. And we examine models of middle cerebral artery occlusion (MCAO) in rats in vivo using OCT. In particular, we show that OCT can perform in vivo detection of cortex and differentiate normal and abnormal cortical anatomy. This OCT system in this study provided an axial resolution of 10~15μ m, the transverse resolution of the system is about 25 μm. OCT can provide cross-sectional images of cortical of adult rats in response to cerebral ischemia injury.We conclude that OCT represents an exciting new approach to visualize, in real-time, pathological changes in the cerebral cortex structures and may offer a new tool for Possible neuroscience clinical applications.

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

    PubMed

    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. PMID:27162767

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

    PubMed Central

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

    2016-01-01

    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. PMID:27162767

  8. Possible involvement of P2X7 receptor activation in microglial neuroprotection against focal cerebral ischemia in rats.

    PubMed

    Yanagisawa, Daijiro; Kitamura, Yoshihisa; Takata, Kazuyuki; Hide, Izumi; Nakata, Yoshihiro; Taniguchi, Takashi

    2008-06-01

    Microglia play important roles in the pathogenic cascade following cerebral ischemia, since they express growth factors, chemokines and regulatory cytokines as well as free radicals and other toxic mediators. P2X7 receptor, a subtype of a family of P2 purinoceptors, is primarily expressed in microglia and macrophages, suggesting that it regulates immune function and inflammatory responses. However, the involvement of ATP in such microglial responses after cerebral ischemia is not yet understood. In this study, we investigated the possible involvement of ATP, especially through the P2X7 receptors, in a rat model of focal cerebral ischemia. In immunohistochemical analysis, P2X7 receptor-like immunoreactivity was predominantly detected in microglia, and then activated microglia accumulated in the ischemic region, in rats subjected to middle cerebral artery occlusion (MCAO) and reperfusion. Intracerebroventricular injection with P2X7 receptor agonist 2'-3'-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP) improved behavioral dysfunction accessed by rota-rod test and ischemic neural injury induced by MCAO. In contrast, P2X7 receptor antagonist adenosine 5'-triphosphate-2',3'-dialdehyde (OxATP) exacerbated ischemic brain damage. These results suggest that microglia play an important role in neuroprotection against rat cerebral ischemia, which is regulated by a P2X7 receptor-mediated ATP signal.

  9. Brazilein inhibits neuronal inflammation induced by cerebral ischemia and oxygen-glucose deprivation through targeting NOD2 expression.

    PubMed

    Yan, Xiao-Jin; Chai, Yu-Shuang; Yuan, Zhi-Yi; Wang, Xin-Pei; Jiang, Jing-Fei; Lei, Fan; Xing, Dong-Ming; DU, Li-Jun

    2016-05-01

    Brazilein is reported to have immunosuppressive effect on cardiovascular and cerebral-vascular diseases. The essential roles of innate immunity in cerebral ischemia are increasingly identified, but no studies concerning the influence of brazilein on the innate immunity receptors have been reported. The present study was designed to investigate the regulation of NOD2 (Nucleotide-binding oligomerization domain-containing protein 2) by brazilein for its protection of neuron in cerebral ischemia in vivo and oxygen-glucose deprivation in vitro. The results showed that brazilein could reverse the elevated expression of NOD2 and TNFα (tumor necrosis factor alpha) elicited by cerebral ischemia and reperfusion. This reduction could also be detected in normal mice and C17.2 cells, indicating that this suppressive effect of brazilein was correlated with NOD2. The results from GFP reporter plasmid assay suggested brazilein inhibited NOD2 gene transcription. In conclusion, brazilein could attenuate NOD2 and TNFα expression in cerebral ischemia and NOD2 may be one possible target of brazilein for its immune suppressive effect in neuro-inflammation. PMID:27478098

  10. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    NASA Astrophysics Data System (ADS)

    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.

  11. Reparative neurogenesis after cerebral ischemia: Clinical application prospects

    SciTech Connect

    Khodanovich, M. Yu.

    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.

  12. Houshiheisan compound prescription protects neurovascular units after cerebral ischemia

    PubMed Central

    Wang, Haizheng; Wang, Lei; Zhang, Nan; Zhang, Qi; Zhao, Hui; Zhang, Qiuxia

    2014-01-01

    Houshiheisan is composed of wind-dispelling (chrysanthemun flower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root) and deficiency-nourishing (ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber) drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immunofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regulated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-β 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-β 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance deposition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra. PMID:25206882

  13. Blood biomarkers in the early stage of cerebral ischemia.

    PubMed

    Maestrini, I; Ducroquet, A; Moulin, S; Leys, D; Cordonnier, C; Bordet, R

    2016-03-01

    In ischemic stroke patients, blood-based biomarkers may be applied for the diagnosis of ischemic origin and subtype, prediction of outcomes and targeted treatment in selected patients. Knowledge of the pathophysiology of cerebral ischemia has led to the evaluation of proteins, neurotransmitters, nucleic acids and lipids as potential biomarkers. The present report focuses on the role of blood-based biomarkers in the early stage of ischemic stroke-within 72h of its onset-as gleaned from studies published in English in such patients. Despite growing interest in their potential role in clinical practice, the application of biomarkers for the management of cerebral ischemia is not currently recommended by guidelines. However, there are some promising clinical biomarkers, as well as the N-methyl-d-aspartate (NMDA) peptide and NMDA-receptor (R) autoantibodies that appear to identify the ischemic nature of stroke, and the glial fibrillary acidic protein (GFAP) that might be able to discriminate between acute ischemic and hemorrhagic strokes. Moreover, genomics and proteomics allow the characterization of differences in gene expression, and protein and metabolite production, in ischemic stroke patients compared with controls and, thus, may help to identify novel markers with sufficient sensitivity and specificity. Additional studies to validate promising biomarkers and to identify novel biomarkers are needed. PMID:26988891

  14. Let-7a gene knockdown protects against cerebral ischemia/reperfusion injury

    PubMed Central

    Wang, Zhong-kun; Liu, Fang-fang; Wang, Yu; Jiang, Xin-mei; Yu, Xue-fan

    2016-01-01

    The microRNA (miRNA) let-7 was one of the first miRNAs to be discovered, and is highly conserved and widely expressed among species. let-7 expression increases in brain tissue after cerebral ischemia/reperfusion injury; however, no studies have reported let-7 effects on nerve injury after cerebral ischemia/reperfusion injury. To investigate the effects of let-7 gene knockdown on cerebral ischemia/reperfusion injury, we established a rat model of cerebral ischemia/reperfusion injury. Quantitative reverse transcription-polymerase chain reaction demonstrated that 12 hours after cerebral ischemia/reperfusion injury, let-7 expression was up-regulated, peaked at 24 hours, and was still higher than that in control rats after 72 hours. Let-7 gene knockdown in rats suppressed microglial activation and inflammatory factor release, reduced neuronal apoptosis and infarct volume in brain tissue after cerebral ischemia/reperfusion injury. Western blot assays and luciferase assays revealed that mitogen-activated protein kinase phosphatase-1 (MKP1) is a direct target of let-7. Let-7 enhanced phosphorylated p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) expression by down-regulating MKP1. These findings suggest that knockdown of let-7 inhibited the activation of p38 MAPK and JNK signaling pathways by up-regulating MKP1 expression, reduced apoptosis and the inflammatory reaction, and exerted a neuroprotective effect following cerebral ischemia/reperfusion injury. PMID:27073379

  15. Suppression of inflammatory response by flurbiprofen following focal cerebral ischemia involves the NF-κB signaling pathway.

    PubMed

    Sun, Bao-Zhu; Chen, Lin; Wu, Qi; Wang, Huan-Liang; Wei, Xin-Bing; Xiang, Yan-Xiao; Zhang, Xiu-Mei

    2014-01-01

    Some studies of animal models of middle cerebral artery occlusion indicate that inflammation plays a key role in the pathogenesis of cerebral ischemia and secondary damage. Flurbiprofen has been suggested to alleviate cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanisms underlying the protective action are still incompletely understood. In this study we want to investigate the protective effect of flurbiprofen after transient middle cerebral artery occlusion (MCAO) in rats and the role of the NF-κB signaling pathway on this neuroprotective effect. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. Flurbiprofen was administrated via tail-vein injection at the onset of reperfusion. HE staining and Immunohistochemistry were carried out to detect the morphological changes in ischemic penumbra cortex. The expression of inflammatory cytokines genes (IL-1β, IL-6 and TNF-α) and the levels of p-NF-κB (p65) in ischemic penumbra cortex were measured by RT-PCR and western blot. Administration of flurbiprofen at the doses of 5 mg/kg and 10 mg/kg significantly attenuated cerebral ischemia/reperfusion injury, as shown by a reduction in the morphological changes and inhibition of pro-inflammatory cytokine expression in ischemic penumbra cortex. Moreover, our findings further demonstrated that the inhibition of NF-κB activity was involved in the neuroprotective effect of flurbiprofen on inflammatory responses. Flurbiprofen protects against cerebral injury by reducing expression of inflammatory cytokines genes and this effect may be partly due to the inhibition of NF-κB signaling pathway.

  16. Suppression of inflammatory response by flurbiprofen following focal cerebral ischemia involves the NF-κB signaling pathway

    PubMed Central

    Sun, Bao-Zhu; Chen, Lin; Wu, Qi; Wang, Huan-Liang; Wei, Xin-Bing; Xiang, Yan-Xiao; Zhang, Xiu-Mei

    2014-01-01

    Some studies of animal models of middle cerebral artery occlusion indicate that inflammation plays a key role in the pathogenesis of cerebral ischemia and secondary damage. Flurbiprofen has been suggested to alleviate cerebral ischemia/reperfusion injury in both focal and global cerebral ischemia models, but the mechanisms underlying the protective action are still incompletely understood. In this study we want to investigate the protective effect of flurbiprofen after transient middle cerebral artery occlusion (MCAO) in rats and the role of the NF-κB signaling pathway on this neuroprotective effect. Male Wistar rats were subjected to transient middle cerebral artery occlusion for 2 h, followed by 24 h reperfusion. Flurbiprofen was administrated via tail-vein injection at the onset of reperfusion. HE staining and Immunohistochemistry were carried out to detect the morphological changes in ischemic penumbra cortex. The expression of inflammatory cytokines genes (IL-1β, IL-6 and TNF-α) and the levels of p-NF-κB (p65) in ischemic penumbra cortex were measured by RT-PCR and western blot. Administration of flurbiprofen at the doses of 5 mg/kg and 10 mg/kg significantly attenuated cerebral ischemia/reperfusion injury, as shown by a reduction in the morphological changes and inhibition of pro-inflammatory cytokine expression in ischemic penumbra cortex. Moreover, our findings further demonstrated that the inhibition of NF-κB activity was involved in the neuroprotective effect of flurbiprofen on inflammatory responses. Flurbiprofen protects against cerebral injury by reducing expression of inflammatory cytokines genes and this effect may be partly due to the inhibition of NF-κB signaling pathway. PMID:25356186

  17. Genistein exerts neuroprotective effect on focal cerebral ischemia injury in rats.

    PubMed

    Aras, Adem Bozkurt; Guven, Mustafa; Akman, Tarik; Alacam, Hasan; Kalkan, Yildiray; Silan, Coskun; Cosar, Murat

    2015-01-01

    Brain ischemia and treatment are one of the important topics in neurological science. Free oxygen radicals and inflammation formed after ischemia are accepted as the most important causes of damage. Currently, there are studies on many chemopreventive agents to prevent cerebral ischemia damage. Our aim is to research the preventive effect of the active ingredient in genistein, previously unstudied, on oxidative damage in cerebral ischemia. Rats were randomly divided into three groups: control group (no medication or surgical procedure), ischemia group, and artery ischemia+genistein group, sacrificed at 24 h after ischemia. The harvested brain tissue from the right hemisphere was investigated histopathologically and for tissue biochemistry. Superoxide dismutase and nuclear respiratory factor 1 values decreased after ischemia and they increased after genistein treatment, while increased malondialdehyde levels after ischemia reduced after treatment. Apoptosis-related cysteine peptidase caspase-3 and caspase-9 values increased after ischemia, but reduced after treatment. Our study revealed that genistein treatment in cerebral ischemia reduced oxidative stress and neuronal degeneration. We believe that genistein treatment may be an alternative treatment method.

  18. Protective effect of extract of Cordyceps sinensis in middle cerebral artery occlusion-induced focal cerebral ischemia in rats

    PubMed Central

    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

  19. Hydrogen sulfide intervention in focal cerebral ischemia/reperfusion injury in rats.

    PubMed

    Li, Xin-Juan; Li, Chao-Kun; Wei, Lin-Yu; Lu, Na; Wang, Guo-Hong; Zhao, Hong-Gang; Li, Dong-Liang

    2015-06-01

    The present study aimed to explore the mechanism underlying the protective effects of hydrogen sulfide against neuronal damage caused by cerebral ischemia/reperfusion. We established the middle cerebral artery occlusion model in rats via the suture method. Ten minutes after middle cerebral artery occlusion, the animals were intraperitoneally injected with hydrogen sulfide donor compound sodium hydrosulfide. Immunofluorescence revealed that the immunoreactivity of P2X7 in the cerebral cortex and hippocampal CA1 region in rats with cerebral ischemia/reperfusion injury decreased with hydrogen sulfide treatment. Furthermore, treatment of these rats with hydrogen sulfide significantly lowered mortality, the Longa neurological deficit scores, and infarct volume. These results indicate that hydrogen sulfide may be protective in rats with local cerebral ischemia/reperfusion injury by down-regulating the expression of P2X7 receptors.

  20. Hydrogen sulfide intervention in focal cerebral ischemia/reperfusion injury in rats

    PubMed Central

    Li, Xin-juan; Li, Chao-kun; Wei, Lin-yu; Lu, Na; Wang, Guo-hong; Zhao, Hong-gang; Li, Dong-liang

    2015-01-01

    The present study aimed to explore the mechanism underlying the protective effects of hydrogen sulfide against neuronal damage caused by cerebral ischemia/reperfusion. We established the middle cerebral artery occlusion model in rats via the suture method. Ten minutes after middle cerebral artery occlusion, the animals were intraperitoneally injected with hydrogen sulfide donor compound sodium hydrosulfide. Immunofluorescence revealed that the immunoreactivity of P2X7 in the cerebral cortex and hippocampal CA1 region in rats with cerebral ischemia/reperfusion injury decreased with hydrogen sulfide treatment. Furthermore, treatment of these rats with hydrogen sulfide significantly lowered mortality, the Longa neurological deficit scores, and infarct volume. These results indicate that hydrogen sulfide may be protective in rats with local cerebral ischemia/reperfusion injury by down-regulating the expression of P2X7 receptors. PMID:26199610

  1. Homocysteine Aggravates Cortical Neural Cell Injury through Neuronal Autophagy Overactivation following Rat Cerebral Ischemia-Reperfusion

    PubMed Central

    Zhao, Yaqian; Huang, Guowei; Chen, Shuang; Gou, Yun; Dong, Zhiping; Zhang, Xumei

    2016-01-01

    Elevated homocysteine (Hcy) levels have been reported to be involved in neurotoxicity after ischemic stroke. However, the underlying mechanisms remain incompletely understood to date. In the current study, we hypothesized that neuronal autophagy activation may be involved in the toxic effect of Hcy on cortical neurons following cerebral ischemia. Brain cell injury was determined by hematoxylin-eosin (HE) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. The level and localization of autophagy were detected by transmission electron microscopy, western blot and immunofluorescence double labeling. The oxidative DNA damage was revealed by immunofluorescence of 8-Hydroxy-2′-deoxyguanosine (8-OHdG). Hcy treatment aggravated neuronal cell death, significantly increased the formation of autophagosomes and the expression of LC3B and Beclin-1 in the brain cortex after middle cerebral artery occlusion-reperfusion (MCAO). Immunofluorescence analysis of LC3B and Beclin-1 distribution indicated that their expression occurred mainly in neurons (NeuN-positive) and hardly in astrocytes (GFAP-positive). 8-OHdG expression was also increased in the ischemic cortex of Hcy-treated animals. Conversely, LC3B and Beclin-1 overexpression and autophagosome accumulation caused by Hcy were partially blocked by the autophagy inhibitor 3-methyladenine (3-MA). Hcy administration enhanced neuronal autophagy, which contributes to cell death following cerebral ischemia. The oxidative damage-mediated autophagy may be a molecular mechanism underlying neuronal cell toxicity of elevated Hcy level. PMID:27455253

  2. Effects of apoptosis-related proteins caspase-3, Bax and Bcl-2 on cerebral ischemia rats.

    PubMed

    Liu, Guangyi; Wang, Tao; Wang, Tinging; Song, Jinming; Zhou, Zhen

    2013-11-01

    Neuron apoptosis is known to mediate a change of ethology following cerebral ischemia-reperfusion injury in rats. Additionally, Bcl-2, Bax and caspase-3 proteins may exert a significant effect on neuron injury. The aim of this study was to investigate the role, mechanism of action and clinical significance of these proteins in neuron apoptosis and functional impairment following cerebral ischemia-reperfusion injury in rats. Sixty male healthy adult Wistar rats were randomly assigned into control (n=6), sham operation (n=6) and experimental (n=48) groups. The model of rat cerebral ischemia-reperfusion injury was set up according to the method of Zea-Longa. Eight subsets of 6 rats-subset were designed according to time points (at 3, 6, 12, 24 and 48 h and at 3, 7 and 14 days). Nerve functional injury was evaluated and graded using nerve function score, balance, coordination function detection and measurement of forelimb placing. The neurons expressing caspase-3, Bax and Bcl-2 in the cortical area, CA3, CA1, stratum lucidum (Slu) and molecular layer of the dentate gyrus (MoDG) of the hippocampus were detected using immunohistochemistry or the TUNEL method. The expression of caspase-3, Bax and Bcl-2 genes was detected by the reverse transcriptase polymerase chain reaction (RT-PCR). The results indicated that, compared to the sham operation group, the score of nerve function and balance beam walking were distinctly higher (P<0.01) and the percentage of rat foreleg touching the angle or margin of the table was significantly lower in the experimental rat group (P<0.01) at 3 h following reperfusion. The expression of TUNEL-positive neurons was high in the cortical area and the CA3 region of the hippocampus (P<0.01), caspase-3 was at peak value in the cortical area and the CA1 region of the hippocampus (P<0.01), Bax was increased in the cortical area and the Slu of the hippocampus (P<0.01) and Bcl-2 was low in the cortical area and the MoDG of the hippocampus (P<0.01) in

  3. Effect of Fluoxetine on Neurogenesis in Hippocampal Dentate Gyrus after Global Transient Cerebral Ischemia in Rats.

    PubMed

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

    2016-07-01

    Changes in cerebral neurogenesis provoked by ischemia and the effect of fluoxetine on this process were studied using a three-vessel occlusion model of global transient cerebral ischemia. The global transient cerebral ischemia was modeled on male Wistar rats by transient occlusion of three major vessels originating from the aortic arch and supplying the brain (brachiocephalic trunk, left subclavian artery, and left common carotid artery). The cells expressing doublecortin (DCX, a marker of young neurons) were counted in the hippocampal dentate gyrus on day 31 after ischemia modeling. It was found that ischemia inhibited neurogenesis in the dentate gyrus in comparison with sham-operated controls (p<0.05), while fluoxetine (20 mg/kg/day) injected over 10 days after surgery restored neurogenesis to the control level (p<0.001). PMID:27496030

  4. Dragon's blood dropping pills have protective effects on focal cerebral ischemia rats model.

    PubMed

    Xin, Nian; Yang, Fang-Ju; Li, Yan; Li, Yu-Juan; Dai, Rong-Ji; Meng, Wei-Wei; Chen, Yan; Deng, Yu-Lin

    2013-12-15

    Dragon's blood is a bright red resin obtained from Dracaena cochinchinensis (Lour.) S.C.Chen (Yunnan, China). As a traditional Chinese medicinal herb, it has great traditional medicinal value and is used for wound healing and to stop bleeding. Its main biological activity comes from phenolic compounds. In this study, phenolic compounds were made into dropping pills and their protective effects were examined by establishing focal cerebral ischemia rats model used method of Middle Cerebral Artery Occlusion (MCAO), and by investigating indexes of neurological scores, infarct volume, cerebral index, cerebral water content and oxidation stress. Compared to model group, high, middle and low groups of Dragon's blood dropping pills could improve the neurological function significantly (p<0.01) and reduce cerebral infarct volume of focal cerebral ischemia rats remarkably (p<0.05-0.01). Meanwhile, each group could alleviate cerebral water content and cerebral index (p<0.05-0.01) and regulate oxidative stress of focal cerebral ischemia rats obviously (p<0.05-0.01). Activities of middle group corresponded with that treated with positive control drug. The results obtained here showed that Dragon's blood dropping pills had protective effects on focal cerebral ischemia rats. PMID:24051215

  5. Dragon's blood dropping pills have protective effects on focal cerebral ischemia rats model.

    PubMed

    Xin, Nian; Yang, Fang-Ju; Li, Yan; Li, Yu-Juan; Dai, Rong-Ji; Meng, Wei-Wei; Chen, Yan; Deng, Yu-Lin

    2013-12-15

    Dragon's blood is a bright red resin obtained from Dracaena cochinchinensis (Lour.) S.C.Chen (Yunnan, China). As a traditional Chinese medicinal herb, it has great traditional medicinal value and is used for wound healing and to stop bleeding. Its main biological activity comes from phenolic compounds. In this study, phenolic compounds were made into dropping pills and their protective effects were examined by establishing focal cerebral ischemia rats model used method of Middle Cerebral Artery Occlusion (MCAO), and by investigating indexes of neurological scores, infarct volume, cerebral index, cerebral water content and oxidation stress. Compared to model group, high, middle and low groups of Dragon's blood dropping pills could improve the neurological function significantly (p<0.01) and reduce cerebral infarct volume of focal cerebral ischemia rats remarkably (p<0.05-0.01). Meanwhile, each group could alleviate cerebral water content and cerebral index (p<0.05-0.01) and regulate oxidative stress of focal cerebral ischemia rats obviously (p<0.05-0.01). Activities of middle group corresponded with that treated with positive control drug. The results obtained here showed that Dragon's blood dropping pills had protective effects on focal cerebral ischemia rats.

  6. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis

    SciTech Connect

    Mayberg, M.R.; Eskridge, J.; Winn, H.R.; Eskridge, J. ); Wilson, S.E. ); Yatsu, F. ); Weiss, D.G. ); Messina, L. ); Hershey, L.A. ); Colling, C. ); Deykin, D. )

    1991-12-18

    The objective of this study was to determine whether carotid endarterectomy provides protection against subsequent cerebral ischemia in men with ischemic symptoms in the distribution of significant ipsilateral internal carotid artery stenosis. The study group was comprised of men who presented within 120 days of onset of symptoms that were consistent with transient ischemic attacks, transient monocular blindness, or recent small completed strokes between July 1988 and February 1991. Among 5,000 patients screened, 189 individuals were randomized with angiographic internal carotid artery stenosis greater than 50% ipsilateral to the presenting symptoms. Forty-eight eligible patients who refused entry were followed up outside of the trial. For a selected cohort of men with symptoms of cerebral or retinal ischemia in the distribution of a high-grade internal carotid artery stenosis, carotid endarterectomy can effectively reduce the risk of subsequent ipsilateral cerebral ischemia. The risk of cerebral ischemia in this subgroup of patients is considerably higher than previously estimated.

  7. Modulated imaging: a novel method for quantifying tissue chromophores in evolving cerebral ischemia

    NASA Astrophysics Data System (ADS)

    Abookasis, David; Mathews, Marlon S.; Lay, Chistopher; Frostig, Ron D.; Tromberg, Bruce J.

    2007-03-01

    The authors report the results of utilizing spatially-modulated near infrared light using Modulated Imaging (MI) technology in imaging cerebral ischemia. MI images of the left parietal somatosensory cortex were obtained post-occlusion and up to three hours following middle cerebral artery occlusion. Tissue chromophore maps were obtained to demonstrate spatiotemporal changes in the distribution of oxy, deoxy, total hemoglobin, and oxygen saturation. MI recorded a decrease in oxyhemoglobin concentration and tissue oxygen saturation and increase in tissue deoxyhemoglobin concentration following occlusion. Optical intrinsic signal was used to detect functional activation of the somatosensory barrel cortex to whisker stimulation. This activation was completely lost following occlusion. Imaging findings in a transient ischemic attack using photothrombosis is also demonstrated.

  8. Neuroprotective effect of p-coumaric acid in rat model of embolic cerebral ischemia

    PubMed Central

    Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Sen, Halil Murat; Ozkan, Adile; Salis, Osman; Sehitoglu, Ibrahim; Kalkan, Yildiray; Silan, Coskun; Deniz, Mustafa; Cosar, Murat

    2015-01-01

    Objective(s): Stroke poses a crucial risk for mortality and morbidity. Our study aimed to investigate the effect of p-coumaric acid on focal cerebral ischemia in rats. Material and Methods: Rats were randomly divided into four groups, namely Group I (control rats), Group II (ischemia rats), Group III (6 hr ischemia + p-coumaric acid rats) and Group IV (24 hr ischemia + p-coumaric acid rats). Cerebral ischemia was induced via intraluminal monofilament occlusion model. In all groups, the brain was removed after the procedure and rats were sacrificed. Malondialdehyde, superoxide dismutase and nuclear respiratory factor-1 were measured in the ischemic hemisphere. The histopathological changes were observed in the right hemisphere within the samples. Functional assessment was performed for neurological deficit scores. Results: Following the treatment, biochemical factors changed significantly. Histopathologically, it was shown that p-coumaric acid decreased the oxidative damage. The neurological deficit scores of p-coumaric acid-treated rats were significantly improved after cerebral ischemia. Conclusion: Our results showed that p-coumaric acid is a neuroprotective agent on account of its strong anti-oxidant and anti-apoptotic features. Moreover, p-coumaric acid decreased the focal ischemia. Extra effort should be made to introduce p-coumaric acid as a promising therapeutic agent to be utilized for treatment of human cerebral ischemia in the future. PMID:26019798

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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, ...

  10. Long-term functional recovery and compensation after cerebral ischemia in rats

    PubMed Central

    Girard, Sylvie; Murray, Katie N.; Rothwell, Nancy J.; Metz, Gerlinde A.S.; Allan, Stuart M.

    2014-01-01

    Cerebral ischemia is one of the most common causes of disabilities in adults and leads to long-term motor and cognitive impairments with limited therapeutic possibilities. Treatment options have proven efficient in preclinical models of cerebral ischemia but have failed in the clinical setting. This limited translation may be due to the suitability of models used and outcomes measured as most studies have focused on the early period after injury with gross motor scales, which have limited correlation to the clinical situation. The aim of this study was to determine long-term functional outcomes after cerebral ischemia in rats, focusing on fine motor function, social and depressive behavior as clinically relevant measures. A secondary objective was to evaluate the effects of an anti-inflammatory treatment (interleukin-1 receptor antagonist (IL-1Ra)) on functional recovery and compensation. Infarct volume was correlated with long-term (25 days) impairments in fine motor skills, but not with emotional components of behavior. Motor impairments could not be detected using conventional neurological tests and only detailed analysis allowed differentiation between recovery and compensation. Acute systemic administration of IL-1Ra (at reperfusion) led to a faster and more complete recovery, but delayed (24 h) IL-1Ra treatment had no effect. In summary functional assessment after brain injury requires detailed motor tests in order to address long-term impairments and compensation processes that are mediated by intact tissues. Functional deficits in skilled movement after brain injury represent ideal predictors of long-term outcomes and should become standard measures in the assessment of preclinical animal models. PMID:24821402

  11. Protective Role of Arginase II in Cerebral Ischemia and Excitotoxicity

    PubMed Central

    Ahmad, Abdullah Shafique; Shah, Zahoor Ahmad; Doré, Sylvain

    2016-01-01

    Background Arginase (Arg), one of the enzymes involved in the urea cycle, provides an essential route for the disposal of excess nitrogen resulting from amino acid and nucleotide metabolism. Two reported subtypes of Arg (ArgI and II) compete with nitric oxide synthase (NOS) to use L-arginine as a substrate, and subsequently regulate NOS activity. It has been reported that Arg has significant effects on circulation that suggest the potential role of this enzyme in regulating vascular function. However, the role of Arg following brain damage has not been elucidated. In this study, we hypothesize that the deletion of ArgII will lead to aggravated brain injury following cerebral ischemia and excitotoxicity. Methods and findings To test our hypothesis, male C57BL/6 wildtype (WT) and ArgII-/- mice were subjected to permanent distal middle cerebral artery occlusion and survived for 7 d. Cerebral blood flow (CBF) data revealed a statistically non-significant decrease in CBF in ArgII-/- mice. However, ArgII-/- mice had significantly higher neurologic deficit scores and brain infarctions. The hypothesis was further tested in a more specific N-methyl-D-aspartate (NMDA)-induced acute excitotoxic model. WT and ArgII-/- mice were given a single intrastriatal injection of 15 nmol NMDA. Forty-eight hours later, the excitotoxic brain damage was significantly worse in ArgII-/- mice. The data from both models confirm the neuroprotective effect of ArgII. Conclusion Targeting ArgII could be considered an integrative part of a multi-modal approach to fight acute brain damage excitotoxicity, ischemic brain injury, and other forms of brain trauma. PMID:27308186

  12. Unilateral cerebral ischemia inhibits optomotor responses of the ipsilateral eye in mice.

    PubMed

    Xiao, Jian; Zhou, Xiantiang; Jiang, Tian; Zhi, Zhi-Na; Li, Qu; Qu, Jia; Chen, Jie-Guang

    2012-06-01

    A reduction in blood flow to the brain causes stroke and damage to neuronal networks. Cerebral ischemia is frequently associated with loss of visual functions. Because retinal and small cerebral vessels are vulnerable to similar risk factors, the loss of vision could result from concurrent retinal ischemia, and it is not clear if visual functions may be inhibited by cerebral ischemia directly. In this study, the distal middle cerebral artery in the right hemisphere of mice was occluded to produce unilateral cerebral ischemia and subsequent infarction. The layer V neurons expressing YFP in transgenic yellow fluorescent protein in transgenic B6.Cg-Tg(Thy1-YFPH)2Jrs/J mice disappeared in the motor and somatosensory cortex, but not in the visual area. The latencies of flash visual evoked potential recorded from two hemispheres were imbalanced, but did not differ markedly from the latencies recorded in controls. However, the optomotor responses of the ipsilateral eye were significantly reduced by 48 h after occlusion. Our results suggest that focused cerebral ischemia may inhibit ipsilateral eye movement in the absence of damage to the visual cortex. This study may provide a platform for further investigation of the relationship between cortical ischemia and visual function. PMID:22744825

  13. Buyanghuanwu decoction promotes angiogenesis after cerebral ischemia/reperfusion injury: mechanisms of brain tissue repair

    PubMed Central

    Zhang, Zhen-qiang; Song, Jun-ying; Jia, Ya-quan; Zhang, Yun-ke

    2016-01-01

    Buyanghuanwu decoction has been shown to protect against cerebral ischemia/reperfusion injury, but the underlying mechanisms remain unclear. In this study, rats were intragastrically given Buyanghuanwu decoction, 15 mL/kg, for 3 days. A rat model of cerebral ischemia/reperfusion injury was established by middle cerebral artery occlusion. In rats administered Buyanghuanwu decoction, infarct volume was reduced, serum vascular endothelial growth factor and integrin αvβ3 levels were increased, and brain tissue vascular endothelial growth factor and CD34 expression levels were increased compared with untreated animals. These effects of Buyanghuanwu decoction were partially suppressed by an angiogenesis inhibitor (administered through the lateral ventricle for 7 consecutive days). These data suggest that Buyanghuanwu decoction promotes angiogenesis, improves cerebral circulation, and enhances brain tissue repair after cerebral ischemia/reperfusion injury. PMID:27127482

  14. The role of Rho/Rho-kinase pathway and the neuroprotective effects of fasudil in chronic cerebral ischemia

    PubMed Central

    Yan, Ya-yun; Wang, Xiao-ming; Jiang, Yan; Chen, Han; He, Jin-ting; Mang, Jing; Shao, Yan-kun; Xu, Zhong-xin

    2015-01-01

    The Rho/Rho-kinase signaling pathway plays an important role in cerebral ischemia/reperfusion injury. However, very few studies have examined in detail the changes in the Rho/Rho-kinase signaling pathway in chronic cerebral ischemia. In this study, rat models of chronic cerebral ischemia were established by permanent bilateral common carotid artery occlusion and intragastrically administered 9 mg/kg fasudil, a powerful ROCK inhibitor, for 9 weeks. Morris water maze results showed that cognitive impairment progressively worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative RT-PCR and western blot analysis showed that the expression levels of Rho-kinase, its substrate myosin-binding subunit, and its related protein alpha smooth muscle actin, significantly increased after chronic cerebral ischemia. TUNEL staining showed that chronic cerebral ischemia could lead to an increase in neuronal apoptosis, as well as the expression level of caspase-3 in the frontal cortex of rats subjected to chronic cerebral ischemia. Fasudil treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, and decreased the expression level of Rho-kinase, myosin-binding subunit and alpha smooth muscle actin. Furthermore, fasudil could regulate cerebral injury by reducing cell apoptosis and decreasing caspase-3 expression in the frontal cortex. These findings demonstrate that fasudil can protect against cognitive impairment induced by chronic cerebral ischemia via the Rho/Rho-kinase signaling pathway and anti-apoptosis mechanism. PMID:26604905

  15. Neuroprotective effects of systemic cerebral endothelial cell transplantation in a rat model of cerebral ischemia.

    PubMed

    Moon, Jong-Hyun; Na, Joo-Young; Lee, Min-Cheol; Choi, Kang-Ho; Lee, Jeong-Kil; Min, Jung-Joon; Kim, Kyung-Tae; Park, Jong-Tae; Park, Man-Seok; Kim, Hyung-Seok

    2016-01-01

    Human cerebral microvascular endothelial cell line (hCMEC)/D3 cells, which are from a stable clonal cell line of human immortalized cerebral endothelial cells, were intra-arterially transplanted through the common carotid artery in a rat model of photochemical-induced cerebral ischemia. Their therapeutic effects on infarct size, blood-brain barrier (BBB) breakdown, and outcome were examined. The hCMEC/D3 cells were genetically modified with the firefly luciferase gene for in vivo imaging post-transplantation. Transplanted hCMEC/D3 cells were identified in the infarcted brain by bioluminescence imaging at 1 day after transplantation. Compared with the control group, the hCMEC/D3-transplanted group showed reduced infarct size on day 3, reduced Evans blue dye leakage on day 1 indicating decreased BBB breakdown, and early recovery from Rotarod test neurological deficits. The hCMEC/D3-transplanted group also showed decreased levels of matrix metalloproteinase (MMP)-9, which were inversely correlated with TIMP-1 levels on post-transplantation days 1 and 3. The expression of tumor necrosis factor-α and interleukin-1β were markedly diminished in the hCMEC/D3-transplanted group compared with controls. The systemically transplanted cells selectively migrated and integrated into the ischemically lesioned area, which accelerated neurological recovery. This new cerebral endothelial cell-based therapy may hold promise for clinical trials in patients with ischemic stroke. PMID:27347342

  16. Neuroprotective effects of systemic cerebral endothelial cell transplantation in a rat model of cerebral ischemia.

    PubMed

    Moon, Jong-Hyun; Na, Joo-Young; Lee, Min-Cheol; Choi, Kang-Ho; Lee, Jeong-Kil; Min, Jung-Joon; Kim, Kyung-Tae; Park, Jong-Tae; Park, Man-Seok; Kim, Hyung-Seok

    2016-01-01

    Human cerebral microvascular endothelial cell line (hCMEC)/D3 cells, which are from a stable clonal cell line of human immortalized cerebral endothelial cells, were intra-arterially transplanted through the common carotid artery in a rat model of photochemical-induced cerebral ischemia. Their therapeutic effects on infarct size, blood-brain barrier (BBB) breakdown, and outcome were examined. The hCMEC/D3 cells were genetically modified with the firefly luciferase gene for in vivo imaging post-transplantation. Transplanted hCMEC/D3 cells were identified in the infarcted brain by bioluminescence imaging at 1 day after transplantation. Compared with the control group, the hCMEC/D3-transplanted group showed reduced infarct size on day 3, reduced Evans blue dye leakage on day 1 indicating decreased BBB breakdown, and early recovery from Rotarod test neurological deficits. The hCMEC/D3-transplanted group also showed decreased levels of matrix metalloproteinase (MMP)-9, which were inversely correlated with TIMP-1 levels on post-transplantation days 1 and 3. The expression of tumor necrosis factor-α and interleukin-1β were markedly diminished in the hCMEC/D3-transplanted group compared with controls. The systemically transplanted cells selectively migrated and integrated into the ischemically lesioned area, which accelerated neurological recovery. This new cerebral endothelial cell-based therapy may hold promise for clinical trials in patients with ischemic stroke.

  17. Naotaifang extract treatment results in increased ferroportin expression in the hippocampus of rats subjected to cerebral ischemia.

    PubMed

    Liao, Jun; Xia, Xing; Wang, Guo-Zuo; Shi, Yong-Mei; Ge, Jin-Wen

    2015-06-01

    The expression of Ferroportin (Fpn) was examined at different time points in rats following focal cerebral ischemia treated with or without the traditional Chinese medicine Naotaifang. Initially, rats were randomly divided into 2, 6, 12, 24 and 72 h groups following middle cerebral artery occlusion (MCAO) and the mRNA and protein level of Fpn was detected by immunohistochemistry and reverse transcription polymerase chain reaction (RT‑PCR) at the above time points. Secondly, the rats were randomly divided into five groups as follows: Sham surgery group, model group, low‑dose group (3 g/kg NTE), medium dose group (9 g/kg NTE) and the high‑dose group (27 g/kg NTE). After 3 days of corresponding therapy by intragastric administration once a day, the regional cerebral ischemia model was reproduced by the MCAO suture method. On the third day, the neurological behavior of the rats was analyzed by neurobehavioral assessment. Fpn in the hippocampal CA2 region was measured by immunohistochemistry and the mRNA level of Fpn was detected by RT‑PCR. Expression of Fpn in the hippocampal CA2 region reached a peak 12 h after surgery (P<0.05, compared with the model group). The high‑dose group (27 g/kg NTE) exhibited a lower neurological behavior score (P<0.05) and a higher level of expression of Fpn at the mRNA and protein level compared with the sham surgery group and model group (P<0.05). Dysregulation of intracellular iron balance is possibly a new mechanism underlying cerebral ischemia. NTE can protect the neuronal population in the hippocampal CA2 region by adjusting the expression of Fpn to balance iron levels following cerebral ischemia.

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

    PubMed

    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".

  19. Ischemia detection using Isoelectric Energy Function.

    PubMed

    Kumar, Amit; Singh, Mandeep

    2016-01-01

    A novel method has been proposed for the detection of ischemia using an isoelectric energy function (IEEF) resulting from ST segment deviations in ECG signals. The method consists of five stages: pre-processing, delineation, measurement of isoelectric energy, a beat characterization algorithm and detection of ischemia. The isoelectric energy threshold is used to differentiate ischemic beats from normal beats for ischemic episode detection. Then, ischemic episodes are classified as transmural or subendocardial. The method is validated for recordings of the annotated European ST-T database (EDB). The results show 98.12% average sensitivity (SE) and 98.16% average specificity (SP). These results are significantly better than those of existing methods cited in the literature. The advantage of the proposed method includes simplicity, ruggedness and automatic discarding of noisy beats. PMID:26623944

  20. Ischemia detection using Isoelectric Energy Function.

    PubMed

    Kumar, Amit; Singh, Mandeep

    2016-01-01

    A novel method has been proposed for the detection of ischemia using an isoelectric energy function (IEEF) resulting from ST segment deviations in ECG signals. The method consists of five stages: pre-processing, delineation, measurement of isoelectric energy, a beat characterization algorithm and detection of ischemia. The isoelectric energy threshold is used to differentiate ischemic beats from normal beats for ischemic episode detection. Then, ischemic episodes are classified as transmural or subendocardial. The method is validated for recordings of the annotated European ST-T database (EDB). The results show 98.12% average sensitivity (SE) and 98.16% average specificity (SP). These results are significantly better than those of existing methods cited in the literature. The advantage of the proposed method includes simplicity, ruggedness and automatic discarding of noisy beats.

  1. Evidence that Patent Foramen Ovale is not a Risk Factor for Cerebral Ischemia in the Elderly

    NASA Technical Reports Server (NTRS)

    Jones, Elizabeth F.; Calafiore, Paul; Donnan, Geoffrey A.; Tonkin, Andrew M.

    1994-01-01

    Patent foramen ovale (PFO) may be a risk factor for ischemic stroke in young patients. The aim of this study was to assess the importance of PFO in subjects with a wider age range using patient-control methodology. Transesophageal contrast echocardiography and carotid imaging were performed in 220 consecutive patients with cerebral ischemia (mean age 66 +/- 13 years) and in 202 community-based control subjects (mean age 64 +/- 11 years). Of patients with stroke, 35 (16%) had PFO compared with 31 control subjects (15%) (p = 0.98). Analysis of PFO prevalence by age did not show a significant difference between patients and control subjects in the age groups <50 years (27% vs 11%p; = 0.33), 50 to 69 years (17% vs 15%; p = 0.78), and > or equal to 70 years (12% vs 17%; p = 0.43). However, the group aged 450 years was relatively small (26 cases, 19 controls). No significant difference in PFO prevalence was detected between patients with cryptogenic stroke (20%), noncryptogenic stroke (14%), and control subjects (15%). These results suggest that PFO is not a risk factor for cerebral ischemia in subjects aged >50 years, which would have major implications for the investigation and management of stroke patients in this age group. Longitudinal studies are now required to assess the incidence of stroke in symptom free patients with PFO.

  2. Neuroprotective effects of tadalafil on gerbil dopaminergic neurons following cerebral ischemia.

    PubMed

    Kim, Kwang Taek; Chung, Kyung Jin; Lee, Han Sae; Ko, Il Gyu; Kim, Chang Ju; Na, Yong Gil; Kim, Khae Hawn

    2013-03-15

    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. PMID:25206715

  3. Protection by vanadium, a contemporary treatment approach to both diabetes and focal cerebral ischemia in rats.

    PubMed

    Liu, Zhenquan; Li, Pengtao; Zhao, Dan; Tang, Huiling; Guo, Jianyou

    2012-01-01

    There is now substantial epidemiological evidence that diabetes is a risk factor for cerebrovascular disease. The protection by vanadium from focal cerebral ischemia in diabetic rats was studied in this paper. Rats with streptozotocin-induced diabetes were subjected to middle cerebral artery occlusion followed by 4 weeks of administration of 0.6 mg/ml sodium orthovanadate in drinking water. Vanadium significantly improved the outcome in diabetic rats after cerebral ischemia and reperfusion in terms of neurobehavioral function. Vanadium reduces brain damage in streptozotocin-induced diabetic rats by imitating action of insulin.

  4. How long is too long for cerebral cooling after ischemia in fetal sheep?

    PubMed

    Davidson, Joanne O; Wassink, Guido; Yuill, Caroline A; Zhang, Frank G; Bennet, Laura; Gunn, Alistair J

    2015-05-01

    Therapeutic hypothermia can partially reduce long-term death and disability in neonates after hypoxic-ischemic encephalopathy. The aim of this study was to determine whether prolonging the duration of cooling from 3 days to 5 days could further improve outcomes of cerebral ischemia in near-term fetal sheep. Fetal sheep (0.85 gestation) received 30 minutes bilateral carotid artery occlusion followed by 3 days of normothermia (n = 8), 3 days of hypothermia (n = 8), or 5 days of hypothermia (n=8) started 3 hours after ischemia. Sham controls received sham ischemia followed by normothermia (n = 8). Cerebral ischemia was associated with profound loss of electroencephalography power and spectral edge, with greater and more rapid recovery in both hypothermia groups (P<0.05). Ischemia was associated with severe loss of neurons in the cortex, hippocampus and thalamus (P < 0.05), with a significant improvement in both hypothermia groups. However, the ischemia-3-day hypothermia group showed greater neuronal survival in the cortex and dentate gyrus compared with ischemia-5-day hypothermia (P < 0.05). Ischemia was associated with induction of iba1-positive microglia, which was attenuated in both hypothermia groups (P < 0.05). Extending the duration of delayed therapeutic hypothermia from 3 to 5 days did not improve outcomes after severe ischemia, and was associated with reduced neuronal survival in some regions. PMID:25605291

  5. Long-term observation of neuronal degeneration and microgliosis in the gerbil dentate gyrus after transient cerebral ischemia.

    PubMed

    Ahn, Ji Hyeon; Shin, Bich Na; Park, Joon Ha; Kim, In Hye; Cho, Jeong Hwi; Chen, BaiHui; Lee, Tae-Kyeong; Tae, Hyun-Jin; Lee, Jae-Chul; Cho, Jun Hwi; Kang, Il Jun; Kim, Young-Myeong; Lee, Yun Lyul; Won, Moo-Ho; Seo, Jeong Yeol

    2016-04-15

    Ischemic insults in the central nervous system evoke activation of microglia. In this study, we investigated long-term changes of neuronal damage and microglial activation in the gerbil dentate gyrus for 60 days after transient cerebral ischemia using immunohistochemistry and western blot. Neuronal damage or death was hardly found in the dentate gyrus after transient ischemia using cresyl violet staining and NeuN immunohistochemistry; however, neuronal degeneration was detected in the polymorphic layer of the dentate gyrus using Fluoro-Jade (F-J) B staining. F-J B-positive cells were significantly increased after ischemia-reperfusion (I-R) and peaked at 3 days post-ischemia, thereafter, F-J B-positive cells were decreased in a time-dependent manner and shown until 30 days post-ischemia; no F-J B-positive cells were observed 60 days after I-R. On the other hand, Iba-1-immunoreactive microglia were hypertrophied after I-R, and numbers of Iba-1-immunoreactive microglia were significantly increased along with the neuronal degeneration and highest 7 days after I-R, thereafter, numbers of Iba-1-immunoreactive microglia were decreased with time, although microglia activation lasted up to 60 days after I-R. In addition, Iba-1 protein level in the dentate gyrus after I-R was changed like immunohistochemical change. Our results, in brief, indicate that transient ischemia-induced neuronal degeneration in the dentate gyrus is maintained for about 30 days after I-R and that microglial activation lasts up to, at least, 60 days after I-R in the gerbil dentate gyrus after transient cerebral ischemia. PMID:27000214

  6. [Cerebral ischemia in Rendu-Osler-Weber disease].

    PubMed

    Delgado Reyes, S; García de la Rocha, M L; Fernández-Armayor Ajo, V; Sierra Sierra, I; Martín Araguz, A; Moreno Martínez, J M

    2000-02-01

    Neurologic manifestations occur in 8-12% of the patients with Rendu-Osler-Weber disease or hereditary hemorrhagic telangiectasia (HHT), principally infectious and hemorrhagic and, less frequently, ischemic ones. More than a half of these neurologic complications are associated with pulmonary arterio-venous malformations (PAVM). The diagnosis of HHT is based on the presence of telangiectases, hemorrhagic events and a family history with an autosomal dominant pattern. We report a case of a patient diagnosed as having HHT with transient ischemic attacks and a PAVM, which was occluded by the use of embolotherapy. Cerebral ischemia in HHT is related to the existence of a PAVM and results from three mechanisms: 1) secondary poliglobulia and hyperviscosity because of the hypoxemia due to a right-left shunt; 2) communication between the airway and the pulmonary circulation during cough access, which produces gas embolism and hemoptysis; 3) and, finally, paradoxical embolism trough the PAVM, the same mechanism proposed to the infectious neurologic manifestations of the disease. When the diagnosis of HHT is suspected, early search and treatment of PAVM, with embolotherapy or surgery, are necessary in order to avoid respiratory problems (hemoptysis, exertional dyspnea, cianosis, clubbing) and neurologic complications. PMID:10769536

  7. Induced hypertension for the treatment of cerebral ischemia after subarachnoid hemorrhage. Direct effect on cerebral blood flow

    SciTech Connect

    Muizelaar, J.P.; Becker, D.P.

    1986-04-01

    The best treatment for symptomatic cerebral ischemia from presumed vasospasm after aneurysmal subarachnoid hemorrhage remains a matter of controversy. A direct effect of any treatment modality on regional cerebral blood flow has never been documented. In a series of 43 patients operated on for ruptured anterior circulation aneurysms, five patients (11.6%) developed clinical signs of cerebral ischemia postoperatively. In four of those patients, the diagnosis of vasospasm was made with measurements of cerebral blood flow (133Xe inhalation or intravenous injection, 10-16 detectors, cerebral blood flow infinity). Treatment with induced arterial hypertension with phenylephrine was instituted. Hemodilution was instituted in one patient; the other three patients already had hematocrits in the range of 33. Within 1 hour, the cerebral blood flow measurement was repeated to document the effect of treatment. The average pretreatment hemispherical blood flow on the operated side was 18.8 mL/100 g per minute, on the contralateral side 21.0 mL/100 g per minute. With treatment these flows increased to 30.8 and 35.8 mL/100 g per minute, respectively. There was also an immediate and obvious positive clinical effect in all patients. The role of measurement of cerebral blood flow in the clinical management of vasospasm is discussed. We stress the theoretical and practical advances of measurements of cerebral blood flow over cerebral angiography, especially in comatose patients.

  8. Systematic investigation of transcription factors critical in the protection against cerebral ischemia by Danhong injection.

    PubMed

    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

  9. Systematic investigation of transcription factors critical in the protection against cerebral ischemia by Danhong injection

    PubMed Central

    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

  10. MicroRNAs: a novel promising therapeutic target for cerebral ischemia/reperfusion injury?

    PubMed Central

    Min, Xiao-li; Wang, Ting-yong; Cao, Yi; Liu, Jia; Li, Jin-tao; Wang, Ting-hua

    2015-01-01

    To determine the molecular mechanism of cerebral ischemia/reperfusion injury, we examined the microRNA (miRNA) expression profile in rat cortex after focal cerebral ischemia/reperfusion injury using miRNA microarrays and bioinformatic tools to systematically analyze Gene Ontology (GO) function classifications, as well as the signaling pathways of genes targeted by these differentially expressed miRNAs. Our results show significantly changed miRNA expression profiles in the reperfusion period after focal cerebral ischemia, with a total of 15 miRNAs up-regulated and 44 miRNAs down-regulated. Target genes of these differentially expressed miRNAs were mainly involved in metabolic and cellular processes, which were identified as hub nodes of a miRNA-GO-network. The most correlated pathways included D-glutamine and D-glutamate metabolism, the renin-angiotensin system, peroxisomes, the PPAR signaling pathway, SNARE interactions in vesicular transport, and the calcium signaling pathway. Our study suggests that miRNAs play an important role in the pathological process of cerebral ischemia/reperfusion injury. Understanding miRNA expression and function may shed light on the molecular mechanism of cerebral ischemia/reperfusion injury. PMID:26807114

  11. Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice

    PubMed Central

    Yang, Jiwon; Ahn, Hye-na; Chang, Minsun; Narasimhan, Purnima; Chan, Pak H.; Song, Yun Seon

    2012-01-01

    Oxidative stress after stroke is associated with the inflammatory system activation in the brain. The complement cascade, especially the degradation products of complement component 3, is a key inflammatory mediator of cerebral ischemia. We have shown that proinflammatory complement component 3 is increased by oxidative stress after ischemic stroke in mice using DNA array. In this study, we investigated whether up-regulation of complement component 3 is directly related to oxidative stress after transient focal cerebral ischemia in mice and oxygen-glucose deprivation in brain cells. Persistent up-regulation of complement component 3 expression was reduced in copper/zinc-superoxide dismutase transgenic mice, and manganese-superoxide dismutase knockout mice showed highly increased complement component 3 levels after transient focal cerebral ischemia. Antioxidant N-tert-butyl-α-phenylnitrone treatment suppressed complement component 3 expression after transient focal cerebral ischemia. Accumulation of complement component 3 in neurons and microglia was decreased by N-tert-butyl-α-phenylnitrone, which reduced infarct volume and impaired neurological deficiency after cerebral ischemia and reperfusion in mice. Small interfering RNA specific for complement component 3 transfection showed a significant increase in brain cells viability after oxygen-glucose deprivation. Our study suggests that the neuroprotective effect of antioxidants through complement component 3 suppression is a new strategy for potential therapeutic approaches in stroke. PMID:23199288

  12. Electroencephalographic Response to Sodium Nitrite May Predict Delayed Cerebral Ischemia After Severe Subarachnoid Hemorrhage

    PubMed Central

    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

  13. Chronic nicotine exposure exacerbates transient focal cerebral ischemia-induced brain injury.

    PubMed

    Li, Chun; Sun, Hong; Arrick, Denise M; Mayhan, William G

    2016-02-01

    Tobacco smoking is a risk factor contributing to the development and progression of ischemic stroke. Among many chemicals in tobacco, nicotine may be a key contributor. We hypothesized that nicotine alters the balance between oxidant and antioxidant networks leading to an increase in brain injury following transient focal cerebral ischemia. Male Sprague-Dawley were treated with nicotine (2 or 4 mg·kg(-1)·day(-1)) for 4 wk via an implanted subcutaneous osmotic minipump and subjected to a 2-h middle cerebral artery occlusion (MCAO). Infarct size and neurological deficits were evaluated at 24 h of reperfusion. Superoxide levels were determined by lucigenin-enhanced chemiluminescence. Expression of oxidant and antioxidant proteins was measured using Western blot analysis. We found that chronic nicotine exposure significantly increased infarct size and worsened neurological deficits. In addition, nicotine significantly elevated superoxide levels of cerebral cortex under basal conditions. Transient focal cerebral ischemia produced an increase in superoxide levels of cerebral cortex in control group, but no further increase was found in the nicotine group. Furthermore, chronic nicotine exposure did not alter protein expression of NADPH oxidase but significantly decreased MnSOD and uncoupling protein-2 (UCP-2) in the cerebral cortex and cerebral arteries. Our findings suggest that nicotine-induced exacerbation in brain damage following transient focal cerebral ischemia may be related to a preexisting oxidative stress via decreasing of MnSOD and UCP-2.

  14. Exercise preconditioning reduces ischemia reperfusion-induced focal cerebral infarct volume through up-regulating the expression of HIF-1α.

    PubMed

    Wang, Lu; Deng, Wenqian; Yuan, Qiongjia; Yang, Huijun

    2015-03-01

    To study the effect and mechanism of exercise preconditioning on focal cerebral ischemia reperfusion induced cerebral infarction via rat model; Sixty Sprague Dawley rats were divided into three groups at random: ischemia reperfusion group (IR, n=24), sham group (sham, n=12) and exercise preconditioning group (EP, n=24). Group EP carried out moderate exercise preconditioning for 4 weeks (swimming with non-weight bearing, 60 minutes/day, 6 days/week), Rats in Group EP and IR were established cerebral ischemia reperfusion injury model by Zea Longa's thread method. The cerebral infarct volume in rat of different group was evaluated after 2%TTC staining, expression of HIF-1α in rats' brain was detected by real-time RT-PCR, immunohistochmeistry method and western blot. No cerebral infarction and significant expression of HIF-1α in Group sham. Compared with Group IR, there was smaller infarct volume and stronger HIF-1α expression in Group EP (P<0.05). Moderate exercise preconditioning reduces ischemia reperfusion induced focal cerebral infarct volume through up-regulating the expression of HIF-1α.

  15. Evaluation of cerebral ischemia using near-infrared spectroscopy with oxygen inhalation

    NASA Astrophysics Data System (ADS)

    Ebihara, Akira; Tanaka, Yuichi; Konno, Takehiko; Kawasaki, Shingo; Fujiwara, Michiyuki; Watanabe, Eiju

    2012-09-01

    Conventional methods presently used to evaluate cerebral hemodynamics are invasive, require physical restraint, and employ equipment that is not easily transportable. Therefore, it is difficult to take repeated measurements at the patient's bedside. An alternative method to evaluate cerebral hemodynamics was developed using near-infrared spectroscopy (NIRS) with oxygen inhalation. The bilateral fronto-temporal areas of 30 normal volunteers and 33 patients with cerebral ischemia were evaluated with the NIRS system. The subjects inhaled oxygen through a mask for 2 min at a flow rate of 8 L/min. Principal component analysis (PCA) was applied to the data, and a topogram was drawn using the calculated weights. NIRS findings were compared with those of single-photon-emission computed tomography (SPECT). In normal volunteers, no laterality of the PCA weights was observed in 25 of 30 cases (83%). In patients with cerebral ischemia, PCA weights in ischemic regions were lower than in normal regions. In 28 of 33 patients (85%) with cerebral ischemia, NIRS findings agreed with those of SPECT. The results suggest that transmission of the changes in systemic SpO2 were attenuated in ischemic regions. The method discussed here should be clinically useful because it can be used to measure cerebral ischemia easily, repeatedly, and noninvasively.

  16. Physiological meaning of cerebral oxygen saturation for piglet with hypoxia-ischemia

    NASA Astrophysics Data System (ADS)

    Ding, Haishu; Huang, Lan; Jen, Chungchien; Hwang, Betau; Lee, Zhiguang; Teng, Yichao; Zheng, Meizhi

    2005-01-01

    The physiological meaning of cerebral oxygen saturation absolute values and the oxygen metabolism of piglet with hypoxia-ischemia (HIE) were researched. The subjects were two piglets. During the total experiment of hypoxia then recovery, the regional cerebral tissue oxygen (rScO2), pulse oxygen saturation (SpO2) were detected non-invasively and the jugular oxygen saturation (SjO2), arterial oxygen saturation (SaO2) were given invasively. The results show that because SjO2 was equal to or larger than rScO2 and SaO2 > ScO2, rScO2 cannot be determined by the weighted sum of SjO2 and SaO2 which had been presented in some papers. According to above-mentioned analysis, the ecchymoma and pathological changes of the vessels due to HIE may be another contribution of rScO2. SjO2 was correlated with SaO2 (R=0.996 and 0.962 for two piglets) and the values of (SaO2-SjO2) are close to constants (29.3+/-8% and 30.3+/-8%).It means that because the subjects were under anesthesia, the oxygen consumption of cerebral tissue kept constants.

  17. Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia.

    PubMed

    Ek, C Joakim; D'Angelo, Barbara; Baburamani, Ana A; Lehner, Christine; Leverin, Anna-Lena; Smith, Peter L P; Nilsson, Holger; Svedin, Pernilla; Hagberg, Henrik; Mallard, Carina

    2015-05-01

    Insults to the developing brain often result in irreparable damage resulting in long-term deficits in motor and cognitive functions. The only treatment today for hypoxic-ischemic encephalopathy (HIE) in newborns is hypothermia, which has limited clinical benefit. We have studied changes to the blood-brain barriers (BBB) as well as regional cerebral blood flow (rCBF) in a neonatal model of HIE to further understand the underlying pathologic mechanisms. Nine-day old mice pups, brain roughly equivalent to the near-term human fetus, were subjected to hypoxia-ischemia. Hypoxia-ischemia increased BBB permeability to small and large molecules within hours after the insult, which normalized in the following days. The opening of the BBB was associated with changes to BBB protein expression whereas gene transcript levels were increased showing direct molecular damage to the BBB but also suggesting compensatory mechanisms. Brain pathology was closely related to reductions in rCBF during the hypoxia as well as the areas with compromised BBB showing that these are intimately linked. The transient opening of the BBB after the insult is likely to contribute to the pathology but at the same time provides an opportunity for therapeutics to better reach the infarcted areas in the brain.

  18. Brain barrier properties and cerebral blood flow in neonatal mice exposed to cerebral hypoxia-ischemia.

    PubMed

    Ek, C Joakim; D'Angelo, Barbara; Baburamani, Ana A; Lehner, Christine; Leverin, Anna-Lena; Smith, Peter L P; Nilsson, Holger; Svedin, Pernilla; Hagberg, Henrik; Mallard, Carina

    2015-05-01

    Insults to the developing brain often result in irreparable damage resulting in long-term deficits in motor and cognitive functions. The only treatment today for hypoxic-ischemic encephalopathy (HIE) in newborns is hypothermia, which has limited clinical benefit. We have studied changes to the blood-brain barriers (BBB) as well as regional cerebral blood flow (rCBF) in a neonatal model of HIE to further understand the underlying pathologic mechanisms. Nine-day old mice pups, brain roughly equivalent to the near-term human fetus, were subjected to hypoxia-ischemia. Hypoxia-ischemia increased BBB permeability to small and large molecules within hours after the insult, which normalized in the following days. The opening of the BBB was associated with changes to BBB protein expression whereas gene transcript levels were increased showing direct molecular damage to the BBB but also suggesting compensatory mechanisms. Brain pathology was closely related to reductions in rCBF during the hypoxia as well as the areas with compromised BBB showing that these are intimately linked. The transient opening of the BBB after the insult is likely to contribute to the pathology but at the same time provides an opportunity for therapeutics to better reach the infarcted areas in the brain. PMID:25627141

  19. MicroRNAs Regulate Mitochondrial Function in Cerebral Ischemia-Reperfusion Injury

    PubMed Central

    Hu, Yue; Deng, Hao; Xu, Shixin; Zhang, Junping

    2015-01-01

    Cerebral ischemia-reperfusion injury involves multiple independently fatal terminal pathways in the mitochondria. These pathways include the reactive oxygen species (ROS) generation caused by changes in mitochondrial membrane potential and calcium overload, resulting in apoptosis via cytochrome c (Cyt c) release. In addition, numerous microRNAs are associated with the overall process. In this review, we first briefly summarize the mitochondrial changes in cerebral ischemia-reperfusion and then describe the possible molecular mechanism of miRNA-regulated mitochondrial function, which likely includes oxidative stress and energy metabolism, as well as apoptosis. On the basis of the preceding analysis, we conclude that studies of microRNAs that regulate mitochondrial function will expedite the development of treatments for cerebral ischemia-reperfusion injury. PMID:26492239

  20. Puerarin protects brain tissue against cerebral ischemia/reperfusion injury by inhibiting the inflammatory response

    PubMed Central

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

    2014-01-01

    Puerarin, a traditional Chinese medicine, exerts a powerful neuroprotective effect in cerebral ischemia/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 significantly improved neurological deficit, 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-α in the ischemic region. These data indicate that puerarin exerts an anti-inflammatory protective effect on brain tissue with ischemia/reperfusion damage by downregulating the expression of multiple inflammatory factors. PMID:25657724

  1. Ulinastatin inhibits cerebral ischemia-induced apoptosis in the hippocampus of gerbils

    PubMed Central

    CHO, YOUNG-SAM; SHIN, MAL-SOON; KO, IL-GYU; KIM, SUNG-EUN; KIM, CHANG-JU; SUNG, YUN-HEE; YOON, HYE-SUN; LEE, BONG-JAE

    2015-01-01

    Ulinastatin is a urinary trypsin inhibitor, originally extracted and purified from human urine. Ulinastatin has cytoprotective effects against ischemic injury in several organs. In the present study, the neuroprotective effects of ulinastatin following ischemic cerebral injury in the hippocampus of gerbils was investigated. To induce transient global ischemia in gerbils, the common carotid arteries were occluded using aneurysm clips for 5 min, and the clips were then removed. Ulinastatin was subcutaneously injected into the gerbils once a day for 7 days at doses of 50,000 or 100,000 U/kg. The gerbils were confronted with a step-down avoidance task, following which tissue samples from the gerbils were examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, western blot analysis for B-cell lymphoma (Bcl-2) and Bcl-2-associated X protein (Bax), immunohistochemistry for caspase-3 and immunofluorescence for 5-bromo-2′-deoxyuridine. The numbers of TUNEL-positive and caspase-3-positive cells in the hippocampal CA1 region increased following cerebral ischemia. The expression of Bax in the hippocampus increased, while the expression of Bcl-2 in the hippocampus decreased following cerebral ischemia. These results confirmed that apoptosis in the hippocampus was enhanced following cerebral ischemia in gerbils. The levels of cell proliferation in the hippocampal dentate gyrus were also enhanced by ischemia, which is possibly an adaptive mechanism to compensate for excessive levels of apoptosis. Ulinastatin treatment inhibited ischemia-induced apoptosis by suppressing apoptosis-associated molecules, and thus ameliorated ischemia-induced short-term memory impairment. The cell proliferation in the hippocampus was also suppressed following ulinastatin treatment. These results suggested the use of ulinastatin as a therapeutic agent for patients with cerebral stroke. PMID:25891426

  2. Ulinastatin inhibits cerebral ischemia-induced apoptosis in the hippocampus of gerbils.

    PubMed

    Cho, Young-Sam; Shin, Mal-Soon; Ko, Il-Gyu; Kim, Sung-Eun; Kim, Chang-Ju; Sung, Yun-Hee; Yoon, Hye-Sun; Lee, Bong-Jae

    2015-08-01

    Ulinastatin is a urinary trypsin inhibitor, originally extracted and purified from human urine. Ulinastatin has cytoprotective effects against ischemic injury in several organs. In the present study, the neuroprotective effects of ulinastatin following ischemic cerebral injury in the hippocampus of gerbils was investigated. To induce transient global ischemia in gerbils, the common carotid arteries were occluded using aneurysm clips for 5 min, and the clips were then removed. Ulinastatin was subcutaneously injected into the gerbils once a day for 7 days at doses of 50,000 or 100,000 U/kg. The gerbils were confronted with a step-down avoidance task, following which tissue samples from the gerbils were examined using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, western blot analysis for B-cell lymphoma (Bcl-2) and Bcl-2-associated X protein (Bax), immunohistochemistry for caspase-3 and immunofluorescence for 5-bromo-2'-deoxyuridine. The numbers of TUNEL-positive and caspase-3-positive cells in the hippocampal CA1 region increased following cerebral ischemia. The expression of Bax in the hippocampus increased, while the expression of Bcl-2 in the hippocampus decreased following cerebral ischemia. These results confirmed that apoptosis in the hippocampus was enhanced following cerebral ischemia in gerbils. The levels of cell proliferation in the hippocampal dentate gyrus were also enhanced by ischemia, which is possibly an adaptive mechanism to compensate for excessive levels of apoptosis. Ulinastatin treatment inhibited ischemia-induced apoptosis by suppressing apoptosis-associated molecules, and thus ameliorated ischemia-induced short-term memory impairment. The cell proliferation in the hippocampus was also suppressed following ulinastatin treatment. These results suggested the use of ulinastatin as a therapeutic agent for patients with cerebral stroke.

  3. Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia.

    PubMed

    Nogawa, S; Forster, C; Zhang, F; Nagayama, M; Ross, M E; Iadecola, C

    1998-09-01

    Focal cerebral ischemia is associated with expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), enzymes whose reaction products contribute to the evolution of ischemic brain injury. We tested the hypothesis that, after cerebral ischemia, nitric oxide (NO) produced by iNOS enhances COX-2 activity, thereby increasing the toxic potential of this enzyme. Cerebral ischemia was produced by middle cerebral artery occlusion in rats or mice. Twenty-four hours after ischemia in rats, iNOS-immunoreactive neutrophils were observed in close proximity (<20 micrometer) to COX-2-positive cells at the periphery of the infarct. In the olfactory bulb, only COX-2 positive cells were observed. Cerebral ischemia increased the concentration of the COX-2 reaction product prostaglandin E2 (PGE2) in the ischemic area and in the ipsilateral olfactory bulb. The iNOS inhibitor aminoguanidine reduced PGE2 concentration in the infarct, where both iNOS and COX-2 were expressed, but not in the olfactory bulb, where only COX-2 was expressed. Postischemic PGE2 accumulation was reduced significantly in iNOS null mice compared with wild-type controls (C57BL/6 or SV129). The data provide evidence that NO produced by iNOS influences COX-2 activity after focal cerebral ischemia. Pro-inflammatory prostanoids and reactive oxygen species produced by COX-2 may be a previously unrecognized factor by which NO contributes to ischemic brain injury. The pathogenic effect of the interaction between NO, or a derived specie, and COX-2 is likely to play a role also in other brain diseases associated with inflammation.

  4. Neuronal damage and calcium accumulation following transient cerebral ischemia in the rat

    SciTech Connect

    Araki, T.; Inoue, T.; Kato, H.; Kogure, K.; Murakami, M. )

    1990-06-01

    The purpose of this study was to examine the distribution of neuronal damage following transient cerebral ischemia in the rat model of four-vessel occlusion utilizing light microscopy as well as {sup 45}Ca-autoradiography. Transient ischemia was induced for 30 min. The animals were allowed to survive for 7 d after ischemia. In the animals subjected to ischemia, the most frequently and seriously damaged areas were the paramedian region of hippocampus, the hippocampal CA1 sector, and the dorsolateral part of striatum, followed by the inferior colliculus, the substantia nigra, the frontal cortex, and the thalamus, which were moderate damaged. Furthermore, the cerebellar Purkinje neurons, the hippocampal CA4 sector, the medial geniculate body, and the hippocampal CA3 sector were slightly affected. {sup 45}Ca-autoradiographyic study also revealed calcium accumulation in the identical sites of ischemic neuronal damage, except for the frontal cortex. Regional cerebral blood flow during 10 min of ischemia was severely decreased in selectively vulnerable areas. The blood flow in the medial geniculate body, the substantia nigra, the inferior colliculus, and the cerebellum was less pronounced than that in the selectively vulnerable areas. The present study demonstrates that transient cerebral ischemia can produce significant neuronal damage not only in the selectively vulnerable regions, but also in the brainstem.

  5. Ischemia detection from morphological QRS angle changes.

    PubMed

    Romero, Daniel; Martínez, Juan Pablo; Laguna, Pablo; Pueyo, Esther

    2016-07-01

    In this paper, an ischemia detector is presented based on the analysis of QRS-derived angles. The detector has been developed by modeling ischemic effects on the QRS angles as a gradual change with a certain transition time and assuming a Laplacian additive modeling error contaminating the angle series. Both standard and non-standard leads were used for analysis. Non-standard leads were obtained by applying the PCA technique over specific lead subsets to represent different potential locations of the ischemic zone. The performance of the proposed detector was tested over a population of 79 patients undergoing percutaneous coronary intervention in one of the major coronary arteries (LAD (n  =  25), RCA (n  =  16) and LCX (n  =  38)). The best detection performance, obtained for standard ECG leads, was achieved in the LAD group with values of sensitivity and specificity of [Formula: see text], [Formula: see text], followed by the RCA group with [Formula: see text], Sp  =  94.4 and the LCX group with [Formula: see text], [Formula: see text], notably outperforming detection based on the ST series in all cases, with the same detector structure. The timing of the detected ischemic events ranged from 30 s up to 150 s (mean  =  66.8 s) following the start of occlusion. We conclude that changes in the QRS angles can be used to detect acute myocardial ischemia. PMID:27243441

  6. Effect of brain microdialysis on aminergic transmitter levels in repeated cerebral global transient ischemia in rat.

    PubMed

    Thaminy, S; Bellissant, E; Maginn, M; Decombe, R; Allain, H; Bentué-Ferrer, D

    1996-12-28

    The effect of repeated transient global ischemia and microdialysis on changes in aminergic neurotransmitter release was investigated using the rat four-vessel occlusion model of global ischemia. To examine the possible transient or permanent changes in neurotransmitter release, ischemia was induced at varying time points in 5 groups of rats. The first ischemia occurred either 24 h (groups I, II, IV, V) or 96 h (group III) following vertebral artery electro-coagulation and guide probe implantation(s), and the second ischemia was induced either 48 h (groups I, IV, V) or 72 h (group II) following the first ischemia. To assess the consequence of repeated microdialysis on the results, one group of rats (group IV) was not dialysed during the first ischemia and another group (group V) was bilaterally dialysed during the second ischemia. Finally, amphetamine-induced neurotransmitter release was also studied in rats submitted to ischemia and compared with that in normal rats. In each case, dopamine, serotonin and their main metabolites were measured by HPLC with electrochemical detection. Monoamine release was inhibited during the second episode of transient ischemia; this non-release was linked to the repeated microdialysis and not to the repeated ischemia. Although the results of chronic studies using brain microdialysis have been widely recognized as valid, the findings presented here indicate that combined with ischemia, probe reinsertion modifies the level of neurotransmitter release. PMID:9007758

  7. Effect of brain microdialysis on aminergic transmitter levels in repeated cerebral global transient ischemia in rat.

    PubMed

    Thaminy, S; Bellissant, E; Maginn, M; Decombe, R; Allain, H; Bentué-Ferrer, D

    1996-12-28

    The effect of repeated transient global ischemia and microdialysis on changes in aminergic neurotransmitter release was investigated using the rat four-vessel occlusion model of global ischemia. To examine the possible transient or permanent changes in neurotransmitter release, ischemia was induced at varying time points in 5 groups of rats. The first ischemia occurred either 24 h (groups I, II, IV, V) or 96 h (group III) following vertebral artery electro-coagulation and guide probe implantation(s), and the second ischemia was induced either 48 h (groups I, IV, V) or 72 h (group II) following the first ischemia. To assess the consequence of repeated microdialysis on the results, one group of rats (group IV) was not dialysed during the first ischemia and another group (group V) was bilaterally dialysed during the second ischemia. Finally, amphetamine-induced neurotransmitter release was also studied in rats submitted to ischemia and compared with that in normal rats. In each case, dopamine, serotonin and their main metabolites were measured by HPLC with electrochemical detection. Monoamine release was inhibited during the second episode of transient ischemia; this non-release was linked to the repeated microdialysis and not to the repeated ischemia. Although the results of chronic studies using brain microdialysis have been widely recognized as valid, the findings presented here indicate that combined with ischemia, probe reinsertion modifies the level of neurotransmitter release.

  8. Anti-inflammatory properties of lipoxin A4 protect against diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury

    PubMed Central

    Han, Jiang-quan; Liu, Cheng-ling; Wang, Zheng-yuan; Liu, Ling; Cheng, Ling; Fan, Ya-dan

    2016-01-01

    Lipoxin A4 can alleviate cerebral ischemia/reperfusion injury by reducing the inflammatory reaction, but it is currently unclear whether it has a protective effect on diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury. In this study, we established rat models of diabetes mellitus using an intraperitoneal injection of streptozotocin. We then induced focal cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. After administration of lipoxin A4 via the lateral ventricle, infarction volume was reduced, the expression levels of pro-inflammatory factors tumor necrosis factor alpha and nuclear factor-kappa B in the cerebral cortex were decreased, and neurological functioning was improved. These findings suggest that lipoxin A4 has strong neuroprotective effects in diabetes mellitus complicated by focal cerebral ischemia/reperfusion injury and that the underlying mechanism is related to the anti-inflammatory action of lipoxin A4. PMID:27212926

  9. Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats.

    PubMed

    Colín-González, Ana Laura; Ortiz-Plata, Alma; Villeda-Hernández, Juana; Barrera, Diana; Molina-Jijón, Eduardo; Pedraza-Chaverrí, José; Maldonado, Perla D

    2011-11-01

    Different garlic products reduce the cerebral ischemic damage due to their antioxidant properties. In this work, we investigated the effect of aged garlic extract (AGE) on cyclooxygenase-2 (COX-2) protein levels and activity, and its role as a possible mechanism of neuroprotection in a cerebral ischemia model. Animals were subjected to 1 h of ischemia plus 24 h of reperfusion. AGE (1.2 ml/kg weight, i.p.) was administered at onset of reperfusion. To evaluate the damage induced by cerebral ischemia, the neurological deficit, the infarct area, and the histological alterations were measured. As an oxidative stress marker to deoxyribonucleic acid, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were determined. Finally, as inflammatory markers, TNFα levels and COX-2 protein levels and activity were measured. AGE treatment diminished the neurological alterations (61.6%), the infarct area (54.8%) and the histological damage (37.7%) induced by cerebral ischemia. AGE administration attenuated the increase in 8-OHdG levels (77.8%), in TNFα levels (76.6%), and in COX-2 protein levels (73.6%) and activity (30.7%) induced after 1 h of ischemia plus 24 h of reperfusion. These data suggest that the neuroprotective effect of AGE is associated not only to its antioxidant properties, but also with its capacity to diminish the increase in TNFα levels and COX-2 protein expression and activity. AGE may have the potential to attenuate the cerebral ischemia-induced inflammation.

  10. Protective effects of mangiferin on cerebral ischemia-reperfusion injury and its mechanisms.

    PubMed

    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. PMID:26656757

  11. Aged garlic extract attenuates cerebral damage and cyclooxygenase-2 induction after ischemia and reperfusion in rats.

    PubMed

    Colín-González, Ana Laura; Ortiz-Plata, Alma; Villeda-Hernández, Juana; Barrera, Diana; Molina-Jijón, Eduardo; Pedraza-Chaverrí, José; Maldonado, Perla D

    2011-11-01

    Different garlic products reduce the cerebral ischemic damage due to their antioxidant properties. In this work, we investigated the effect of aged garlic extract (AGE) on cyclooxygenase-2 (COX-2) protein levels and activity, and its role as a possible mechanism of neuroprotection in a cerebral ischemia model. Animals were subjected to 1 h of ischemia plus 24 h of reperfusion. AGE (1.2 ml/kg weight, i.p.) was administered at onset of reperfusion. To evaluate the damage induced by cerebral ischemia, the neurological deficit, the infarct area, and the histological alterations were measured. As an oxidative stress marker to deoxyribonucleic acid, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were determined. Finally, as inflammatory markers, TNFα levels and COX-2 protein levels and activity were measured. AGE treatment diminished the neurological alterations (61.6%), the infarct area (54.8%) and the histological damage (37.7%) induced by cerebral ischemia. AGE administration attenuated the increase in 8-OHdG levels (77.8%), in TNFα levels (76.6%), and in COX-2 protein levels (73.6%) and activity (30.7%) induced after 1 h of ischemia plus 24 h of reperfusion. These data suggest that the neuroprotective effect of AGE is associated not only to its antioxidant properties, but also with its capacity to diminish the increase in TNFα levels and COX-2 protein expression and activity. AGE may have the potential to attenuate the cerebral ischemia-induced inflammation. PMID:21850441

  12. Comparative analysis of autophagy and tauopathy related markers in cerebral ischemia and Alzheimer's disease animal models.

    PubMed

    Villamil-Ortiz, Javier G; Cardona-Gomez, Gloria P

    2015-01-01

    Alzheimer's disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long-term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2-Vessel Occlusion) rat model (1,15, and 30 days post-ischemia). Our findings confirmed neuronal loss and hyperphosphorylated tau aggregation in the somatosensory cortex (SS-Cx) of the 3xTg-AD mice in the late stage (aged 18 months), which was supported by a failure in autophagy. These results were in contrast to those obtained in the SS-Cx of the CI rats, in which we detected neuronal loss and tauopathy at 1 and 15 days post-ischemia, and this phenomenon was reversed at 30 days. We proposed that this phenomenon was associated with autophagy induction in the late stage, since the data showed a decrease in p-mTOR activity, an association of Beclin-1 and Vps34, a progressive reduction in PHF-1, an increase in LC3B puncta and autophago-lysosomes formation were observed. Furthermore, the survival pathways remained unaffected. Together, our comparative study suggest that autophagy could ameliorates tauopathy in CI but not in AD, suggesting a differential temporal approach to the induction of neuroprotection and the prevention of neurodegeneration.

  13. Hyperexpressed Netrin-1 Promoted Neural Stem Cells Migration in Mice after Focal Cerebral Ischemia

    PubMed Central

    Lu, Haiyan; Song, Xiaoyan; Wang, Feng; Wang, Guodong; Wu, Yuncheng; Wang, Qiaoshu; Wang, Yongting; Yang, Guo-Yuan; Zhang, Zhijun

    2016-01-01

    Endogenous Netrin-1 (NT-1) protein was significantly increased after cerebral ischemia, which may participate in the repair after transient cerebral ischemic injury. In this work, we explored whether NT-1 can be steadily overexpressed by adeno-associated virus (AAV) and the exogenous NT-1 can promote neural stem cells migration from the subventricular zone (SVZ) region after cerebral ischemia. Adult CD-1 mice were injected stereotacticly with AAV carrying NT-1 gene (AAV-NT-1). Mice underwent 60 min of middle cerebral artery (MCA) occlusion 1 week after injection. We found that NT-1 mainly expressed in neuron and astrocyte, and the expression level of NT-1 significantly increased 1 week after AAV-NT-1 gene transfer and lasted for 28 days, even after transient middle cerebral artery occlusion (tMCAO) as well (p < 0.05). Immunohistochemistry results showed that the number of neural stem cells was greatly increased in the SVZ region of AAV-NT-1-transduced mice compared with control mice. Our study showed that overexpressed NT-1 promoted neural stem cells migration from SVZ. This result suggested that NT-1 is a promising factor for repairing and remodeling after focal cerebral ischemia. PMID:27746720

  14. Protection mechanism of early hyperbaric oxygen therapy in rats with permanent cerebral ischemia.

    PubMed

    Yu, Min; Xue, Yixue; Liang, Weidi; Zhang, Yupeng; Zhang, Zhiqiang

    2015-10-01

    [Purpose] The purpose of this study was to investigate whether early hyperbaric oxygen is useful in rats with permanent cerebral ischemia, and whether its mechanism relates to the inhibition of the tumor necrosis factor-alpha-protein kinase C-alpha pathway. [Subjects] Healthy, male Sprague-Dawley rats (N = 108) were the subjects. [Methods] After middle cerebral artery occlusion models were successfully made, rats were randomly divided into sham-operated, cerebral ischemia, and hyperbaric oxygen groups. At 4 and 12 hours after modeling, the volume of cerebral infarction was determined by triphenyltetrazolium chloride staining, and brain water content was measured using the dry and wet method. The expression of tumor necrosis factor-alpha and protein kinase C-alpha in the ischemic penumbra tissue was measured using Western blot analysis. [Results] The data showed that at 4 and 12 hours after modeling, cerebral infarct volume and brain water content decreased in the hyperbaric oxygen group, and expression of tumor necrosis factor-alpha and phospho-protein kinase C-alpha in the ischemic penumbra tissue also decreased. [Conclusion] Our study demonstrates that early hyperbaric oxygen therapy has protective effects on brain tissue after cerebral ischemia, possibly via inhibition of tumor necrosis factor-alpha and phospho-protein kinase C-alpha.

  15. Effect of mild hypothermia on focal cerebral ischemia. Review of experimental studies.

    PubMed

    Miyazawa, Takahito; Tamura, Akira; Fukui, Shinji; Hossmann, Konstantin-Alexander

    2003-07-01

    The purposes of this review are to clarify the effect of hypothermia therapy on focal cerebral ischemia in rats, and to consider the relevancy of its application to human focal cerebral ischemia. Since 1990, 26 reports confirming the brain-protecting effect of hypothermia in rat focal cerebral ischemia models have been published. Seventy-four experimental groups in these 26 reports were classified as having transient middle cerebral arterial occlusion (MCAO) with mild hypothermia (group A; 43 groups), permanent MCAO with mild hypothermia (group B; 14 groups), permanent MCAO with deep hypothermia (group C; 8 groups) and transient or permanent MCAO with mild hyperthermia (group D; 9 groups). The results were evaluated as the % infarct volume change caused by hypothermia or hyperthermia compared with the infarct volume in normothermic animals. The effectiveness was confirmed in 36 (83%) of the 43 groups in group A, 10 (71%) of the 14 in group B, and six (75%) of the eight in group C. The infarct volume of eight of the nine groups in group D was markedly aggravated. The percent infarct volume change was 55.3% +/- 27.1% in group A, 57.6% +/- 24.7% in group B, 60.8% +/- 45.5% in group C, and 189.7% +/- 89.4% in group D. For effective reduction of the infarct volume, hypothermia should be started during ischemia or within 1 h, at latest, after the beginning of reperfusion in the rat transient MCAO model. However, it is not clear whether this neuroprotective effect of hypothermia can also be observed in the chronic stage, such as several months later. Keeping the body temperature normothermic in order to avoid mild hyperthermia seems to be rather important for not aggravating cerebral infarction. Clinical randomized studies on the efficacy of mild hypothermia for focal cerebral ischemia and sophisticated mild hypothermia therapy techniques are mandatory.

  16. Recombinant Fv-Hsp70 protein mediates neuroprotection after focal cerebral ischemia in rats

    PubMed Central

    Zhan, Xinhua; Ander, Bradley P; Liao, Isaac H; Hansen, James E; Kim, Chester; Clements, Douglas; Weisbart, Richard H; Nishimura, Robert N; Sharp, Frank R

    2010-01-01

    Background and Purpose This study investigated the effects of intravenous recombinant Fv-Hsp70 protein on infarction volume and behavior following experimental ischemic stroke. Methods Focal cerebral ischemia was produced by occluding the middle cerebral artery (MCA) using the intraluminal suture technique. Rats subjected to 2 hours of focal ischemia were allowed to survive 24 h. At 2 ¼ h and 3 h after onset of ischemia, Fv-Hsp70 recombinant protein (0.5 mg / kg) or saline was injected via the tail vein. Sensory-motor function and infarction volume were assessed at 24 h following ischemia. Results Administration of Fv-Hsp70 following focal cerebral ischemia significantly decreased infarct volume by 68% and significantly improved sensory-motor function compared to the saline-treated control group. Western blots showed Fv-Hsp70 in ischemic but not in control brain; and Fv-Hsp70 suppressed endogenous Hsp70. Conclusion Fv-Hsp70 protects ischemic brain in this experimental stroke model. PMID:20075343

  17. Slit Modulates Cerebrovascular Inflammation and Mediates Neuroprotection Against Global Cerebral Ischemia

    PubMed Central

    Altay, Tamer; McLaughlin, BethAnn; Wu, Jane Y.; Park, T.S.; Gidday, Jeffrey M.

    2008-01-01

    Cerebrovascular inflammation contributes to secondary brain injury following ischemia. Recent in vitro studies of cell migration and molecular guidance mechanisms have indicated that the Slit family of secreted proteins can exert repellant effects on leukocyte recruitment in response to chemoattractants. Utilizing intravital microscopy, we addressed the role of Slit in modulating leukocyte dynamics in the mouse cortical venular microcirculation in vivo following TNFα application or global cerebral ischemia. We also studied whether Slit affected neuronal survival in the mouse global ischemia model as well as in mixed neuronal-glial cultures subjected to oxygen-glucose deprivation. We found that systemically administered Slit significantly attenuated cerebral microvessel leukocyte-endothelial adherence occurring 4 h after TNFα and 24 h after global cerebral ischemia. Administration of RoboN, the soluble receptor for Slit, exacerbated the acute chemotactic response to TNFα. These findings are indicative of a tonic repellant effect of endogenous Slit in brain under acute proinflammatory conditions. Three days of continuous systemic administration of Slit following global ischemia significantly attenuated the delayed neuronal death of hippocampal CA1 pyramidal cells. Moreover, Slit abrogated neuronal death in mixed neuronal-glial cultures exposed to oxygen-glucose deprivation. The ability of Slit to reduce the recruitment of immune cells to ischemic brain and to provide cytoprotective effects suggests that this protein may serve as a novel anti-inflammatory and neuroprotective target for stroke therapy. PMID:17714707

  18. Modulation of NADPH oxidase activation in cerebral ischemia/reperfusion injury in rats.

    PubMed

    Genovese, Tiziana; Mazzon, Emanuela; Paterniti, Irene; Esposito, Emanuela; Bramanti, Placido; Cuzzocrea, Salvatore

    2011-02-01

    NADPH oxidase is a major complex that produces reactive oxygen species (ROSs) during the ischemic period and aggravates brain damage and cell death after ischemic injury. Although many approaches have been tested for preventing production of ROSs by NADPH oxidase in ischemic brain injury, the regulatory mechanisms of NADPH oxidase activity after cerebral ischemia are still unclear. The aim of this study is identifying apocynin as a critical modulator of NADPH oxidase and elucidating its role as a neuroprotectant in an experimental model of brain ischemia in rat. Treatment of apocynin 5min before of reperfusion attenuated cerebral ischemia in rats. Administration of apocynin showed marked reduction in infarct size compared with that of control rats. Medial carotid artery occlusion (MCAo)-induced cerebral ischemia was also associated with an increase in, nitrotyrosine formation, as well as IL-1β expression, IκB degradation and ICAM expression in ischemic regions. These expressions were markedly inhibited by the treatment of apocynin. We also demonstrated that apocynin reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia-reperfusion brain injury. This new understanding of apocynin induced adaptation to ischemic stress and inflammation could suggest novel avenues for clinical intervention during ischemic and inflammatory diseases. PMID:21138737

  19. Protective effects of Echium amoenum Fisch. and C.A. Mey. against cerebral ischemia in the rats

    PubMed Central

    Safaeian, Leila; Tameh, Abolfazl Azami; Ghannadi, Alireza; Naghani, Elmira Akbari; Tavazoei, Hamed; Alavi, Samaneh Sadat

    2015-01-01

    Background: This study was designed to evaluate the protective effect of Echium amoenum total anthocyanin extract (ETAE) on partial/transient cerebral ischemia in the rats. Materials and Methods: Rats received ETAE (50, 100 and 200 mg/kg, i.p.) 30 min before the induction of cerebral ischemia. Cerebral ischemia was induced by bilateral common carotid arteries occlusion (BCCAO) for 30 min, followed by 72 h reperfusion. The neurological deficit, brain performance, and sensory motor function were assessed 48 h and 72 h after surgery. After sacrification, the brains were evaluated for myeloperoxidase (MPO) activity and histopathological changes. Results: Our results showed that motor function significantly decreased in ischemia/reperfusion (I/R) group as compared to the sham group. Histopathological analysis exhibited the shrinkage and atrophy of the neurons in I/R group. ETAE at the dose of 200 mg/kg improved spontaneous activity and memory induced by cerebral ischemia compared to the control group and also decreased brain MPO activity following cerebral ischemia. However, it could not affect the ability to climbing, body proprioception, vibrissae touch and brain water content. In addition, pretreatment with ETAE at higher doses significantly reduced ischemia-induced neuronal loss of the brain. 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. PMID:26261809

  20. Point application with Angong Niuhuang sticker protects hippocampal and cortical neurons in rats with cerebral ischemia

    PubMed Central

    Zhang, Dong-shu; Liu, Yuan-liang; Zhu, Dao-qi; Huang, Xiao-jing; Luo, Chao-hua

    2015-01-01

    Angong Niuhuang pill, a Chinese materia medica preparation, can improve neurological functions after acute ischemic stroke. Because of its inconvenient application and toxic components (Cinnabaris and Realgar), we used transdermal enhancers to deliver Angong Niuhuang pill by modern technology, which expanded the safe dose range and clinical indications. In this study, Angong Niuhuang stickers administered at different point application doses (1.35, 2.7, and 5.4 g/kg) were administered to the Dazhui (DU14), Qihai (RN6) and Mingmen (DU4) of rats with chronic cerebral ischemia, for 4 weeks. The Morris water maze was used to determine the learning and memory ability of rats. Hematoxylin-eosin staining and Nissl staining were used to observe neuronal damage of the cortex and hippocampal CA1 region in rats with chronic cerebral ischemia. The middle- and high-dose point application of Angong Niuhuang stickers attenuated neuronal damage in the cortex and hippocampal CA1 region, and improved the memory of rats with chronic cerebral ischemia with an efficacy similar to interventions by electroacupuncture at Dazhui (DU14), Qihai (RN6) and Mingmen (DU4). Our experimental findings indicate that point application with Angong Niuhuang stickers can improve cognitive function after chronic cerebral ischemia in rats and is neuroprotective with an equivalent efficacy to acupuncture. PMID:25883629

  1. Reconsideration of Hemodynamic Cerebral Ischemia Using Recent PET/SPECT Studies.

    PubMed

    Nakagawara, Jyoji

    2016-01-01

    Hemodynamic cerebral ischemia has been conceptually confirmed by positron emission tomography (PET) imaging, and misery perfusion could be compensated with both vascular and metabolic reserve; however, these compensatory reserve capacities do not always respond in the same manner from short-term to long-term compromise of hemodynamic cerebral ischemia.In patients with acute misery perfusion, CMRO2 is immediately compensated by a marked increase of OEF combined with a limited increase of CBV. In patients with chronic misery perfusion, a moderate increase of OEF is compatible with a moderate increase of CBV, which could correlate with a moderate decrease of vascular reserve (VR). In moyamoya disease with long-standing misery perfusion, hemodynamic cerebral ischemia is initially compensated with a great deal of vasodilation, and can then be followed with an increased OEF in response to the degree of progression.The stage of hemodynamic cerebral ischemia has been defined by an increase of OEF, but could be reconsidered from different patterns of the engagement of compensatory reserve capacities, and misery perfusion could be classified into three subtypes, such as acute, chronic, and long-standing misery perfusion. PMID:27637635

  2. Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration

    PubMed Central

    Liao, Ru-jia; Jiang, Lei; Wang, Rong-rong; Zhao, Hua-wei; Chen, Ying; Li, Ya; Wang, Lu; Jie, Li-Yong; Zhou, Yu-dong; Zhang, Xiang-nan; Chen, Zhong; Hu, Wei-wei

    2015-01-01

    The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn’t been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function. Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration. H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Moreover, histamine upregulated the GTP-bound small GTPase Rac1, while a Rac1 inhibitor, NSC23766, abrogated the neuroprotection of histidine and its promotion of astrocyte migration. Our data indicated that a dose/stage-dependent histidine treatment, mediated by H2 receptor, promoted astrocyte migration towards the infarct core, which benefited long-term post-cerebral ischemia neurological recovery. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes. PMID:26481857

  3. Cerebral ischemia and asymptomatic coronary artery disease: a prospective study of 83 patients

    SciTech Connect

    Di Pasquale, G.; Andreoli, A.; Pinelli, G.; Grazi, P.; Manini, G.; Tognetti, F.; Testa, C.

    1986-11-01

    A prospective cardiologic evaluation was performed in 83 consecutive patients with transient cerebral ischemia or mild stroke and without symptoms or electrocardiographic signs of ischemic heart disease. Patients were studied with an electrocardiographic exercise test; a positive test was followed by exercise Thallium-201 myocardial scintigraphy. Results were compared to those obtained in a group of 83 age and sex-matched healthy subjects submitted to the same study protocol. Asymptomatic coronary artery disease was detected in 28% of cerebrovascular patients with adequate electrocardiographic exercise test. A scintigraphic perfusion defect of variable extension was found in 19 of them. In the control group the electrocardiographic exercise test was positive in only 6% (p less than 0.01). Our results support the concept that: asymptomatic ischemic heart disease is often associated with cerebrovascular disease; therefore cerebral ischemic attacks may be a marker of coronary artery disease, an active investigation of the heart should be considered in cerebrovascular patients in order to plan optimal, comprehensive management.

  4. Failure in neuroprotection of remote limb ischemic postconditioning in the hippocampus of a gerbil model of transient cerebral ischemia.

    PubMed

    Lee, Jae-Chul; Tae, Hyun-Jin; Chen, Bai Hui; Cho, Jeong Hwi; Kim, In Hye; Ahn, Ji Hyeon; Park, Joon Ha; Shin, Bich-Na; Lee, Hui Young; Cho, Young Shin; Cho, Jun Hwi; Hong, Seongkweon; Choi, Soo Young; Won, Moo-Ho; Park, Chan Woo

    2015-11-15

    Remote ischemic postconditioning (RIPoC) has been proven to provide potent protection of the heart and brain against ischemia-reperfusion injury. However, despite the evidence of cerebral protection with RIPoC is compelling, RIPoC-mediated neuroprotection against transient cerebral ischemic insult is still mired in controversy. In this study, we examined the effect of RIPoC induced by sublathal transient hind limb ischemia on neuronal death in the hippocampus following 5 min of transient cerebral ischemia in gerbils. Animals were randomly assigned to sham-, ischemia-, sham plus (+) RIPoC- and ischemia+RIPoC-groups. RIPoC was induced by three cycles of 5-min and 10-min occlusion-reperfusion of both femoral arteries at predetermined points in time (0, 1, 3, 6, 12 and 24h after transient cerebral ischemia). CV staining, F-J B histofluorescence staining and NeuN immunohistochemistry were carried out to examine neuroprotection in the RIPoC-mediated hippocampus 5 days after ischemia-reperfusion. In the ischemia-group, we found a significant loss of pyramidal cells in the stratum pyramidale (SP) of the hippocampal CA1 region at 5 days post-ischemia compared with the sham-group. In all of the ischemia+RIPoC-groups, the loss of pyramidal cells in the CA1 region at 5 days post-ischemia was not different from that in the ischemia-group. Our present findings indicate that RIPoC does not prevent hippocampal CA1 pyramidal cells from neuronal death induced by transient cerebral ischemia.

  5. Neuronal damage using fluoro-Jade B histofluorescence and gliosis in the gerbil septum submitted to various durations of cerebral ischemia.

    PubMed

    Park, Chan Woo; Lee, Jae-Chul; Ahn, Ji Hyeon; Lee, Dae Hwan; Cho, Geum-Sil; Yan, Bing Chun; Park, Joon Ha; Kim, In Hye; Lee, Hui Young; Won, Moo-Ho; Cho, Jun Hwi

    2013-10-01

    The extent of neuronal damage/death in some brain regions is highly correlated to duration time of transient ischemia. In the present study, we carried out neuronal degeneration/death and glial changes in the septum 4 days after 5, 10, 15, and 20 min of transient cerebral ischemia using gerbils. To examine neuronal damage, Fluoro-Jade B (F-J B, a marker for neuronal degeneration) histofluorescence staining was used. F-J B positive ((+)) cells were detected in the septo-hippocampal nucleus (SHN) of the septum only in the 20 min ischemia-group; the mean number of F-J B(+) neurons was 14.9 ± 2.5/400 μm(2) in a section. Gliosis of astrocytes and microglia was examined using anti-glial fibrillary acidic protein (GFAP) and anti-ionized calcium-binding adapter molecule 1 (Iba-1), respectively. In all the ischemia-groups, GFAP- and Iba-1-immunoreactive astrocytes and microglia, respectively, were increased in number, and apparently tended to be increased in their immunoreactivity. Especially, in the 20 min ischemia-group, the number and immunoreactivity of Iba-immunoreactive microglia was highest and strongest in the ischemic SHN 4 days after ischemia-reperfusion. In brief, our findings showed that neuronal damage/death in the SHN occurred and gliosis was apparently increased in the 20 min ischemia-group at 4 days after ischemia-reperfusion.

  6. Mechanism of Mitochondrial Connexin43′s Protection of the Neurovascular Unit under Acute Cerebral Ischemia-Reperfusion Injury

    PubMed Central

    Hou, Shuai; Shen, Ping-Ping; Zhao, Ming-Ming; Liu, Xiu-Ping; Xie, Hong-Yan; Deng, Fang; Feng, Jia-Chun

    2016-01-01

    We observed mitochondrial connexin43 (mtCx43) expression under cerebral ischemia-reperfusion (I/R) injury, analyzed its regulation, and explored its protective mechanisms. Wistar rats were divided into groups based on injections received before middle cerebral artery occlusion (MCAO). Cerebral infarction volume was detected by 2,3,5-triphenyltetrazolim chloride staining, and cell apoptosis was observed by transferase dUTP nick end labeling. We used transmission electron microscopy to observe mitochondrial morphology and determined superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. MtCx43, p-mtCx43, protein kinase C (PKC), and p-PKC expression were detected by Western blot. Compared with those in the IR group, cerebral infarction volumes in the carbenoxolone (CBX) and diazoxide (DZX) groups were obviously smaller, and the apoptosis indices were down-regulated. Mitochondrial morphology was damaged after I/R, especially in the IR and 5-hydroxydecanoic acid (5-HD) groups. Similarly, decreased SOD activity and increased MDA were observed after MCAO; CBX, DZX, and phorbol-12-myristate-13-acetate (PMA) reduced mitochondrial functional injury. Expression of mtCx43 and p-mtCx43 and the p-Cx43/Cx43 ratio were significantly lower in the IR group than in the sham group. These abnormalities were ameliorated by CBX, DZX, and PMA. MtCx43 may protect the neurovascular unit from acute cerebral IR injury via PKC activation induced by mitoKATP channel agonists. PMID:27164087

  7. Adjudin protects against cerebral ischemia reperfusion injury by inhibition of neuroinflammation and blood-brain barrier disruption

    PubMed Central

    2014-01-01

    Neuroinflammation mediated by activation of microglia and interruption of the blood-brain barrier (BBB) is an important factor that contributes to neuron death and infarct area diffusion in ischemia reperfusion injury. Finding novel molecules to regulate neuroinflammation is of significant clinical value. We have previously shown that adjudin, a small molecule compound known to possess antispermatogenic function, attenuates microglia activation by suppression of the NF-κB pathway. In this study we continued to explore whether adjudin could be neuroprotective by using the transient middle cerebral artery occlusion (tMCAO) model. Adjudin treatment after reperfusion significantly decreased the infarction volume and neuroscore compared to the vehicle group. Staining of CD11b showed that adjudin markedly inhibited microglial activation in both the cortex and the striatum, accompanied by a reduction in the expression and release of cytokines TNF-α, IL-1β and IL-6. Concomitantly, adjudin noticeably prevented BBB disruption after ischemia and reperfusion, as indicated by the reduction of IgG detection in the brain cortex and striatum versus the vehicle group. This finding was also corroborated by immunofluorescence staining and immunoblotting of tight junction-related proteins ZO-1, JAM-A and Occludin, where the reduction of these proteins could be attenuated by adjudin treatment. Moreover, adjudin obviously inhibited the elevated MMP-9 activity after stroke. Together these data demonstrate that adjudin protects against cerebral ischemia reperfusion injury, and we present an effective neuroinflammation modulator with clinical potential. PMID:24927761

  8. Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

    PubMed Central

    Hou, Sheng Tao; Nilchi, Ladan; Li, Xuesheng; Gangaraju, Sandhya; Jiang, Susan X.; Aylsworth, Amy; Monette, Robert; Slinn, Jacqueline

    2015-01-01

    Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia. PMID:25601765

  9. Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage.

    PubMed

    Hou, Sheng Tao; Nilchi, Ladan; Li, Xuesheng; Gangaraju, Sandhya; Jiang, Susan X; Aylsworth, Amy; Monette, Robert; Slinn, Jacqueline

    2015-01-01

    Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia.

  10. Evaluation of Neuroprotective Effect of Thymoquinone Nanoformulation in the Rodent Cerebral Ischemia-Reperfusion Model

    PubMed Central

    Xiao, Xiao-Yu; Zhu, Ying-Xian; Bu, Ju-Yuan; Li, Guo-Wei; Zhou, Jian-Hui

    2016-01-01

    The purpose of the present study was to evaluate the neuroprotective efficacy of optimized thymoquinone loaded PLGA-chitosan nanoparticles delivered via nose to brain route in the rodent cerebral ischemia-reperfusion model. The neuroprotective efficacy of the optimized thymoquinone loaded PLGA-chitosan nanoparticles was evaluated in middle cerebral artery occluded rats by various pharmacodynamic and biochemical studies. The pharmacokinetics of thymoquinone loaded PLGA-chitosan nanoparticles in the brain and blood plasma together with qualitative localization of florescent labelled PLGA-chitosan nanoparticles in brain tissues were also determined. Intranasal delivery of optimized thymoquinone loaded PLGA-chitosan nanoparticles (183.5 ± 8.2 nm, 33.63 ± 2.25 mV) to brain significantly reduced the ischemia infarct volume and enhanced the locomotor activity and grip strength in the middle cerebral artery occluded rats. Biochemical studies showed that intranasal delivery of thymoquinone loaded PLGA-chitosan nanoparticles significantly reduced the lipid peroxidation but elevated the glutathione, catalase, and superoxide dismutase in the brain of middle cerebral artery occluded rats. The pharmacokinetic and localization studies showed that thymoquinone loaded PLGA-chitosan nanoparticles facilitated the delivery of thymoquinone to brain by intranasal nose to brain transport pathways and enhanced their pharmacokinetic profile in brain tissues. Thus, intranasal delivery of thymoquinone loaded PLGA-chitosan nanoparticles to brain could be potentially used for the neuroprotection and treatment of cerebral ischemia. PMID:27725936

  11. Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats.

    PubMed

    Yasuda, Nodoka; Ishii, Takayuki; Oyama, Dai; Fukuta, Tatsuya; Agato, Yurika; Sato, Akihiko; Shimizu, Kosuke; Asai, Tomohiro; Asakawa, Tomohiro; Kan, Toshiyuki; Yamada, Shizuo; Ohizumi, Yasushi; Oku, Naoto

    2014-04-22

    Nobiletin, a citrus polymethoxylated flavone, is reported to possess various pharmacological activities such as anticancer, anti-inflammation, and antioxidant effects. Recently, nobiletin was shown to provide therapeutic benefit for the treatment of Alzheimer׳s disease by activating cAMP-response element-binding protein (CREB). In the present study, we investigated whether nobiletin could protect the brain against ischemia-reperfusion (I/R) injury and improve functional outcome in cerebral I/R model rats, since CREB activation is known to protect neuronal cells in cerebral ischemia. Nobiletin was injected twice at 0 and 1h after the start of reperfusion in transient middle cerebral artery occlusion (t-MCAO) rats. Cerebral I/R induced prominent brain damage in the ischemic hemisphere of t-MCAO rat brains; however, nobiletin treatment significantly reduced the infarct volume and suppressed the brain edema. Immunohistochemical and TUNEL staining indicated that nobiletin treatment significantly suppressed neutrophil invasion into the ischemic region and significantly decreased apoptotic brain cell death in ischemic hemisphere, suggesting that the anti-inflammatory effect and anti-apoptotic effect should be regarded as the neuroprotective mechanism of nobiletin. Moreover, nobiletin treatment ameliorated motor functional deficits in the ischemic rats compared with those deficits of the vehicle-treated group. These results indicate that nobiletin is a potential neuroprotectant for the treatment of cerebral I/R injury.

  12. Sulforaphane exerts neuroprotective effects via suppression of the inflammatory response in a rat model of focal cerebral ischemia

    PubMed Central

    Ma, Li-Li; Xing, Guo-Ping; Yu, Yin; Liang, Hui; Yu, Tian-Xia; Zheng, Wei-Hong; Lai, Tian-Bao

    2015-01-01

    Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Sulforaphane exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema. However, the possible mechanisms of sulforaphane after cerebral ischemia/reperfusion injury have not been fully elucidated. Therefore, in the present study, we investigated the effect of sulforaphane on inflammatory reaction and the potential molecular mechanisms in cerebral ischemia rats. We found that sulforaphane significantly attenuated the blood-brain barrier (BBB) disruption; decreased the levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β; reduced the nitric oxide (NO) levels and inducible nitric oxide synthase (iNOS) activity; inhibited the expression of iNOS and cyclooxygenase-2 (COX-2). In addition, sulforaphane inhibits the expression of p-NF-κB p65 after focal cerebral ischemia-reperfusion injury. Taken together, our results suggest that sulforaphane suppresses the inflammatory response via inhibiting the NF-κB signaling pathway in a rat model of focal cerebral ischemia, and sulforaphane may be a potential therapeutic agent for the treatment of cerebral ischemia injury. PMID:26770373

  13. Neuronal damage using fluoro-jade B histofluorescence and gliosis in the striatum after various durations of transient cerebral ischemia in gerbils.

    PubMed

    Ohk, Taek Geun; Yoo, Ki-Yeon; Park, Seung Min; Shin, Bich Na; Kim, In Hye; Park, Joon Ha; Ahn, Hee Cheol; Lee, Young Joo; Kim, Myong Jo; Kim, Tae Young; Won, Moo-Ho; Cho, Jun Hwi

    2012-04-01

    Ischemic damage occurs well in vulnerable regions of the brain, including the hippocampus and striatum. In the present study, we examined neuronal damage/death and glial changes in the striatum 4 days after 5, 10, 15 and 20 min of transient cerebral ischemia using the gerbil. Spontaneous motor activity was increased with the duration time of ischemia-reperfusion (I-R). To examine neuronal damage, we used Fluoro-Jade B (F-J B, a marker for neuronal degeneration) histofluorescence staining. F-J B positive cells were detected only in the 20 min ischemia-group, not in the other groups. In addition, we examined gliosis of astrocytes and microglia using anti-glial fibrillary acidic protein (GFAP) and anti- ionized calcium-binding adapter molecule 1 (Iba-1), respectively. In the 5 min ischemia-group, GFAP-immunoreactive astrocytes were distinctively increased in number, and the immunoreactivity was stronger than that in the sham-group. In the 10, 15 and 20 min ischemia-groups, GFAP-immunoreactivity was more increased with the duration of I-R. On the other hand, the immunoreactivity and the number of Iba-1-immunoreactive microglia were distinctively increased in the 5 and 10 min ischemia-groups. In the 15 min ischemia-group, cell bodies of microglia were largest, and the immunoreactivity was highest; however, in the 20 min ischemia-group, the immunoreactivity was low compared to the 15 min ischemia-group. The results of western blotting for GFAP and Iba-1 were similar to the immunohistochemical data. In brief, these findings showed that neuronal death could be detected only in the 20 min ischemia-group 4 days after I-R, and the change pattern of astrocytes and microglia were apparently different according to the duration time of I-R.

  14. Neuroprotective effects of SMADs in a rat model of cerebral ischemia/reperfusion

    PubMed Central

    Liu, Fang-fang; Liu, Chao-ying; Li, Xiao-ping; Zheng, Sheng-zhe; Li, Qing-quan; Liu, Qun; Song, Lei

    2015-01-01

    Previous studies have shown that up-regulation of transforming growth factor β1 results in neuroprotective effects. However, the role of the transforming growth factor β1 downstream molecule, SMAD2/3, following ischemia/reperfusion remains unclear. Here, we investigated the neuroprotective effects of SMAD2/3 by analyzing the relationships between SMAD2/3 expression and cell apoptosis and inflammation in the brain of a rat model of cerebral ischemia/reperfusion. Levels of SMAD2/3 mRNA were up-regulated in the ischemic penumbra 6 hours after cerebral ischemia/reperfusion, reached a peak after 72 hours and were then decreased at 7 days. Phosphorylated SMAD2/3 protein levels at the aforementioned time points were consistent with the mRNA levels. Over-expression of SMAD3 in the brains of the ischemia/reperfusion model rats via delivery of an adeno-associated virus containing the SMAD3 gene could reduce tumor necrosis factor-α and interleukin-1β mRNA levels, down-regulate expression of the pro-apoptotic gene, capase-3, and up-regulate expression of the anti-apoptotic protein, Bcl-2. The SMAD3 protein level was negatively correlated with cell apoptosis. These findings indicate that SMAD3 exhibits neuroprotective effects on the brain after ischemia/reperfusion through anti-inflammatory and anti-apoptotic pathways. PMID:25878593

  15. Hyperoxic Reperfusion after Global Cerebral Ischemia Promotes Inflammation and Long-Term Hippocampal Neuronal Death

    PubMed Central

    Hazelton, Julie L.; Balan, Irina; Elmer, Greg I.; Kristian, Tibor; Rosenthal, Robert E.; Krause, Gary; Sanderson, Thomas H.

    2010-01-01

    Abstract In this study we tested the hypothesis that long-term neuropathological outcome is worsened by hyperoxic compared to normoxic reperfusion in a rat global cerebral ischemia model. Adult male rats were anesthetized and subjected to bilateral carotid arterial occlusion plus bleeding hypotension for 10 min. The rats were randomized to one of four protocols: ischemia/normoxia (21% oxygen for 1 h), ischemia/hyperoxia (100% oxygen for 1 h), sham/normoxia, and sham/hyperoxia. Hippocampal CA1 neuronal survival and activation of microglia and astrocytes were measured in the hippocampi of the animals at 7 and 30 days post-ischemia. Morris water maze testing of memory was performed on days 23–30. Compared to normoxic reperfusion, hyperoxic ventilation resulted in a significant decrease in normal-appearing neurons at 7 and 30 days, and increased activation of microglia and astrocytes at 7, but not at 30, days of reperfusion. Behavioral deficits were also observed following hyperoxic, but not normoxic, reperfusion. We conclude that early post-ischemic hyperoxic reperfusion is followed by greater hippocampal neuronal death and cellular inflammatory reactions compared to normoxic reperfusion. The results of these long-term outcome studies, taken together with previously published results from short-term experiments performed with large animals, support the hypothesis that neurological outcome can be improved by avoiding hyperoxic resuscitation after global cerebral ischemia such as that which accompanies cardiac arrest. PMID:20059303

  16. Neuroprotective effects of Withania coagulans root extract on CA1 hippocampus following cerebral ischemia in rats

    PubMed Central

    Sarbishegi, Maryam; Heidari, Zahra; Mahmoudzadeh- Sagheb, Hamidreza; Valizadeh, Moharram; Doostkami, Mahboobeh

    2016-01-01

    Objective: Oxygen free radicals may be implicated in the pathogenesis of ischemia reperfusion damage. The beneficial effects of antioxidant nutrients, as well as complex plant extracts, on cerebral ischemia-reperfusion injuries are well known. This study was conducted to determine the effects of the hydro-alcoholic root extract of Withania coagulans on CA1 hippocampus oxidative damages following global cerebral ischemia/reperfusion in rat. Materials and Methods: Male Wistar rats were randomly divided in five groups: control, sham operated, Ischemia/ Reperfiusion (IR), and Withania Coagulans Extract (WCE) 500 and 1000mg/kg + I/R groups. Ischemia was induced by ligation of bilateral common carotid arteries for 30 min after 30 days of WCE administration. Three days after, the animals were sacrificed, their brains were fixed for histological analysis (NISSL and TUNEL staining) and some samples were prepared for measurement of malondialdehyde (MDA) level and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activity in hippocampus. Results: WCE showed neuroprotective activity by significant decrease in MDA level and increase in the SOD, CAT and GPx activity in pretreated groups as compared to I/R groups (p<0.001). The number of intact neurons was increased while the number of TUNEL positive neurons in CA1 hippocampal region in pretreated groups were decreased as compared to I/R group (p<0.001). Conclusion: WCE showed potent neuroprotective activity against oxidative stress-induced injuries caused by global cerebral ischemia/ reperfusion in rats probably by radical scavenging and antioxidant activities. PMID:27516980

  17. Ellagic acid improves electrocardiogram waves and blood pressure against global cerebral ischemia rat experimental models

    PubMed Central

    Nejad, Khojasteh Hoseiny; Dianat, Mahin; Sarkaki, Alireza; Naseri, Mohammad Kazem Gharib; Badavi, Mohammad; Farbood, Yaghoub

    2015-01-01

    Background: Global cerebral ischemia (GCIR) arises in patients that are shown a variety of clinical difficulty including cardiac arrest, asphyxia, and shock. In spite of advances in understanding of the brain, ischemia and protective effects to improve ischemic injury still remain unknown. The aim of our study was to investigate the effect of ellagic acid (EA) pretreatment in the rat models of global cerebral ischemia reperfusion. Methods: This experimental study was conducted in 2014 at the Physiology Research Center of the Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Adult male Wistar rats (250–300 g) were used in this study. GCIR was induced by bilateral vertebral and common carotid arteries occlusion (4-VO). 32 rats were divided randomly to four groups: 1) So (Sham) received normal saline as vehicle of EA, 2) EA, 3) normal saline + GCIR, and 4) EA + GCIR. After anesthesia (a mix of xylazine and ketamine), animal subjected to 20 minutes of ischemia followed by 30 minutes of reperfusion in related groups. EA (100 mg/kg, dissolved in normal saline) or 1.5 ml/kg normal saline was administered (gavage, 10 days) to the related groups. EEG was recorded from NTS in GCIR treated groups. Results: Present data showed that: 1) EEG in GCIR treated groups was flattened; 2) Blood pressure, voltage of QRS and P-R interval were reduced significantly in the ischemic groups compared to before ischemia, and pretreatment with EA prevented this reduction; and 3) MDA level and heart rate was increased by GCIR and pretreatment with EA reduced MDA level and restored the HR to normal level. Conclusion: Results indicate that global cerebral ischemia-reperfusion impairs certain heart functions and ellagic acid as an antioxidant can restore these parameters. The results of this study suggest the possible utility of ellagic acid in patients with brain stroke. PMID:26396728

  18. Potential targets for protecting against hippocampal cell apoptosis after transient cerebral ischemia-reperfusion injury in aged rats

    PubMed Central

    Ji, Xiangyu; Zhang, Li’na; Liu, Ran; Liu, Yingzhi; Song, Jianfang; Dong, He; Jia, Yanfang; Zhou, Zangong

    2014-01-01

    Mitochondria play an important role in neuronal apoptosis caused by cerebral ischemia, and the role is mediated by the expression of mitochondrial proteins. This study investigated the involvement of mitochondrial proteins in hippocampal cell apoptosis after transient cerebral ischemia-reperfusion injury in aged rats using a comparative proteomics strategy. Our experimental results show that the aged rat brain is sensitive to ischemia-reperfusion injury and that transient ischemia led to cell apoptosis in the hippocampus and changes in memory and cognition of aged rats. Differential proteomics analysis suggested that this phenomenon may be mediated by mitochondrial proteins associated with energy metabolism and apoptosis in aged rats. This study provides potential drug targets for the treatment of transient cerebral ischemia-reperfusion injury. PMID:25206771

  19. Deterioration of baroreflex by transient global cerebral ischemia: its correlation with the degree of ischemia or post-ischemic hypoperfusion in the medulla oblongata.

    PubMed

    Kurihara, J; Sahara, T; Kato, H

    1989-12-01

    In a canine model of transient global cerebral ischemia, the correlation between the decrease in baroreflex sensitivity (BRS) following 5-min ischemia and the degree of ischemia or post-ischemic hypoperfusion was investigated. Although the medulla oblongata and the cerebral cortex suffered a similar degree of ischemia, the extent of post-ischemic decrease in BRS was inversely correlated with the residual blood flow during ischemia in the medulla, but not with that in the cerebral cortex. A similar degree of post-ischemic hypoperfusion occurred in the medulla and the cerebral cortex. However, the extent of decrease in BRS was not correlated with the degree of hypoperfusion, and the cortical EEG was not significantly affected. These results suggest that the decrease in BRS may be due to the functional damage in the medulla and that the selective decrease in BRS without concomitant impairment of the EEG cannot be ascribed to the regional difference in the degree of ischemia or post-ischemic hypoperfusion. PMID:2615041

  20. [The pathogenetic prerequisites for the application of the general magnetic therapy in the children presenting with cerebral ischemia].

    PubMed

    Denisova, O I; Davydkin, N F; Kulikov, A G

    2014-01-01

    This article presents the analysis of the current literature and the original data of the authors providing the rationale for the use of magnetic therapy for the treatment of the children presenting with cerebral ischemia taking into consideration pathogenesis of this disease. It is demonstrated that the application of the general magnetic field decreases the tone of the cerebral vessels and improves blood flow to the brain which increases resistance to cerebral hypoxia. The results of investigations into the microcirculatory changes and liquor dynamics in conjunction with the ventriculometric measurements give evidence of the effectiveness of the combined treatment of cerebral ischemia making use of general magnetic therapy. PMID:25536760

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

    PubMed

    Panickar, Kiran S; Jang, Saebyeol

    2013-08-01

    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, energy failure, free radical production, excitotoxicity, altered calcium homeostasis, and activation of proteases all of which affect brain functioning and also contribute to longterm disabilities including cognitive decline. Inflammation, mitochondrial dysfunction, increased oxidative/nitrosative stress, and intracellular calcium overload contribute to brain injury including cell death and brain edema. However, there is a paucity of agents that can effectively reduce cerebral damage and hence considerable attention has focused on developing newer agents with more efficacy and fewer side-effects. Polyphenols are natural compounds with variable phenolic structures and are rich in vegetables, fruits, grains, bark, roots, tea, and wine. Most polyphenols have antioxidant, anti-inflammatory, and anti-apoptotic properties and their protective effects on mitochondrial functioning, glutamate uptake, and regulating intracellular calcium levels in ischemic injury in vitro have been demonstrated. This review will assess the current status of the potential effects of polyphenols in reducing cerebral injury and improving cognitive function in ischemia in animal and human studies. In addition, the review will also examine available patents in nutrition and agriculture that relates to cerebral ischemic injury with an emphasis on plant polyphenols.

  2. LXW7 ameliorates focal cerebral ischemia injury and attenuates inflammatory responses in activated microglia in rats

    PubMed Central

    Fang, T.; Zhou, D.; Lu, L.; Tong, X.; Wu, J.; Yi, L.

    2016-01-01

    Inflammation plays a pivotal role in ischemic stroke, when activated microglia release excessive pro-inflammatory mediators. The inhibition of integrin αvβ3 improves outcomes in rat focal cerebral ischemia models. However, the mechanisms by which microglia are neuroprotective remain unclear. This study evaluated whether post-ischemic treatment with another integrin αvβ3 inhibitor, the cyclic arginine-glycine-aspartic acid (RGD) peptide-cGRGDdvc (LXW7), alleviates cerebral ischemic injury. The anti-inflammatory effect of LXW7 in activated microglia within rat focal cerebral ischemia models was examined. A total of 108 Sprague-Dawley rats (250–280 g) were subjected to middle cerebral artery occlusion (MCAO). After 2 h, the rats were given an intravenous injection of LXW7 (100 μg/kg) or phosphate-buffered saline (PBS). Neurological scores, infarct volumes, brain water content (BWC) and histology alterations were determined. The expressions of pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)], and Iba1-positive activated microglia, within peri-ischemic brain tissue, were assessed with ELISA, western blot and immunofluorescence staining. Infarct volumes and BWC were significantly lower in LXW7-treated rats compared to those in the MCAO + PBS (control) group. The LXW7 treatment lowered the expression of pro-inflammatory cytokines. There was a reduction of Iba1-positive activated microglia, and the TNF-α and IL-1β expressions were attenuated. However, there was no difference in the Zea Longa scores between the ischemia and LXW7 groups. The results suggest that LXW7 protected against focal cerebral ischemia and attenuated inflammation in activated microglia. LXW7 may be neuroprotective during acute MCAO-induced brain damage and microglia-related neurodegenerative diseases. PMID:27533766

  3. High-Resolution Magnetic Resonance Angiography of the Mouse Brain: Application to Murine Focal Cerebral Ischemia Models

    NASA Astrophysics Data System (ADS)

    Beckmann, Nicolau; Stirnimann, Roger; Bochelen, Damien

    1999-10-01

    Three-dimensional time-of-flight high-resolution magnetic resonance angiography was applied to visualize the cerebral vasculature of the mouse brain. In normal mice, angiograms of good quality, showing the essential details of the arterial cerebrovascular anatomy, could be obtained in only 2.5 min without the use of contrast agents. Signals from slowly flowing blood, e.g., in veins, could also be detected after administration of a blood pool contrast agent. The technique was applied to mouse models of permanent and transient brain ischemia, involving the occlusion of the middle cerebral artery. High-resolution magnetic resonance angiography proved to be a very useful tool for verifying the success of the occlusion in these models.

  4. Quantification of infarct size on focal cerebral ischemia model of rats using a simple and economical method.

    PubMed

    Yang, Y; Shuaib, A; Li, Q

    1998-10-01

    Quantification of infarct size is a very useful index to assess models of focal cerebral ischemia and effects of new therapies. Currently-used image analysis systems to carry out this task usually involve dedicated and expensive equipment. We present a low-cost and simple method to perform the image acquisition and analysis. Twelve Wistar rats were subject to focal cerebral ischemia and scarified 24 h after the insult. 2,3,5-triphenyl tetrazolium chloride (TTC) stain was used as a conventional method to differentiate ischemic damage from healthy brain tissue. Digital images were captured from the stained coronal sections using a flatbed color scanner and analyzed with a commercial image processing software. To evaluate the accuracy and reproducibility of this method, the data obtained with the current procedure was correlated with those from a dedicated standard image analysis system and intra-observor correlation coefficient was estimated. Also the sensitivity of this method in quantification of infarct volume was tested in two different experimental settings. There was close correlation in the outcome of infarct size measurement between the current method and the standard system (r = 0.93, p < 0.001). A high agreement of measurement of the percentage of infarct volume between two different examiners with the same source of samples (r = 0.98, p < 0.001). We demonstrated that this method was sensitive in detection of difference of infarct sizes when placebo-treated animals (n = 6) were compared to the group treated with a neuroprotective agent (n = 6). Our data demonstrated that ischemic lesion of focal cerebral ischemia in rat can be accurately and reproducibly quantified using this method. The low-cost and simplicity of this method may facilitate the application in determination of ischemic damage.

  5. Erythropoietin Modulates Cerebral and Serum Degradation Products from Excess Calpain Activation following Prenatal Hypoxia-Ischemia.

    PubMed

    Jantzie, Lauren L; Winer, Jesse L; Corbett, Christopher J; Robinson, Shenandoah

    2016-01-01

    Preterm infants suffer central nervous system (CNS) injury from hypoxia-ischemia and inflammation - termed encephalopathy of prematurity. Mature CNS injury activates caspase and calpain proteases. Erythropoietin (EPO) limits apoptosis mediated by activated caspases, but its role in modulating calpain activation has not yet been investigated extensively following injury to the developing CNS. We hypothesized that excess calpain activation degrades developmentally regulated molecules essential for CNS circuit formation, myelination and axon integrity, including neuronal potassium-chloride co-transporter (KCC2), myelin basic protein (MBP) and phosphorylated neurofilament (pNF), respectively. Further, we predicted that post-injury EPO treatment could mitigate CNS calpain-mediated degradation. Using prenatal transient systemic hypoxia-ischemia (TSHI) in rats to mimic CNS injury from extreme preterm birth, and postnatal EPO treatment with a clinically relevant dosing regimen, we found sustained postnatal excess cortical calpain activation following prenatal TSHI, as shown by the cleavage of alpha II-spectrin (αII-spectrin) into 145-kDa αII-spectrin degradation products (αII-SDPs) and p35 into p25. Postnatal expression of the endogenous calpain inhibitor calpastatin was also reduced following prenatal TSHI. Calpain substrate expression following TSHI, including cortical KCC2, MBP and NF, was modulated by postnatal EPO treatment. Calpain activation was reflected in serum levels of αII-SDPs and KCC2 fragments, and notably, EPO treatment also modulated KCC2 fragment levels. Together, these data indicate that excess calpain activity contributes to the pathogenesis of encephalopathy of prematurity. Serum biomarkers of calpain activation may detect ongoing cerebral injury and responsiveness to EPO or similar neuroprotective strategies. PMID:26551007

  6. Regional cerebral blood flow during hypoxia-ischemia in immature rats

    SciTech Connect

    Vannucci, R.C.; Lyons, D.T.; Vasta, F.

    1988-02-01

    Immature rats subjected to a combination of unilateral common carotid artery ligation and hypoxia sustain brain damage confined largely to the ipsilateral cerebral hemisphere. To ascertain the extent and distribution of ischemic alterations in the brains of these small animals, we modified the Sakurada technique to measure regional cerebral blood flow using carbon-14 autoradiography. Seven-day-old rats underwent right common carotid artery ligation following which they were rendered hypoxic with 8% O2 at 37 degrees C. Before and during hypoxia, the rat pups received an injection of iodo(/sup 14/C)antipyrine for determination of regional cerebral blood flow. Blood flows to individual structures of the ipsilateral cerebral hemisphere were not influenced by arterial occlusion alone; flows to the contralateral hemisphere and to the brainstem and cerebellum actually increased by 25-50%. Hypoxia-ischemia was associated with decreases in regional cerebral blood flow of the ipsilateral hemisphere such that by 2 hours, flows to subcortical white matter, neocortex, striatum, and thalamus were 15, 17, 34, and 41% of control, respectively. The hierarchy of the blood flow reductions correlated closely with the distribution and extent of ischemic neuronal necrosis. However, unlike the pathologic pattern of this model, the degree of ischemia appeared homogeneous within each brain region. Blood flows to contralateral cerebral hemispheric structures were relatively unchanged from prehypoxic values, whereas flows to the brainstem and cerebellum nearly doubled and tripled, respectively. Thus, ischemia is the predominant factor that determines the topography of tissue injury to major regions of immature rat brain, whereas metabolic factors may influence the heterogeneous pattern of damage seen within individual structures.

  7. Beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral ischemia-reperfusion injury in rats.

    PubMed

    Sun, Lingyan; Tian, Xia; Gou, Lingshan; Ling, Xin; Wang, Ling; Feng, Yan; Yin, Xiaoxing; Liu, Yi

    2013-07-01

    Theanine and caffeine, 2 naturally occurring components in tea, have repeatedly been shown to deliver unique cognitive benefits when consumed in combination. In this study, we assessed the beneficial synergistic effects of concurrent treatment with theanine and caffeine against cerebral damage in rats. Theanine and caffeine had no effect on physiological variables, including pH, partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2), mean arterial blood pressure, plasma glucose, or regional cerebral blood flow. Treatment with theanine (1 mg/kg body mass, intraperitoneal injection) alone significantly reduced cerebral infarction induced by cerebral ischemia-reperfusion, but caffeine (10 mg/kg, intravenous administration) alone only had a marginal effect. However, the combination of theanine plus caffeine resulted in a significant reduction of cerebral infarction and brain edema compared with theanine monotherapy. Meanwhile, increased malondialdehyde levels as well as decreased superoxide dismutase activity, glutathione peroxidase activity, and glutathione levels observed in the cerebral cortex after cerebral ischemia-reperfusion were significantly ameliorated by the combination therapy. Furthermore, the elevated inflammatory response levels observed in the cortex after cerebral ischemia-reperfusion were markedly attenuated by the combined treatment. Thus, it is suggested that the neuroprotective potential of a combination therapy with theanine and caffeine against cerebral ischemia-reperfusion is partly ascribed to their antioxidant and anti-inflammatory properties.

  8. Activation of PPARγ by 12/15-lipoxygenase during cerebral ischemia-reperfusion injury.

    PubMed

    Han, Jing; Sun, Li; Xu, Yanwei; Liang, Hao; Cheng, Yan

    2015-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) expression and activity are increased in brain ischemic injury and its agonists have shown potential for brain injury protection. The influence of 12/15-lipoxygenase (12/15-LOX) on the activity of PPARγ in oxygen-glucose deprivation (OGD) and ischemia-reperfusion (I/R) was investigated. A middle cerebral artery occlusion/reperfusion model with Sprague Dawley (SD) rats was established. For I/R intervention, the rats were treated with the 12/15-LOX-derived product 12-hydroxyeicosatetraenoic acid (12-HETE) for 30 min before cerebral artery occlusion. Primary cortical neurons from SD rats were used to establish an OGD cell model. 12-HETE or a 12/15-LOX antisense oligonucleotide (asON-12/15-LOX) was added to OGD-treated neurons. Western blots, immunofluorescence and enzyme-linked immunosorbent assays detected protein. Reverse transcription-polymerase chain reaction analyzed the expression of the PPARγ target genes. PPARγ-DNA binding activity was determined by peroxisome proliferator responsive element luciferase reporter vectors. 12/15-LOX total protein increased significantly with I/R, and expression of 12-HETE was also upregulated. 12-HETE treatment increased PPARγ protein expression and inhibited inducible nitric oxide synthase protein expression, which was upregulated with I/R. PPARγ nuclear protein and 12/15-LOX total protein expression in OGD-treated neurons increased significantly. 12-HETE treatment increased the expression of PPARγ nuclear protein, upregulated the mRNA levels of PPARγ target genes (lipoprotein lipase and acyl-CoA oxidase) and enhanced PPARγ-DNA binding activity. asON-12/15-LOX treatment inhibited 12/15-LOX and PPARγ protein expression and lipoprotein lipase mRNA. Cerebral I/R injury in rats and OGD treatment in neurons promoted 12/15-LOX expression, and 12-HETE activated PPARγ. Therefore, PPARγ can be activated by the 12/15-LOX pathway during cerebral I/R injury. PMID:25395029

  9. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion.

    PubMed

    Ma, Chun-Ye; Yin, Lin

    2016-07-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury. PMID:27630693

  10. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion

    PubMed Central

    Ma, Chun-ye; Yin, Lin

    2016-01-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury.

  11. Neuroprotective effect of angiotensin II type 2 receptor during cerebral ischemia/reperfusion

    PubMed Central

    Ma, Chun-ye; Yin, Lin

    2016-01-01

    Angiotensin II type 2 receptor (AT2R) activation has been shown to protect against stroke, but its precise mechanism remains poorly understood. We investigated whether the protective effect of AT2R against ischemia/reperfusion injury is mediated by the suppression of immune and inflammatory responses. Rat models of middle cerebral artery occlusion were intraperitoneally injected with physiological saline, the AT2R agonist CGP42112 (1 mg/kg per day) or antagonist PD123319 (1 mg/kg per day). In the CGP42112 group, AT2R expression increased, the infarct area decreased, interleukin-1β and tumor necrosis factor-α expression decreased, and interleukin-10 expression increased compared with the saline group. Antagonisin AT2R using PD123319 produced the opposite effects. These results indicate that AT2R activation suppresses immune and inflammatory responses, and protects against cerebral ischemia/reperfusion injury. PMID:27630693

  12. Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus.

    PubMed

    Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

    2014-08-01

    Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions.

  13. Neuroprotective effect of pretreatment with ganoderma lucidum in cerebral ischemia/reperfusion injury in rat hippocampus

    PubMed Central

    Zhang, Wangxin; Zhang, Quiling; Deng, Wen; Li, Yalu; Xing, Guoqing; Shi, Xinjun; Du, Yifeng

    2014-01-01

    Ganoderma lucidum is a traditional Chinese medicine, which has been shown to have both anti-oxidative and anti-inflammatory effects, and noticeably decreases both the infarct area and neuronal apoptosis of the ischemic cortex. This study aimed to investigate the protective effects and mechanisms of pretreatment with ganoderma lucidum (by intragastric administration) in cerebral ischemia/reperfusion injury in rats. Our results showed that pretreatment with ganoderma lucidum for 3 and 7 days reduced neuronal loss in the hippocampus, diminished the content of malondialdehyde in the hippocampus and serum, decreased the levels of tumor necrosis factor-α and interleukin-8 in the hippocampus, and increased the activity of superoxide dismutase in the hippocampus and serum. These results suggest that pretreatment with ganoderma lucidum was protective against cerebral ischemia/reperfusion injury through its anti-oxidative and anti-inflammatory actions. PMID:25317156

  14. Immediate remote ischemic postconditioning after hypoxia ischemia in piglets protects cerebral white matter but not grey matter

    PubMed Central

    Ezzati, Mojgan; Bainbridge, Alan; Broad, Kevin D; Kawano, Go; Oliver-Taylor, Aaron; Rocha-Ferreira, Eridan; Alonso-Alconada, Daniel; Fierens, Igor; Rostami, Jamshid; Jane Hassell, K; Tachtsidis, Ilias; Gressens, Pierre; Hristova, Mariya; Bennett, Kate; Lebon, Sophie; Fleiss, Bobbi; Yellon, Derek; Hausenloy, Derek J; Golay, Xavier

    2015-01-01

    Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. Our aim was to assess whether RIPostC is protective following cerebral hypoxia-ischemia in a piglet model of neonatal encephalopathy (NE) using magnetic resonance spectroscopy (MRS) biomarkers and immunohistochemistry. After hypoxia-ischemia (HI), 16 Large White female newborn piglets were randomized to: (i) no intervention (n = 8); (ii) RIPostC – with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (n = 8). RIPostC reduced the hypoxic-ischemic-induced increase in white matter proton MRS lactate/N acetyl aspartate (p = 0.005) and increased whole brain phosphorus-31 MRS ATP (p = 0.039) over the 48 h after HI. Cell death was reduced with RIPostC in the periventricular white matter (p = 0.03), internal capsule (p = 0.002) and corpus callosum (p = 0.021); there was reduced microglial activation in corpus callosum (p = 0.001) and more surviving oligodendrocytes in corpus callosum (p = 0.029) and periventricular white matter (p = 0.001). Changes in gene expression were detected in the white matter at 48 h, including KATP channel and endothelin A receptor. Immediate RIPostC is a potentially safe and promising brain protective therapy for babies with NE with protection in white but not grey matter. PMID:26661194

  15. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain.

    PubMed

    Mun, Chin Hee; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2010-09-01

    Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in cerebral ischemia by maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia. Matrix metalloproteinases (MMPs) are up-regulated by ischemic injury and degrade the basement membrane if brain vessels to promote cell death and tissue injury. We previously reported that agmatine, synthesized from L-arginine by arginine decarboxylase (ADC) which is expressed in endothelial cells, has shown a direct increased eNOS expression and decreased MMPs expression in bEnd3 cells. But, there are few reports about the regulation of eNOS by agmatine in ischemic animal model. In the present study, we examined the expression of eNOS and MMPs by agmatine treatment after transient global ischemia in vivo. Global ischemia was induced with four vessel occlusion (4-VO) and agmatine (100 mg/kg) was administered intraperitoneally at the onset of reperfusion. The animals were euthanized at 6 and 24 hours after global ischemia and prepared for other analysis. Global ischemia led severe neuronal damage in the rat hippocampus and cerebral cortex, but agmatine treatment protected neurons from ischemic injury. Moreover, the level and expression of eNOS was increased by agmatine treatment, whereas inducible NOS (iNOS) and MMP-9 protein expressions were decreased in the brain. These results suggest that agmatine protects microvessels in the brain by activation eNOS as well as reduces extracellular matrix degradation during the early phase of ischemic insult.

  16. Regulation of endothelial nitric oxide synthase by agmatine after transient global cerebral ischemia in rat brain.

    PubMed

    Mun, Chin Hee; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2010-09-01

    Nitric oxide (NO) production by endothelial nitric oxide synthase (eNOS) plays a protective role in cerebral ischemia by maintaining vascular permeability, whereas NO derived from neuronal and inducible NOS is neurotoxic and can participate in neuronal damage occurring in ischemia. Matrix metalloproteinases (MMPs) are up-regulated by ischemic injury and degrade the basement membrane if brain vessels to promote cell death and tissue injury. We previously reported that agmatine, synthesized from L-arginine by arginine decarboxylase (ADC) which is expressed in endothelial cells, has shown a direct increased eNOS expression and decreased MMPs expression in bEnd3 cells. But, there are few reports about the regulation of eNOS by agmatine in ischemic animal model. In the present study, we examined the expression of eNOS and MMPs by agmatine treatment after transient global ischemia in vivo. Global ischemia was induced with four vessel occlusion (4-VO) and agmatine (100 mg/kg) was administered intraperitoneally at the onset of reperfusion. The animals were euthanized at 6 and 24 hours after global ischemia and prepared for other analysis. Global ischemia led severe neuronal damage in the rat hippocampus and cerebral cortex, but agmatine treatment protected neurons from ischemic injury. Moreover, the level and expression of eNOS was increased by agmatine treatment, whereas inducible NOS (iNOS) and MMP-9 protein expressions were decreased in the brain. These results suggest that agmatine protects microvessels in the brain by activation eNOS as well as reduces extracellular matrix degradation during the early phase of ischemic insult. PMID:21212863

  17. The role of melatonin in multiple sclerosis, Huntington's disease and cerebral ischemia.

    PubMed

    Escribano, Begoña M; Colín-González, Ana L; Santamaría, Abel; Túnez, Isaac

    2014-01-01

    Melatonin is produced and released by the pineal gland in a circadian rhythm. This neurohormone has proven to be an antioxidant and anti-inflammatory molecule able to reduce or mitigate cell damage associated with oxidative stress and inflammation, and this phenomenon underlies neurodegenerative disorders. These facts have drawn attention to this indole, triggering interest in evaluating its changes and in its relationship to the processes indicated, and analyzing its role in the mechanisms involved at the onset and development of neurodegenerative diseases, as well as its therapeutic potential. Multiple sclerosis, the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, and neuronal and oxidative damage. In its early diagnosis, it often requires a differential screening with other neurodegenerative diseases with similar symptoms, such as Huntington's disease, an autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. On the other hand, cerebral ischemia is a major cause of human disability all over the world. Although a cerebral stroke can occur as the result of different damaging insults, severe ischemia produces the death of neuronal cells within minutes. Changes in melatonin levels have been observed in these processes (Huntington's disease, multiple sclerosis and cerebral ischemia) as part of their pathogenic features. This review aims to update and discuss the role played by melatonin during neurodegenerative processes, specifically in multiple sclerosis, Huntington's disease, and cerebral ischemia, and its possible therapeutic use. We also provide readers with an update on the many neuroprotective mechanisms exerted by this neurohormone in the Central Nervous System. PMID:25106623

  18. Greatly improved survival and neuroprotection in aquaporin-4-knockout mice following global cerebral ischemia.

    PubMed

    Katada, Ryuichi; Akdemir, Gokhan; Asavapanumas, Nithi; Ratelade, Julien; Zhang, Hua; Verkman, A S

    2014-02-01

    Aquaporin-4 (AQP4), the principal water channel in astrocytes, is involved in brain water movement, inflammation, and neuroexcitation. In this study, there was strong neuroprotection in mice lacking AQP4 in a model of global cerebral ischemia produced by transient, bilateral carotid artery occlusion (BCAO). Survival and neurological outcome were greatly improved in the AQP4(-/-) vs. AQP4(+/+) mice after occlusion, with large and robust differences in both outbred (CD1) and inbred (C57bl/6) mouse strains without or with mechanical ventilation. Improved survival was also seen in mice lacking the scaffold protein α-syntrophin, which manifest reduced astrocyte water permeability secondary to defective AQP4 plasma membrane targeting. Intracranial pressure elevation and brain water accumulation were much reduced in the AQP4(-/-) vs. AQP4(+/+) mice after carotid artery occlusion, as were blood-brain barrier (BBB) disruption and neuronal loss. Brain slices from AQP4(-/-) mice showed significantly reduced cell swelling and cytotoxicity in response to oxygen-glucose deprivation, compared with slices from AQP4(+/+) mice. Our findings suggest that the neuroprotective effect of AQP4 deletion in global cerebral ischemia involves reduced astrocyte swelling and brain water accumulation, resulting in reduced BBB disruption, inflammation, and neuron death. AQP4 water transport inhibition may improve survival and neurological outcome after cardiac arrest and in other conditions associated with global cerebral ischemia. PMID:24186965

  19. Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia

    PubMed Central

    Clarke, William R.; Grubb, Robert L.; Videen, Tom O.; Adams, Harold P.; Derdeyn, Colin P.

    2014-01-01

    Objective: To determine whether strict blood pressure (BP) control is the best medical management for patients with symptomatic carotid artery occlusion and hemodynamic cerebral ischemia. Methods: In this prospective observational cohort study, we analyzed data from 91 participants in the nonsurgical group of the Carotid Occlusion Surgery Study (COSS) who had recent symptomatic internal carotid artery occlusion and hemodynamic cerebral ischemia manifested by ipsilateral increased oxygen extraction fraction. The target BP goal in COSS was ≤130/85 mm Hg. We compared the occurrence of ipsilateral ischemic stroke during follow-up in the 41 participants with mean BP ≤130/85 mm Hg to the remaining 50 with higher BP. Results: Of 16 total ipsilateral ischemic strokes that occurred during follow-up, 3 occurred in the 41 participants with mean follow-up BP of ≤130/85 mm Hg, compared to 13 in the remaining 50 participants with mean follow-up BP >130/85 mm Hg (hazard ratio 3.742, 95% confidence interval 1.065–13.152, log-rank p = 0.027). Conclusion: BPs ≤130/85 mm Hg were associated with lower subsequent stroke risk in these patients. Classification of evidence: This study provides Class III evidence that control of hypertension ≤130/85 mm Hg is associated with a reduced risk of subsequent ipsilateral ischemic stroke in patients with recently symptomatic carotid occlusion and hemodynamic cerebral ischemia (increased oxygen extraction fraction). PMID:24532276

  20. Pharmacological evaluation of glutamate transporter 1 (GLT-1) mediated neuroprotection following cerebral ischemia/reperfusion injury.

    PubMed

    Verma, Rajkumar; Mishra, Vikas; Sasmal, Dinakar; Raghubir, Ram

    2010-07-25

    Recently glutamate transporters have emerged as a potential therapeutic target in a wide range of acute and chronic neurological disorders, owing to their novel mode of action. The modulation of GLT-1, a major glutamate transporter has been shown to exert neuroprotection in various models of ischemic injury and motoneuron degeneration. Therefore, an attempt was made to explore its neuroprotective potential in cerebral ischemia/reperfusion injury using ceftriaxone, a GLT-1 modulator. Pre-treatment with ceftriaxone (100mg/kg. i.v) for five days resulted in a significant reduction (P<0.01) in neurological deficit as well as cerebral infarct volume after 1h of ischemia followed by 24h of reperfusion injury. It also caused a significant (P<0.05) upregulation of GLT-1 mRNA, protein and glutamine synthetase (GS) activity. Furthermore, inhibition of ceftriaxone-mediated increased glutamine synthetase activity by dihydrokainate (DHK), a GLT-1 specific inhibitor, confirms the specific effect of ceftriaxone on GLT-1 activity. In addition, ceftriaxone also induced a significant (P<0.01) increase in [(3)H]-glutamate uptake, mediated by GLT-1 in glial enriched preparation, as evidenced by use of DHK and DL-threo-beta-benzyloxyaspartate (DL-TBOA). Thus, the present study provides overwhelming evidence that modulation of GLT-1 protein expression and activity confers neuroprotection in cerebral ischemia/reperfusion injury.

  1. Neuroprotective effect of Shenqi Fuzheng injection pretreatment in aged rats with cerebral ischemia/reperfusion injury

    PubMed Central

    Cai, Ying-min; Zhang, Yong; Zhang, Peng-bo; Zhen, Lu-ming; Sun, Xiao-ju; Wang, Zhi-ling; Xu, Ren-yan; Xue, Rong-liang

    2016-01-01

    Shenqi Fuzheng injection is extracted from the Chinese herbs Radix Astragali and Radix Codonopsis. The aim of the present study was to investigate the neuroprotective effects of Shenqi Fuzheng injection in cerebral ischemia and reperfusion. Aged rats (20–22 months) were divided into three groups: sham, model, and treatment. Shenqi Fuzheng injection or saline (40 mL/kg) was injected into the tail vein daily for 1 week, after which a cerebral ischemia/reperfusion injury model was established. Compared with model rats that received saline, rats in the treatment group had smaller infarct volumes, lower brain water and malondialdehyde content, lower brain Ca2+ levels, lower activities of serum lactate dehydrogenase and creatine kinase, and higher superoxide dismutase activity. In addition, the treatment group showed less damage to the brain tissue ultrastructure and better neurological function. Our findings indicate that Shenqi Fuzheng injection exerts neuroprotective effects in aged rats with cerebral ischemia/reperfusion injury, and that the underlying mechanism relies on oxygen free radical scavenging and inhibition of brain Ca2+ accumulation. PMID:26981095

  2. System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia

    PubMed Central

    Zhu, Yan; Guo, Zhili; Zhang, Liangxiao; Zhang, Yingying; Chen, Yinying; Nan, Jingyi; Zhao, Buchang; Xiao, Hongbin; Wang, Zhong; Wang, Yongyan

    2015-01-01

    The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke. PMID:26621314

  3. Total flavonoid of Litsea coreana leve exerts anti-oxidative effects and alleviates focal cerebral ischemia/reperfusion injury

    PubMed Central

    Dong, Shuying; Tong, Xuhui; Li, Jun; Huang, Cheng; Hu, Chengmu; Jiao, Hao; Gu, Yuchen

    2013-01-01

    In this study, we hypothesized that total flavonoid of Litsea coreana leve (TFLC) protects against focal cerebral ischemia/reperfusion injury. TFLC (25, 50, 100 mg/kg) was administered orally to a rat model of focal ischemia/reperfusion injury, while the free radical scavenging agent, edaravone, was used as a positive control drug. Results of neurological deficit scoring, 2,3,5-triphenyl tetrazolium chloride staining, hematoxylin-eosin staining and biochemical tests showed that TFLC at different doses significantly alleviated cerebral ischemia-induced neurological deficits and histopathological changes, and reduced infarct volume. Moreover, it suppressed the increase in the levels of nitrates plus nitrites, malondialdehyde and lactate dehydrogenase, and it diminished the reduction in gluta-thione, superoxide dismutase and catalase activities induced by cerebral ischemia/reperfusion in-jury. Compared with edaravone, the protective effects of TFLC at low and medium doses (25, 50 mg/kg) against cerebral ischemia/reperfusion injury were weaker, while the protective effects at high dose (100 mg/kg) were similar. Our experimental findings suggest that TFLC exerts neuroprotective effects against focal cerebral ischemia/reperfusion injury in rats, and that the effects may be asso-ciated with its antioxidant activities. PMID:25206640

  4. Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats.

    PubMed

    Kondoh, Takashi; Uneyama, Hisayuki; Nishino, Hitoo; Torii, Kunio

    2002-12-20

    Reduction of cerebral edema, an early symptom of ischemia, is one of the most important remedies for reducing subsequent chronic neural damage in stroke. Melatonin, a metabolite of tryptophan released from the pineal gland, has been found to be effective against neurotoxicity in vitro. The present study was aimed to demonstrate the effectiveness of melatonin in vivo in reducing ischemia-induced edema using magnetic resonance imaging (MRI). Rats were subjected to middle cerebral artery (MCA) occlusion/reperfusion surgery. Melatonin was administered twice (6.0 mg/kg, p.o.): just prior to 1 h MCA occlusion and 1 day after the surgery. T2-weighted multislice spin-echo images were acquired 1 day after the surgery. Increases in T2-weighted signals in ischemic sites of the brain were clearly observed after MCA occlusion. The signal increase was found mainly in the striatum and in the cerebral cortex in saline-treated control rats. In the melatonin-treated group, the total volume of cerebral edema was reduced by 45.3% compared to control group (P < 0.01). The protective effect of melatonin against cerebral edema was more clearly observed in the cerebral cortex (reduced by 56.1%, P < 0.01), while the reduction of edema volume in the striatum was weak (reduced by 23.0%). The present MRI study clearly demonstrated that melatonin is effective in reducing edema formation in ischemic animals in vivo, especially in the cerebral cortex. Melatonin may be highly useful in preventing cortical dysfunctions such as motor, sensory, memory, and psychological impairments.

  5. Method of empirical dependences in estimation and prediction of activity of creatine kinase isoenzymes in cerebral ischemia

    NASA Astrophysics Data System (ADS)

    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.

  6. The CB1 antagonist, SR141716A, is protective in permanent photothrombotic cerebral ischemia.

    PubMed

    Reichenbach, Zachary Wilmer; Li, Hongbo; Ward, Sara Jane; Tuma, Ronald F

    2016-09-01

    Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke. We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor. Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury. The CB1 antagonist was found to be protective in this model. As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor. Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment. With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research. PMID:27453059

  7. Does rat global transient cerebral ischemia serve as an appropriate model to study emotional disturbances?

    PubMed

    Bantsiele, Guy Bernard; Bentué-Ferrer, Danièle; Amiot, Noëlla; Allain, Hervé; Bourin, Michel; Reymann, Jean-Michel

    2004-12-01

    We used two validated psychopharmacological methods, the forced swimming test (FST 20 min and 5 min) and the elevated plus-maze (EPM), to quantify depression-like and anxiety-like behavior induced by transient global cerebral ischemia in the rat. We also validated use of these methods for the study of antidepressant (imipramine) and anti-anxiety drugs (diazepam). Twelve days after surgery to provoke transient global ischemia, spontaneous motor activity was 40% higher in ischemic rats than in sham-operated controls. Duration of immobility during the FST 20 min and 5 min was 28 and 30% shorter, respectively, than in controls. Treatment with imipramine (3 x 30 mg/kg i.p.) induced a significantly shorter duration of immobility during the FST 5 min, but with no difference between ischemia and control rats. The EPM demonstrated that ischemia did not induce any change in the six behavior parameters measured. Diazepam (1.5 mg/kg i.p.) induced significant anxiolytic effects which were similar in ischemic and sham-operated animals. Both tests failed to demonstrate perturbed performance but conversely, these findings did disclose the sensitivity of ischemia-exposed rats to the action of imipramine and diazepam, demonstrating the usefulness of these tests as psychopharmocological tools for evaluating the effect of psychotropics in the ischemic rat.

  8. Neuronal damage in hippocampal subregions induced by various durations of transient cerebral ischemia in gerbils using Fluoro-Jade B histofluorescence.

    PubMed

    Yu, Dong-Kun; Yoo, Ki-Yeon; Shin, Bich Na; Kim, In Hye; Park, Joon Ha; Lee, Choong Hyun; Choi, Jung Hoon; Cho, Yong-Jun; Kang, Il-Jun; Kim, Young-Myeong; Won, Moo-Ho

    2012-02-01

    Although there are many studies on ischemic brain damage in the gerbil, which is a good model of transient cerebral ischemia, studies on neuronal damage according to the duration of ischemia-reperfusion (I-R) time are limited. We carried out neuronal damage in the gerbil hippocampus after various durations of I-R (5, 10, 15 and 20 min) using Fluoro-Jade B (F-J B, a maker for neuronal degeneration) histofluorescence as well as cresyl violet (CV) staining. The changes of CV positive ((+)) neurons were well detected in the hippocampal CA1 region, not in the other regions. F-J B histofluorescence staining showed apparent neuronal damage in all the hippocampal subregions. In the CA1, most of the pyramidal neurons of the stratum pyramidale (SP) were stained with F-J B (about 100/mm(2) in a section), and F-J B(+) neurons in the other ischemia-groups were not changed. In the CA2, a few F-J B(+) neurons were detected in the SP of the 5 min ischemia-group, and F-J B(+) neurons were gradually increased with the longer time of ischemia: in the 20 min ischemia-group, the mean number of F-J B(+) neurons was about 85/mm(2) in a section. In the CA3, some F-J B(+) neurons were observed only in the SP of the 20 min ischemia-group. In the dentate gyrus, some F-J B positive neurons were detected only in the polymorphic layer (PL) of the 5 min ischemia-group, and the number of F-J B(+) neurons were gradually increased with the longer ischemic time. Our findings indicate that F-J B histofluorescence showed a very high quality of neuronal damage in all the hippocampal subregions.

  9. Platelet-activating factor receptor (PAFR) plays a crucial role in experimental global cerebral ischemia and reperfusion.

    PubMed

    Toscano, Eliana Cristina de Brito; Silva, Bruno Costa; Victoria, Edna Constaza Gómez; Cardoso, Ana Clara de Souza; Miranda, Aline Silva de; Sugimoto, Michelle Adriane; Sousa, Lirlândia Pires; Carvalho, Bárbara Andrade de; Kangussu, Lucas Miranda; Silva, Daniele Gonçalves da; Rodrigues, Flávia Guimarães; Barcelos, Lucíola da Silva; Vasconcelos, Anilton César; Amaral, Flávio Almeida; Teixeira, Mauro Martins; Teixeira, Antônio Lúcio; Rachid, Milene Alvarenga

    2016-06-01

    Stroke is one of the most frequent causes of death and disability worldwide leading to a significant clinical and socioeconomic burden. Although different mechanisms are involved in the pathogenesis of stroke, inflammatory response occurs after ischemia and contributes to the expansion of brain injury. Platelet-activating factor receptor (PAF) plays crucial roles in both physiological and pathological conditions in the brain. PAF receptor (PAFR) may be expressed on cellular and nuclear membranes of various cell types, especially leukocytes, platelets, endothelial cells, neuronal cells and microglia. Herein, using mice lacking the PAFR receptor (PAFR(-/-)), we investigate a potential role for this receptor during experimental transient global cerebral ischemia and reperfusion (BCCAo). In PAFR deficiency, we observed a significant improvement in the neurological deficits, which were associated with a reduction of brain infarcted area as evaluated by triphenyltetrazolium chloride (TTC). Moreover, a decrease in the percentage of necrotic cavities areas and in the frequency of ischemic neurons was also found by employing histometric analysis. In addition, in PAFR(-/-) mice there was prevention of caspase-3 activation and decreased vascular permeability and brain edema. Decreased brain levels of the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta) and the chemokine (C-X-C motif) ligand 1 (CXCL1) by ELISA were also detected in PAFR(-/-) BCCAo animals. Taken together, our results suggest that PAFR activation might be crucial for the global brain ischemia and reperfusion injury.

  10. Neurological function following cerebral ischemia/reperfusion is improved by the Ruyi Zhenbao pill in a rats

    PubMed Central

    WANG, TIAN; DUAN, SIJIN; WANG, HAIPING; SUN, SHAN; HAN, BING; FU, FENGHUA

    2016-01-01

    The present study aimed to investigate the effect and underlying mechanisms of the Ruyi Zhenbao pill on neurological function following cerebral ischemia/reperfusion in rats. Male Sprague-Dawley rats underwent middle cerebral artery occlusion following reperfusion. The rats received intragastrically either sodium carboxymethyl cellulose (control and model groups) or Ruyi Zhenbao pill at doses of 0.2, 0.4 or 0.8 g/kg. Neurological function was assessed by cylinder, adhesive and beam-walking tests after 14-day Ruyi Zhenbao pill treatment. Neurogenesis and angiogenesis were detected using immunofluorescence staining. The expression levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assays. Treatment with 0.4 and 0.8 g/kg Ruyi Zhenbao for 14 days significantly improved neurological function, and increased the number of von Willebrand Factor- and neuronal nuclear antigen-positive cells in the ischemic hemisphere of rats. Ruyi Zhenbao pill treatment also significantly enhanced the expression levels of BDNF, NGF and VEGF in the ischemic hemisphere. The results demonstrated that the Ruyi Zhenbao pill improved neurological function following ischemia in rats. The mechanisms of the Ruyi Zhenbao pill are associated with increasing the expression levels of BDNF, NGF and VEGF, and subsequently promoting neurogenesis and angiogenesis in the ischemic zone. PMID:26893831

  11. Acute ethanol effects on focal cerebral ischemia in fasted rats.

    PubMed

    Zhao, Y J; Yang, G Y; Ben-Joseph, O; Ross, B D; Chenevert, T L; Domino, E F

    1998-05-01

    The effects of acute ethanol intoxication were investigated in a rat model of unilateral middle cerebral artery occlusion. Groups of 5 to 8 male Sprague-Dawley rats were subjected to 4 hr of left middle cerebral artery occlusion. All groups were deprived of food overnight and were pretreated intraperitoneally with 5% dextrose solution (10 ml/kg), 20% ethyl alcohol in 5% dextrose solution (2 g/kg), or 30% ethyl alcohol in a 5% dextrose solution (3 g/kg) 1 hr before middle cerebral artery occlusion. Regional cerebral blood flow during ipsilateral occlusion was approximately 9.1 to 10% of baseline in all groups. The mean % brain water content in control, 2 g/kg ethanol-treated groups, and 3 g/kg ethanol-treated groups were: in the ischemic core--81.6, 81.2, and 82.4; intermediate zone--80.5, 80.6, and 81.7; and outer zone--79.7, 79.7, and 80.8, respectively. Brain Na+ and K+ content in the three groups was related to water content, but much greater with ethanol pretreatment. The water content of the intermediate zones in the 3 g/kg ethanol-treated animals was significantly greater than in the control (p < 0.01 and 0.001) and the 2 g/kg ethanol-treated groups. One-way analysis of variance indicated a significant dose-effect relationship in which the lower dose of ethanol tended to reduce ischemic core water content, and the larger dose increased ischemic core water, compared with the control. None of the overnight fasted groups had any significant hyperglycemia. The group given 3 g/kg i.p. ethanol 1 hr before had exacerbated edema formation with a mean whole blood level of ethanol of approximately 230 mg/dl. The neurotoxic effects of high concentrations of ethanol were unrelated to any change in plasma glucose concentrations.

  12. Luoyutong Treatment Promotes Functional Recovery and Neuronal Plasticity after Cerebral Ischemia-Reperfusion Injury in Rats

    PubMed Central

    Wang, Ning-qun; Wang, Li-ye; Zhao, Hai-ping; Liu, Ping; Wang, Rong-liang; Song, Jue-xian; Gao, Li; Ji, Xun-ming; Luo, Yu-min

    2015-01-01

    Luoyutong (LYT) capsule has been used to treat cerebrovascular diseases clinically in China and is now patented and approved by the State Food and Drug Administration. In this retrospective validation study we investigated the ability of LYT to protect against cerebral ischemia-reperfusion injury in rats. Cerebral ischemia-reperfusion injury was induced by middle cerebral artery occlusion followed by reperfusion. Capsule containing LYT (high dose and medium dose) as treatment group and Citicoline Sodium as positive control treatment group were administered daily to rats 30 min after reperfusion. Treatment was continued for either 3 days or 14 days. A saline solution was administered to control animals. Behavior tests were performed after 3 and 14 days of treatment. Our findings revealed that LYT treatment improved the neurological outcome, decreased cerebral infarction volume, and reduced apoptosis. Additionally, LYT improved neural plasticity, as the expression of synaptophysin, microtubule associated protein, and myelin basic protein was upregulated by LYT treatment, while neurofilament 200 expression was reduced. Moreover, levels of brain derived neurotrophic factor and basic fibroblast growth factor were increased. Our results suggest that LYT treatment may protect against ischemic injury and improve neural plasticity. PMID:26697095

  13. Neuroprotective effect of Cerebralcare Granule after cerebral ischemia/reperfusion injury

    PubMed Central

    Zhang, Xiao-xiao; He, Fen-fen; Yan, Gui-lin; Li, Ha-ni; Li, Dan; Ma, Yan-ling; Wang, Fang; Xu, Nan; Cao, Fei

    2016-01-01

    Cerebralcare Granule (CG) improves cerebral microcirculation and relieves vasospasm, but studies investigating its therapeutic effect on cerebral ischemia/reperfusion injury are lacking. In the present study, we administered CG (0.3, 0.1 and 0.03 g/mL intragastrically) to rats for 7 consecutive days. We then performed transient occlusion of the middle cerebral artery, followed by reperfusion, and administered CG daily for a further 3 or 7 days. Compared with no treatment, high-dose CG markedly improved neurological function assessed using the Bederson and Garcia scales. At 3 days, animals in the high-dose CG group had smaller infarct volumes, greater interleukin-10 expression, and fewer interleukin-1β-immunoreactive cells than those in the untreated model group. Furthermore, at 7 days, high-dose CG-treated rats had more vascular endothelial growth factor-immunoreactive cells, elevated angiopoietin-1 and vascular endothelial growth factor expression, and improved blood coagulation and flow indices compared with untreated model animals. These results suggest that CG exerts specific neuroprotective effects against cerebral ischemia/reperfusion injury. PMID:27212924

  14. Misoprostol, an anti-ulcer agent and PGE2 receptor agonist, protects against cerebral ischemia

    PubMed Central

    Li, Jun; Liang, Xibin; Wang, Qian; Breyer, Richard M.; McCullough, Louise; Andreasson, Katrin

    2008-01-01

    Induction of COX-2 activity in cerebral ischemia results in increased neuronal injury and infarct size. Recent studies investigating neurotoxic mechanisms of COX-2 demonstrate both toxic and paradoxically protective effects of downstream prostaglandin receptor signaling pathways. We tested whether misoprostol, a PGE2 receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE2 EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion–reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2 h after MCAO, resulted in significant rescue of infarct volume at 24 and 72 h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3−/− mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3−/− mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE2 EP2 and/or EP4 receptors. PMID:18472336

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

    PubMed Central

    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-hour transient MCAO produced by intraluminal suture blockade followed by 23 hours of reperfusion. In nine AQP4+/+ and nine AQP4−/− mice, infarct volume was significantly reduced by an average of 39 ± 4 % at 24 hours 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. PMID:25449874

  16. Electroacupuncture Ameliorates Cerebral Ischemia-Reperfusion Injury by Regulation of Autophagy and Apoptosis

    PubMed Central

    Shu, Shi; Li, Chun-Ming; You, Yan-Li; Qian, Xiao-Lu

    2016-01-01

    Background. The therapeutic mechanisms of cerebral ischemia treatment by acupuncture are yet not well addressed. Objective. We investigated the effects of electroacupuncture (EA) at GV26 observing the expression of autophagy-related proteins Beclin-1 and LC3B and proportion of apoptotic cells and Bcl-2 positive cells in MCAO/R model rats. Methods. Sprague-Dawley (SD) male rats were randomly assigned to 7 groups: model groups (M6h, M24h, and M72h), EA treatment groups (T6h, T24h, and T72h), and sham operation group (S). Neurological deficit and cerebral infarction volume were measured to assess the improvement effect, while the expression of Beclin-1 and LC3B and proportion of Tunel-positive and Bcl-2 positive cells were examined to explore EA effect on autophagy and apoptosis. Results. EA significantly decreased neurological deficit scores and the volume of cerebral infarction. Beclin-1 was significantly decreased in T24h, while LC3B-II/LC3B-I ratio markedly reduced in 6th hour. EA groups markedly reduced the number of Tunel positive cells, especially in T24h. Meanwhile, the number of Bcl-2 positive cells obviously increased after EA treatment, especially in T6h and T24h. Conclusions. The alleviation of inadequate autophagy and apoptosis may be a key mechanism involved in the reflex regulation of EA at GV26 to treat cerebral ischemia. PMID:27800003

  17. Time course of motor and cognitive functions after chronic cerebral ischemia in rats.

    PubMed

    Damodaran, Thenmoly; Hassan, Zurina; Navaratnam, Visweswaran; Muzaimi, Mustapha; Ng, Gandi; Müller, Christian P; Liao, Ping; Dringenberg, Hans C

    2014-12-15

    Cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequent occurrence of irreversible brain damage and subsequent loss of neuronal function which lead to cognitive impairment and some motor dysfunction. In the present study, the real time course of motor and cognitive functions were evaluated following the chronic cerebral ischemia induced by permanent, bilateral occlusion of the common carotid arteries (PBOCCA). Male Sprague Dawley rats (200-300g) were subjected to PBOCCA or sham-operated surgery and tested 1, 2, 3 and 4 weeks following the ischemic insult. The results showed that PBOCCA significantly reduced step-through latency in a passive avoidance task at all time points when compared to the sham-operated group. PBOCCA rats also showed significant increase in escape latencies during training in the Morris water maze, as well as a reduction of the percentage of times spend in target quadrant of the maze at all time points following the occlusion. Importantly, there were no significant changes in locomotor activity between PBOCCA and sham-operated groups. The BDNF expression in the hippocampus was 29.3±3.1% and 40.1±2.6% on day 14 and 28 post PBOCCA, respectively compared to sham-operated group. Present data suggest that the PBOCCA procedure effectively induces behavioral, cognitive symptoms associated with cerebral ischemia and, consequently, provides a valuable model to study ischemia and related neurodegenerative disorder such as Alzheimer's disease and vascular dementia. PMID:25239606

  18. Post-ischemic salubrinal treatment results in a neuroprotective role in global cerebral ischemia.

    PubMed

    Anuncibay-Soto, Berta; Pérez-Rodríguez, Diego; Santos-Galdiano, María; Font, Enrique; Regueiro-Purriños, Marta; Fernández-López, Arsenio

    2016-07-01

    This study describes the neuroprotective effect of treatment with salubrinal 1 and 24 h following 15 min of ischemia in a two-vessel occlusion model of global cerebral ischemia. The purpose of this study was to determine if salubrinal, an enhancer of the unfolded protein response, reduces the neural damage modulating the inflammatory response. The study was performed in CA1 and CA3 hippocampal areas as well as in the cerebral cortex whose different vulnerability to ischemic damage is widely described. Characterization of proteins was made by western blot, immunofluorescence, and ELISA, whereas mRNA levels were measured by Quantitative PCR. The salubrinal treatment decreased the cell demise in CA1 at 7 days as well as the levels of matrix metalloprotease 9 (MMP-9) in CA1 and cerebral cortex at 48 h and ICAM-1 and VCAM-1 cell adhesion molecules. However, increases in tumor necrosis factor α and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory markers were observed at 24 h. Glial fibrillary acidic protein levels were not modified by salubrinal treatment in CA1 and cerebral cortex. We describe a neuroprotective effect of the post-ischemic treatment with salubrinal, measured as a decrease both in CA1 cell demise and in the blood-brain barrier impairment. We hypothesize that the ability of salubrinal to counteract the CA1 cell demise is because of a reduced ability of this structure to elicit unfolded protein response which would account for its greater ischemic vulnerability. Data of both treated and non-treated animals suggest that the neurovascular unit present a structure-dependent response to ischemia and a different course time for CA1/cerebral cortex compared with CA3. Finally, our study reveals a high responsiveness of endothelial cells to salubrinal in contrast to the limited responsiveness of astrocytes. The alleviation of ER stress by enhancing UPR with salubrinal treatment reduces the ischemic damage. This effect

  19. Post-ischemic salubrinal treatment results in a neuroprotective role in global cerebral ischemia.

    PubMed

    Anuncibay-Soto, Berta; Pérez-Rodríguez, Diego; Santos-Galdiano, María; Font, Enrique; Regueiro-Purriños, Marta; Fernández-López, Arsenio

    2016-07-01

    This study describes the neuroprotective effect of treatment with salubrinal 1 and 24 h following 15 min of ischemia in a two-vessel occlusion model of global cerebral ischemia. The purpose of this study was to determine if salubrinal, an enhancer of the unfolded protein response, reduces the neural damage modulating the inflammatory response. The study was performed in CA1 and CA3 hippocampal areas as well as in the cerebral cortex whose different vulnerability to ischemic damage is widely described. Characterization of proteins was made by western blot, immunofluorescence, and ELISA, whereas mRNA levels were measured by Quantitative PCR. The salubrinal treatment decreased the cell demise in CA1 at 7 days as well as the levels of matrix metalloprotease 9 (MMP-9) in CA1 and cerebral cortex at 48 h and ICAM-1 and VCAM-1 cell adhesion molecules. However, increases in tumor necrosis factor α and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory markers were observed at 24 h. Glial fibrillary acidic protein levels were not modified by salubrinal treatment in CA1 and cerebral cortex. We describe a neuroprotective effect of the post-ischemic treatment with salubrinal, measured as a decrease both in CA1 cell demise and in the blood-brain barrier impairment. We hypothesize that the ability of salubrinal to counteract the CA1 cell demise is because of a reduced ability of this structure to elicit unfolded protein response which would account for its greater ischemic vulnerability. Data of both treated and non-treated animals suggest that the neurovascular unit present a structure-dependent response to ischemia and a different course time for CA1/cerebral cortex compared with CA3. Finally, our study reveals a high responsiveness of endothelial cells to salubrinal in contrast to the limited responsiveness of astrocytes. The alleviation of ER stress by enhancing UPR with salubrinal treatment reduces the ischemic damage. This effect

  20. Neuroprotective effects of Ilexonin A following transient focal cerebral ischemia in rats

    PubMed Central

    XU, AI-LING; ZHENG, GUAN-YI; WANG, ZHI-JIAN; CHEN, XIAO-DONG; JIANG, QIONG

    2016-01-01

    Ilexonin A is a compound isolated from the root of a plant commonly used in traditional Chinese medicine. The aim of the present study was to investigate the possible protective mechanism of Ilexonin A in rats subjected to occlusion of the middle cerebral artery (MCAO). Transient focal cerebral ischemia was induced by 2 h of MCAO, followed by reperfusion. Ilexonin A at doses of 20, 40 and 80 mg/kg were administered via intraperitoneal injection immediately following ischemia/reperfusion. The expression levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule-1 (Iba-1), vascular endothelial growth factor (VEGF), fetal liver kinase-1 (Flk-1) and Nestin were examined using immunostaining and Western blot analysis of the peri-infarct region following ischemia/reperfusion. Ilexonin A significantly decreased the infarct volume and improved neurological deficits in a dose-dependent manner. The expression levels of VEGF, Flk-1 and Nestin were significantly increased in the rats treated with Ilexonin A, compared with the rats administered with saline. Following treatment with Ilexonin A, a higher number of GFAP-positive astrocytes were found in the Ilexonin A-treated rats at 1, 3 and 7 days, compared with the rats exposed to ischemia only, however, there were fewer astrocytes at 14 days, compared with the ischemia group. Ilexonin A significantly decreased the protein expression of Iba-1. The results of the present study suggested that the protective effects of Ilexonin A were associated with revascularization, neuronal regeneration, and the regulation of astrocyte and microglia cell activation. PMID:26936330

  1. Enhancement of an outwardly rectifying chloride channel in hippocampal pyramidal neurons after cerebral ischemia.

    PubMed

    Li, Jianguo; Chang, Quanzhong; Li, Xiaoming; Li, Xiawen; Qiao, Jiantian; Gao, Tianming

    2016-08-01

    Cerebral ischemia induces delayed, selective neuronal death in the CA1 region of the hippocampus. The underlying molecular mechanisms remain unclear, but it is known that apoptosis is involved in this process. Chloride efflux has been implicated in the progression of apoptosis in various cell types. Using both the inside-out and whole-cell configurations of the patch-clamp technique, the present study characterized an outwardly rectifying chloride channel (ORCC) in acutely dissociated pyramid neurons in the hippocampus of adult rats. The channel had a nonlinear current-voltage relationship with a conductance of 42.26±1.2pS in the positive voltage range and 18.23±0.96pS in the negative voltage range, indicating an outward rectification pattern. The channel is Cl(-) selective, and the open probability is voltage-dependent. It can be blocked by the classical Cl(-) channel blockers DIDS, SITS, NPPB and glibenclamide. We examined the different changes in ORCC activity in CA1 and CA3 pyramidal neurons at 6, 24 and 48h after transient forebrain ischemia. In the vulnerable CA1 neurons, ORCC activity was persistently enhanced after ischemic insult, whereas in the invulnerable CA3 neurons, no significant changes occurred. Further analysis of channel kinetics suggested that multiple openings are a major contributor to the increase in channel activity after ischemia. Pharmacological blockade of the ORCC partly attenuated cell death in the hippocampal neurons. We propose that the enhanced activity of ORCC might contribute to selective neuronal damage in the CA1 region after cerebral ischemia, and that ORCC may be a therapeutic target against ischemia-induced cell death. PMID:27181516

  2. Protective effect of Spatholobus suberectus on brain tissues in cerebral ischemia

    PubMed Central

    Zhang, Rui; Liu, Cui; Liu, Xuejun; Guo, Yunliang

    2016-01-01

    Cerebral ischemia is the major causes the neuronal damages throughout the world. Present investigation evaluates the neuroprotective effect of (SS) in cerebral ischemic rat. All the rats were separated in to four group such as control group, ischemia/reperfusion (I/R) group and Spatholobus suberectus (100 and 200 mg/kg, p.o.) treated group which receives extract for 15 days prior to I/R. At the end of protocol all the rats were sacrificed and brain was isolated for the biochemical estimation. Further, oxidative stress was estimated by measuring the level of malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GPX) in the brain tissue. Moreover other parameters like cytokine (IL-10 and TNF-α), nuclear factor kappa B p65 (NF-κB), caspase 3, brain ATP level and DNA damage by comet assay was estimated in the brain tissues of cerebral ischemic rats. Result of the study suggested that treatment with Spatholobus suberectus significantly (P<0.01) decreases the MDA and NO level and increases in the activity of SOD and GPX in the brain tissues of cerebral ischemic rats compared to I/R rats. Moreover, treatment with SS significantly increases the expressions of IL-10 and brain ATP and decreases the expressions of TNF-α, caspase 3 and NF-κB in the brain tissues of cerebral ischemic rats compared to I/R rats. Comet assay also postulates that SS treated rats brain shows less DNA damage than ischemic rats. Present study concludes the neuroprorective effect of Spatholobus suberectus in cerebral ischemic rats by its antioxidant, anti apoptotic and anti-inflammatory activity. PMID:27725876

  3. Serine Racemase Deletion Protects Against Cerebral Ischemia And Excitotoxicity

    PubMed Central

    Mustafa, Asif K.; Ahmad, Abdullah S.; Zeynalov, Emil; Gazi, Sadia K.; Sikka, Gautam; Ehmsen, Jeffrey T.; Barrow, Roxanne K.; Coyle, Joseph T.; Snyder, Solomon H.; Doré, Sylvain

    2010-01-01

    D-serine, formed from L-serine by serine racemase (SR), is a physiologic co-agonist at NMDA receptors. Using mice with targeted deletion of SR, we demonstrate a role for D-serine in NMDA receptor mediated neurotoxicity and stroke. Brain cultures of SR deleted mice display markedly diminished nitric oxide (NO) formation and neurotoxicity. In intact SR knockout mice NO formation and nitrosylation of NO targets are substantially reduced. Infarct volume following middle cerebral artery occlusion is dramatically diminished in several regions of the brains of SR mutant mice despite evidence of increased NMDA receptor number and sensitivity. PMID:20107067

  4. PPAR{gamma} agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

    SciTech Connect

    Lee, Seong-Ryong; Kim, Hahn-Young; Hong, Jung-Suk; Baek, Won-Ki; Park, Jong-Wook

    2009-02-27

    Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonist, has shown protective effects against ischemic insult in various tissues. Pioglitazone is also reported to reduce matrix metalloproteinase (MMP) activity. MMPs can remodel extracellular matrix components in many pathological conditions. The current study was designed to investigate whether the neuroprotection of pioglitazone is related to its MMP inhibition in focal cerebral ischemia. Mice were subjected to 90 min focal ischemia and reperfusion. In gel zymography, pioglitazone reduced the upregulation of active form of MMP-9 after ischemia. In in situ zymograms, pioglitazone also reduced the gelatinase activity induced by ischemia. After co-incubation with pioglitazone, in situ gelatinase activity was directly reduced. Pioglitazone reduced the infarct volume significantly compared with controls. These results demonstrate that pioglitazone may reduce MMP-9 activity and neuronal damage following focal ischemia. The reduction of MMP-9 activity may have a possible therapeutic effect for the management of brain injury after focal ischemia.

  5. Glycogen Synthase Kinase 3β Influences Injury Following Cerebral Ischemia/Reperfusion in Rats.

    PubMed

    Li, Yixin; Zhu, Jin; Liu, Yuanling; Chen, Xi; Lei, Shipeng; Li, Lingyu; Jiang, Beibei; Tan, Li; Yu, Shanshan; Zhao, Yong

    2016-01-01

    Abnormal activation of GSK-3β is associated with psychiatric and neurodegenerative disorders. However, no study has examined the effect of GSK-3β on cerebral ischemia/reperfusion injury. We used oxygen-glucose deprivation/reoxygenation (OGD/R) and middle cerebral artery occlusion (MCAO) as models of ischemia/reperfusion in rats in vitro and in vivo. Our study showed that knockdown of GSK-3β with a GSK-3β siRNA virus improved injury and increased viability of neurons subjected to OGD/R. Levels of total Nrf2, nuclear Nrf2, and Nrf2 downstream proteins sulfiredoxin (Srx1) and thioredoxin (Trx1) increased after transfection with the GSK-3β siRNA virus. GSK-3β siRNA increased SOD activity and decreased MDA levels. Overexpression of GSK-3β with a pcDNA-GSK-3β virus showed opposite results. We also demonstrated that intracerebroventricular injection of GSK-3β siRNA in rats ameliorated neurological deficits, reduced brain infarct volume and water content, and reduced damage to cerebral cortical neurons after MCAO. Changes in total Nrf2, nuclear Nrf2, Srx1, Trx1, SOD, and MDA were similar to those observed in vitro. Our results show for the first time that GSK-3β can influence cerebral ischemia/reperfusion injury. The effects may be due to regulating the Nrf2/ARE pathway and decreasing oxidative stress. These results suggest a potential new drug target for clinical treatment of stroke. PMID:27019634

  6. Spatiotemporal expression of Nogo-66 receptor after focal cerebral ischemia

    PubMed Central

    Cao, Yue; Dong, Ya-xian; Xu, Jie; Chu, Guo-liang; Yang, Zhi-hua; Liu, Yan-ming

    2016-01-01

    NgR, the receptor for the neurite outgrowth inhibitor Nogo-66, plays a critical role in the plasticity and regeneration of the nervous system after injury such as ischemic stroke. In the present study, we used immunohistochemistry to investigate the regional expression of NgR in rat brain following middle cerebral artery occlusion (MCAO). NgR protein expression was not observed in the center of the lesion, but was elevated in the marginal zone compared with control and sham-operated rats. The cerebral cortex and hippocampus (CA1, CA2, and CA3) showed the greatest expression of NgR. Furthermore, NgR expression was higher in the ipsilesional hemisphere than on the control side in the same coronal section. Although time-dependent changes in NgR expression across brain regions had their own characteristics, the overall trend complied with the following rules: NgR expression changes with time showed two peaks and one trough; the first peak in expression appeared between 1 and 3 days after MCAO; expression declined at 5 days; and the second peak occurred at 28 days. PMID:26981102

  7. Evaluation of Aged Garlic Extract Neuroprotective Effect in a Focal Model of Cerebral Ischemia

    NASA Astrophysics Data System (ADS)

    Aguilera, Penélope; Maldonado, Perla D.; Ortiz-Plata, Alma; Barrera, Diana; Chánez-Cárdenas, María Elena

    2008-02-01

    The oxidant species generated in cerebral ischemia have been implicated as important mediators of neuronal injury through damage to lipids, DNA, and proteins. Since ischemia as well as reperfusion insults generate oxidative stress, the administration of antioxidants may limit oxidative damage and ameliorate disease progression. The present work shows the transitory neuroprotective effect of the aged garlic extract (AGE) administration (a proposed antioxidant compound) in a middle cerebral artery occlusion (MCAO) model in rats and established its therapeutic window. To determine the optimal time of administration, animal received AGE (1.2 mL/kg) intraperitoneally 30 min before onset of reperfusion (-0.5 R), at the beginning of reperfusion (0R), or 1 h after onset of reperfusion (1R). Additional doses were administrated after 1, 2, or 3 h after onset of reperfusion. To establish the therapeutic window of AGE, the infarct area was determined for each treatment after different times of reperfusion. Results show that the administration of AGE at the onset of reperfusion reduced the infarct area by 70% (evaluated after 2 h reperfusion). The therapeutic window of AGE was determined. Repeated doses did not extend the temporal window of protection. A significant reduction in the nitrotyrosine level was observed in the brain tissue subjected to MCAO after AGE treatment at the onset of reperfusion. Data in the present work show that AGE exerts a transitory neuroprotective effect in response to ischemia/reperfusion-induced neuronal injury.

  8. Neuroprotective Effects of Isosteviol Sodium Injection on Acute Focal Cerebral Ischemia in Rats

    PubMed Central

    Hu, Hui; Sun, Xiao ou; Tian, Fang; Zhang, Hao; Liu, Qing; Tan, Wen

    2016-01-01

    Previous report has indicated that isosteviol has neuroprotective effects. However, isosteviol was administered preventively before ischemia and the inclusion criteria were limited. In the present study, a more soluble and injectable form of isosteviol sodium (STVNA) was administered intravenously hours after transient or permanent middle cerebral artery occlusion (tMCAO or pMCAO) to investigate its neuroprotective effects in rats. The rats were assessed for neurobehavioral deficits 24 hours after ischemia and sacrificed for infarct volume quantification and histology evaluation. STVNA 10 mg·kg−1 can significantly reduce the infarct volumes compared with vehicle in animals subjected to tMCAO and is twice as potent as previously reported. Additionally, the therapeutic window study showed that STVNA could reduce the infarct volume compared with the vehicle group when administered 4 hours after reperfusion. A similar effect was also observed in animals treated 4 hours after pMCAO. Assessment of neurobehavioral deficits after 24 hours showed that STVNA treatment significantly reduced neurobehavioral impairments. The number of restored NeuN-labeled neurons was increased and the number of TUNEL positive cells was reduced in animals that received STVNA treatment compared with vehicle group. All of these findings suggest that STVNA might provide therapeutic benefits against cerebral ischemia-induced injury. PMID:27047634

  9. Changes in the expression of DNA-binding/differentiation protein inhibitors in neurons and glial cells of the gerbil hippocampus following transient global cerebral ischemia

    PubMed Central

    LEE, JAE-CHUL; CHEN, BAI HUI; CHO, JEONG-HWI; KIM, IN HYE; AHN, JI HYEON; PARK, JOON HA; TAE, HYUN-JIN; CHO, GEUM-SIL; YAN, BING CHUN; KIM, DAE WON; HWANG, IN KOO; PARK, JINSEU; LEE, YUN LYUL; CHOI, SOO YOUNG; WON, MOO-HO

    2015-01-01

    Inhibitors of DNA-binding/differentiation (ID) proteins bind to basic helix-loop-helix (bHLH) transcription factors, including those that regulate differentiation and cell-cycle progression during development, and regulate gene transcription. However, little is known about the role of ID proteins in the brain under transient cerebral ischemic conditions. In the present study, we examined the effects of ischemia-reperfusion (I-R) injury on the immunoreactivity and protein levels of IDs 1–4 in the gerbil hippocampus proper Cornu Ammonis regions CA1–3 following 5 min of transient cerebral ischemia. Strong ID1 immunoreactivity was detected in the nuclei of pyramidal neurons in the hippocampal CA1–3 regions; immunoreactivity was significantly changed following I-R in the CA1 region, but not in the CA2/3 region. Five days following I-R, ID1 immunoreactivity was not detected in the CA1 pyramidal neurons. ID1 immunoreactivity was detected only in GABAergic interneurons in the ischemic CA1 region. Weak ID4 immunoreactivity was detected in non-pyramidal cells, and immunoreactivity was again only changed in the ischemic CA1 region. Five days following I-R, strong ID4 immunoreactivity was detected in non-pyramidal cells, which were identified as microglia, and not astrocytes, in the ischemic CA1 region. Furthermore, changes in the protein levels of ID1 and ID4 in the ischemic CA1 region studied by western blot were consistent with patterns of immunoreactivity. In summary, these results indicate that immunoreactivity and protein levels of ID1 and ID4 are distinctively altered following transient cerebral ischemia only in the CA1 region, and that the changes in ID1 and ID4 expression may relate to the ischemia-induced delayed neuronal death. PMID:25503067

  10. Evaluation of combination therapy in animal models of cerebral ischemia.

    PubMed

    O'Collins, Victoria E; Macleod, Malcolm R; Donnan, Geoffrey A; Howells, David W

    2012-04-01

    Combination therapy has been identified as a promising strategy to improve stroke management. We conducted a systematic review and meta-analysis of evidence from animal models of ischemic stroke to determine whether combining treatments improved efficacy. Multiple databases were searched and data were extracted from focal ischemia experiments comparing control groups, single treatments, and combination treatments. Of 11,430 papers identified, 142 met the inclusion criteria; these tested 126 treatments in 373 experiments using 8,037 animals (I(2)=85 to 96%). Taken together, single treatments reduced infarct size by 20% and improved neurological score by 12% compared with control; a second therapy improved efficacy by an additional 18% and 25%, respectively. Publication bias may affect combination efficacy for infarct size but not neurological score. Combining thrombolysis with other therapies may extend the time window from 4.4 to 8 hours in animal models, although testing beyond 6 hours is required to confirm this. Benefits of additional therapy decreased as the efficacy of the primary treatment increased, with combination efficacy reaching a ceiling at 60% to 80% protection. Combining treatments may bring benefits and extend the time window for treatment. More evidence is needed due to potential publication bias and heterogeneity.

  11. Cerebral ischemia initiates an immediate innate immune response in neonates during cardiac surgery

    PubMed Central

    2013-01-01

    Background A robust inflammatory response occurs in the hours and days following cerebral ischemia. However, little is known about the immediate innate immune response in the first minutes after an ischemic insult in humans. We utilized the use of circulatory arrest during cardiac surgery to assess this. Methods Twelve neonates diagnosed with an aortic arch obstruction underwent cardiac surgery with cardiopulmonary bypass and approximately 30 minutes of deep hypothermic circulatory arrest (DHCA, representing cerebral ischemia). Blood samples were drawn from the vena cava superior immediately after DHCA and at various other time points from preoperatively to 24 hours after surgery. The innate immune response was assessed by neutrophil and monocyte count and phenotype using FACS, and concentrations of cytokines IL-1β, IL-6, IL-8, IL-10, TNFα, sVCAM-1 and MCP-1 were assessed using multiplex immunoassay. Results were compared to a simultaneously drawn sample from the arterial cannula. Twelve other neonates were randomly allocated to undergo the same procedure but with continuous antegrade cerebral perfusion (ACP). Results Immediately after cerebral ischemia (DHCA), neutrophil and monocyte counts were higher in venous blood than arterial (P = 0.03 and P = 0.02 respectively). The phenotypes of these cells showed an activated state (both P <0.01). Most striking was the increase in the ‘non-classical’ monocyte subpopulations (CD16intermediate; arterial 6.6% vs. venous 14%; CD16+ 13% vs. 22%, both P <0.01). Also, higher IL-6 and lower sVCAM-1 concentrations were found in venous blood (both P = 0.03). In contrast, in the ACP group, all inflammatory parameters remained stable. Conclusions In neonates, approximately 30 minutes of cerebral ischemia during deep hypothermia elicits an immediate innate immune response, especially of the monocyte compartment. This phenomenon may hold important clues for the understanding of the inflammatory response to stroke and its

  12. PUMA is invovled in ischemia/reperfusion-induced apoptosis of mouse cerebral astrocytes.

    PubMed

    Chen, H; Tian, M; Jin, L; Jia, H; Jin, Y

    2015-01-22

    PUMA (p53-upregulated modulator of apoptosis), a BH3-only member of the Bcl-2 protein family, is required for p53-dependent and p53-independent forms of apoptosis. PUMA has been invovled in the onset and progress of several diseases, including cancer, acquired immunodeficiency syndrome, and ischemic brain disease. Although many studies have shown that ischemia and reperfusion (I/R) can induce the apoptosis of astrocytes, the role of PUMA in I/R-mediated apoptosis of cerebral astrocyte apoptosis remains unclear. To mimic in vivo I/R conditions, primary mouse cerebral astrocytes were incubated in a combinational cultural condition of oxygen, glucose, and serum deprivation (OSGD) for 1 h followed by reperfusion (OSGD/R). Cell death determination assays and cell viability assays indicated that OSGD and OSGD/R induce the apoptosis of primary cerebral astrocytes. The expression of PUMA was significantly elevated in primary cerebral astrocytes during OSGD/R. Moreover, targeted down-regulation of PUMA by siRNA transfection significantly decreased the OSGD/R-induced apoptosis of primary cerebral astrocytes. We also found that OSGD and OSGD/R triggered the release of cytochrome c in astrocytes, indicating the dependence on a mitochondrial apoptotic pathway. Reactive oxygen species (ROS) was extremely generated during OSGD and OSGD/R, and the elimination of ROS by treated with N-acetyl-L-cysteine (NAC) remarkably inhibited the expression of PUMA and the apoptosis of primary cerebral astrocytes. The activation of Caspase 3 and Caspase 9 was extremely elevated in primary cerebral astrocytes during OSGD. In addition, we found that knockdown of PUMA led to the depressed expression of Bax, cleaved caspase-9 and caspase-3 during OSGD/R. These results indicate that PUMA is invovled in the apoptosis of cerebral astrocytes upon I/R injury.

  13. Activation of the calcium-sensing receptor promotes apoptosis by modulating the JNK/p38 MAPK pathway in focal cerebral ischemia-reperfusion in mice

    PubMed Central

    Zhen, Yilan; Ding, Caijuan; Sun, Jiaqiang; Wang, Yanan; Li, Sheng; Dong, Liuyi

    2016-01-01

    Exact mechanism of cerebral ischemic stroke remains unclear. The calcium-sensing receptor (CaSR), a G-protein coupled receptor, has been reported to participate in the pathology of myocardial ischemia-reperfusion (I/R) injury and myocardial hypertrophy. Nevertheless, only a limited number of studies have been conducted to investigate the role of CaSR in cerebral ischemic stroke. This study was to investigate the effect of CaSR activation on cerebral ischemic stroke. Male adult Kunming mice were subjected to 2-h focal cerebral ischemia followed by 22-h reperfusion. Then, the brain was collected, and the expression of CaSR, JNK, p38, Bcl-2, and Bax was detected by Western blot assay. The morphology of neurons in the brain was evaluated by HE staining. Neurological function was scored, and the infarct volume was determined by TTC (triphenyltetrazolium chloride) staining. Results showed that ischemia/reperfusion (I/R) increased CaSR expression and induced neuronal apoptosis in the brain. Gadolinium trichloride (GdCl3), an agonist of CaSR, further deteriorated neurological dysfunction, increased infarct volume, enhanced CaSR expression, and promoted neuronal apoptosis. In addition, GdCl3 unregulated expression of Bax, p-JNK, and p-p38, and down-regulated Bcl-2 expression during I/R, which were attenuated by NPS2390, an inhibitor of CaSR. In conclusion, the CaSR activation promotes apoptosis in focal cerebral I/R in mice, which may be related to the activation of JNK/p38 MAPK signalling pathway. Targeting CaSR may be a novel strategy for the prevention and treatment of cerebral ischemic stroke. PMID:27158378

  14. The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia

    PubMed Central

    Choy, Fong Chan; Klarić, Thomas S.; Koblar, Simon A.; Lewis, Martin D.

    2015-01-01

    Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies. PMID:26690124

  15. Prenatal ischemia deteriorates white matter, brain organization, and function: implications for prematurity and cerebral palsy.

    PubMed

    Coq, Jacques-Olivier; Delcour, Maxime; Massicotte, Vicky S; Baud, Olivier; Barbe, Mary F

    2016-03-01

    Cerebral palsy (CP) describes a group of neurodevelopmental disorders of posture and movement that are frequently associated with sensory, behavioral, and cognitive impairments. The clinical picture of CP has changed with improved neonatal care over the past few decades, resulting in higher survival rates of infants born very preterm. Children born preterm seem particularly vulnerable to perinatal hypoxia-ischemia insults at birth. Animal models of CP are crucial for elucidating underlying mechanisms and for development of strategies of neuroprotection and remediation. Most animal models of CP are based on hypoxia-ischemia around the time of birth. In this review, we focus on alterations of brain organization and functions, especially sensorimotor changes, induced by prenatal ischemia in rodents and rabbits, and relate these alterations to neurodevelopmental disorders found in preterm children. We also discuss recent literature that addresses the relationship between neural and myelin plasticity, as well as possible contributions of white matter injury to the emergence of brain dysfunctions induced by prenatal ischemia.

  16. Trefoil Factor 3 as an Endocrine Neuroprotective Factor from the Liver in Experimental Cerebral Ischemia/Reperfusion Injury

    PubMed Central

    Liu, Shu Q.; Roberts, Derek; Zhang, Brian; Ren, Yupeng; Zhang, Li-Qun; Wu, Yu H.

    2013-01-01

    Cerebral ischemia, while causing neuronal injury, can activate innate neuroprotective mechanisms, minimizing neuronal death. In this report, we demonstrate that experimental cerebral ischemia/reperfusion injury in the mouse causes upregulation of the secretory protein trefoil factor 3 (TFF3) in the hepatocyte in association with an increase in serum TFF3. Partial hepatectomy (~60% liver resection) immediately following cerebral injury significantly lowered the serum level of TFF3, suggesting a contribution of the liver to the elevation of serum TFF3. Compared to wild-type mice, TFF3-/- mice exhibited a significantly higher activity of caspase 3 and level of cell death in the ischemic cerebral lesion, a larger fraction of cerebral infarcts, and a smaller fraction of the injured cerebral hemisphere, accompanied by severer forelimb motor deficits. Intravenous administration of recombinant TFF3 reversed changes in cerebral injury and forelimb motor function due to TFF3 deficiency. These observations suggest an endocrine neuroprotective mechanism involving TFF3 from the liver in experimental cerebral ischemia/reperfusion injury. PMID:24204940

  17. Optical Monitoring and Detection of Spinal Cord Ischemia

    PubMed Central

    Mesquita, Rickson C.; D’Souza, Angela; Bilfinger, Thomas V.; Galler, Robert M.; Emanuel, Asher; Schenkel, Steven S.; Yodh, Arjun G.; Floyd, Thomas F.

    2013-01-01

    Spinal cord ischemia can lead to paralysis or paraparesis, but if detected early it may be amenable to treatment. Current methods use evoked potentials for detection of spinal cord ischemia, a decades old technology whose warning signs are indirect and significantly delayed from the onset of ischemia. Here we introduce and demonstrate a prototype fiber optic device that directly measures spinal cord blood flow and oxygenation. This technical advance in neurological monitoring promises a new standard of care for detection of spinal cord ischemia and the opportunity for early intervention. We demonstrate the probe in an adult Dorset sheep model. Both open and percutaneous approaches were evaluated during pharmacologic, physiological, and mechanical interventions designed to induce variations in spinal cord blood flow and oxygenation. The induced variations were rapidly and reproducibly detected, demonstrating direct measurement of spinal cord ischemia in real-time. In the future, this form of hemodynamic spinal cord diagnosis could significantly improve monitoring and management in a broad range of patients, including those undergoing thoracic and abdominal aortic revascularization, spine stabilization procedures for scoliosis and trauma, spinal cord tumor resection, and those requiring management of spinal cord injury in intensive care settings. PMID:24358279

  18. Potential neuroprotection of protodioscin against cerebral ischemia-reperfusion injury in rats through intervening inflammation and apoptosis.

    PubMed

    Zhang, Xinxin; Xue, Xuanji; Xian, Liang; Guo, Zengjun; Ito, Yoichiro; Sun, Wenji

    2016-09-01

    The aim of the current research is to investigate the cerebral-protection of protodioscin on a transient cerebral ischemia-reperfusion (I/R) model and to explore its possible underlying mechanisms. The rats were preconditioned with protodioscin at the doses of 25 and 50mgkg(-1) prior to surgery. Then the animals were subjected to right middle cerebral artery occlusion (MCAO) using an intraluminal method by inserting a thread (90min surgery). After the blood flow was restored in 24h via withdrawing the thread, some representative indicators for the cerebral injury were evaluated by various methods including TTC-staining, TUNEL, immunohistochemistry, and Western blotting. As compared with the operated rats without drug intervening, treatment with protodioscin apparently lowered the death rate and improved motor coordination abilities through reducing the deficit scores and cerebral infarct volume. What's more, an apparent decrease in neuron apoptosis detected in hippocampus CA1 and cortex of the ipsilateral hemisphere might attribute to alleviate the increase in Caspase-3 and Bax/Bcl-2 ratio. Meanwhile, concentrations of several main pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) in the serum were also significantly suppressed. Finally, the NF-κB and IκBa protein expressions in the cytoplasm of right injured brain were remarkably up-regulated, while NF-κB in nucleus was down-regulated. Therefore, these observed findings demonstrated that protodioscin appeared to reveal potential neuroprotection against the I/R injury due to its anti-inflammatory and anti-apoptosis properties. This therapeutic effect was probably mediated by the inactivation of NF-κB signal pathways. PMID:27343977

  19. Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells

    SciTech Connect

    Schock, Sarah C.; Edrissi, Hamidreza; Burger, Dylan; Cadonic, Robert; Hakim, Antoine; Thompson, Charlie

    2014-07-18

    Highlights: • Microparticles are elevated in the plasma in a rodent model of chronic cerebral ischemia. • These microparticles initiate apoptosis in cultured cells. • Microparticles contain caspase 3 and they activate receptors for TNF-α and TRAIL. - Abstract: Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells.

  20. Continuous adenosine A2A receptor antagonism after focal cerebral ischemia in spontaneously hypertensive rats.

    PubMed

    Fronz, Ulrike; Deten, Alexander; Baumann, Frank; Kranz, Alexander; Weidlich, Sarah; Härtig, Wolfgang; Nieber, Karen; Boltze, Johannes; Wagner, Daniel-Christoph

    2014-02-01

    Antagonism of the adenosine A2A receptor (A2AR) has been shown to elicit substantial neuroprotective properties when given immediately after cerebral ischemia. We asked whether the continuous application of a selective A2AR antagonist within a clinically relevant time window will be a feasible and effective approach to treat focal cerebral ischemia. To answer this question, we subjected 20 male spontaneously hypertensive rats to permanent middle cerebral artery occlusion and randomized them equally to a verum and a control group. Two hours after stroke onset, the animals received a subcutaneous implantation of an osmotic minipump filled with 5 mg kg(-1) day(-1) 8-(3-chlorostyryl) caffeine (CSC) or vehicle solution. The serum level of CSC was measured twice a day for three consecutive days. The infarct volume was determined at days 1 and 3 using magnetic resonance imaging. We found the serum level of CSC showing a bell-shaped curve with its maximum at 36 h. The infarct volume was not affected by continuous CSC treatment. These results suggest that delayed and continuous CSC application was not sufficient to treat acute ischemic stroke, potentially due to unfavorable hepatic elimination and metabolization of the pharmaceutical. PMID:24170241

  1. Brain-targeting delivery for RNAi neuroprotection against cerebral ischemia reperfusion injury.

    PubMed

    An, Sai; Kuang, Yuyang; Shen, Teng; Li, Jianfeng; Ma, Haojun; Guo, Yubo; He, Xi; Jiang, Chen

    2013-11-01

    Nanoparticles (NPs) with modification of brain-targeting molecules have been extensively exploited for therapeutic gene delivery across the blood-brain barrier (BBB). As one of the effective RNA interference (RNAi) approaches, short hairpin RNA (shRNA) has been proved to be promising in the field of gene therapy. Apoptosis signal-regulating kinase 1 (Ask1) has been reported to be an important target for gene therapy against cerebral ischemia reperfusion injury. In this study, dendrigraft poly-l-lysine (DGL) was decorated by dermorphin (a μ-opiate receptor agonist) through PEG for efficient brain-targeting, then complexed with anti-Ask1 shRNA plasmid DNA, yielding the DGL-PEG-dermorphin/shRNA NPs. The DGL-PEG-dermorphin/shRNA NPs were characterized and estimated the brain-targeting ability. In vitro, increased cellular uptake and transfection efficiency were explored; in vivo, preferable accumulation and gene transfection in brain were showed in images. The DGL-PEG-dermorphin/shRNA NPs also revealed high efficiency of neuroprotection. As a result of RNAi, corresponding mRNA was distinctly degraded, expression of Ask1 protein was obviously suppressed, apoptotic cell death was apparently decreased and cerebral infarct area was significantly reduced. Above all, DGL-PEG-dermorphin/shRNA NPs were proved to be efficient and safe for brain-targeting RNAi neuroprotection against cerebral ischemia reperfusion injury.

  2. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota.

    PubMed

    Sun, Jing; Wang, Fangyan; Ling, Zongxin; Yu, Xichong; Chen, Wenqian; Li, Haixiao; Jin, Jiangtao; Pang, Mengqi; Zhang, Huiqing; Yu, Junjie; Liu, Jiaming

    2016-07-01

    Diabetes is known to exacerbate cerebral ischemia/reperfusion (I/R) injury. Here, we investigated the effects of Clostridium butyricum on cerebral I/R injury in the diabetic mice subjected to 30min of bilateral common carotid arteries occlusion (BCCAO). The cognitive impairment, the blood glucose level, neuronal injury, apoptosis, and expressions of Akt, phospho-Akt (p-Akt), and caspase-3 level were assessed. Meanwhile, the changes of gut microbiota in composition and diversity in the colonic feces were evaluated. Our results showed that diabetic mice subjected to BCCAO exhibited worsened cognitive impairment, cell damage and apoptosis. These were all attenuated by C. butyricum. Moreover, C. butyricum reversed cerebral I/R induced decreases in p-Akt expression and increases in caspase-3 expression, leading to inhibiting neuronal apoptosis. C. butyricum partly restored cerebral I/R induced decreases of fecal microbiota diversity, changes of fecal microbiota composition. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain probiotics might prove to be useful therapeutic adjuncts in cerebral I/R injury with diabetes. PMID:27037183

  3. Effect of hydrogen gas on the survival rate of mice following global cerebral ischemia.

    PubMed

    Nagatani, Kimihiro; Wada, Kojiro; Takeuchi, Satoru; Kobayashi, Hiroaki; Uozumi, Yoichi; Otani, Naoki; Fujita, Masanori; Tachibana, Shoichi; Nawashiro, Hiroshi

    2012-06-01

    Global cerebral ischemia and reperfusion (I/R) often result in high mortality. Free radicals have been reported to play an important role in global cerebral I/R, and therefore, reduction of these might improve the outcome. Here, we investigated the effect of hydrogen gas (H2) (a strong free radical scavenger) on the survival rate of mice following global cerebral I/R. We further examined the histopathological outcome and also the brain water content (as a possible determinant of mortality). Male C57BL/6J mice were subjected to global cerebral I/R by means of 45-min bilateral common carotid artery occlusion (BCCAO). A total of 160 mice were divided into three groups: sham surgery (sham group), BCCAO without H2 (BCCAO group), and BCCAO treated with 1.3% H2 (BCCAO + H2 group). We observed that H2 treatment significantly (P = 0.0232) improved the 7-day survival rate of mice, from 8.3% (BCCAO group, n = 12) to 50% (BCCAO + H2 group, n = 10). Histopathological analysis revealed that H2 treatment significantly attenuated neuronal injury and autophagy in the hippocampal cornu ammonis 1 sector and also brain edema, after 24 h of reperfusion. The beneficial effects of H2 treatment on brain injury were associated with significantly lower levels of oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde) in the brain tissue. Thus, we believe that H2 may be an effective treatment for global cerebral I/R.

  4. Exercise-induced Myocardial Ischemia Detected by Cardiopulmonary Exercise Testing

    PubMed Central

    Chaudhry, Sundeep; Arena, Ross; Wasserman, Karlman; Hansen, James E.; Lewis, Gregory D.; Myers, Jonathan; Chronos, Nicolas; Boden, William E.

    2010-01-01

    Cardiopulmonary exercise testing (CPET) is a well-accepted physiologic evaluation technique in patients diagnosed with heart failure and in individuals presenting with unexplained dyspnea on exertion. Several variables obtained during CPET, including oxygen consumption relative to heart rate (VO2/HR or O2-pulse) and work rate (VO2/Watt) provide consistent, quantitative patterns of abnormal physiologic responses to graded exercise when left ventricular dysfunction is caused by myocardial ischemia. This concept paper describes both the methodology and clinical application of CPET associated with myocardial ischemia. Initial evidence indicates left ventricular dysfunction induced by myocardial ischemia may be accurately detected by an abnormal CPET response. CPET testing may complement current non-invasive testing modalities that elicit inducible ischemia. It provides a physiologic quantification of the work rate, heart rate and O2 uptake at which myocardial ischemia develops. In conclusion, the potential value of adding CPET with gas exchange measurements is likely to be of great value in diagnosing and quantifying both overt and occult myocardial ischemia and its reversibility with treatment. PMID:19231322

  5. Neuroprotective and Functional Improvement Effects of Methylene Blue in Global Cerebral Ischemia.

    PubMed

    Lu, Qing; Tucker, Donovan; Dong, Yan; Zhao, Ningjun; Zhang, Quanguang

    2016-10-01

    Transient global cerebral ischemia (GCI) causes delayed neuronal cell death in the vulnerable hippocampus CA1 subfield, as well as behavioral deficits. Ischemia reperfusion (I/R) produces excessive reactive oxygen species and plays a key role in brain injury. The mitochondrial electron respiratory chain is the main cellular source of free radical generation, and dysfunction of mitochondria has a significant impact on the neuronal cell death in ischemic brain. The aim of the present study is to investigate the potential beneficial effects of methylene blue (MB) in a four-vessel occlusion (4VO) GCI model on adult male rats. MB was delivered at a dose of 0.5 mg/kg/day for 7 days, through a mini-pump implanted subcutaneously after GCI. We first found that MB significantly improved ischemic neuronal survival in the hippocampal CA1 region as measured by cresyl violet staining as well as NeuN staining. We also found that MB has the ability to rescue ischemia-induced decreases of cytochrome c oxidase activity and ATP generation in the CA1 region following I/R. Further analysis with labeling of MitoTracker® Red revealed that the depolarization of mitochondrial membrane potential (MMP) was markedly attenuated following MB treatment. In addition, the induction of caspase-3, caspase-8, and caspase-9 activities and the increased numbers of TUNEL-positive cells of the CA1 region were significantly reduced by MB application. Correspondingly, Barnes maze tests showed that the deterioration of spatial learning and memory performance following GCI was significantly improved in the MB-treatment group compared to the ischemic control group. In summary, our study suggests that MB may be a promising therapeutic agent targeting neuronal cell death and cognitive deficits following transient global cerebral ischemia.

  6. Neuroprotection of Chrysanthemum indicum Linne against cerebral ischemia/reperfusion injury by anti-inflammatory effect in gerbils.

    PubMed

    Yoo, Ki-Yeon; Kim, In Hye; Cho, Jeong-Hwi; Ahn, Ji Hyeon; Park, Joon Ha; Lee, Jae-Chul; Tae, Hyun-Jin; Kim, Dae Won; Kim, Jong-Dai; Hong, Seongkweon; Won, Moo-Ho; Kang, Il Jun

    2016-02-01

    In this study, we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne (CIL) extract, which has been used as a botanical drug in East Asia, against ischemic damage and to explore the underlying mechanism involving the anti-inflammatory approach. A gerbil was given CIL extract for 7 consecutive days followed by bilateral carotid artery occlusion to make a cerebral ischemia/reperfusion model. Then, we found that CIL extracts protected pyramidal neurons in the hippocampal CA1 region (CA1) from ischemic damage using neuronal nucleus immunohistochemistry and Fluoro-Jade B histofluorescence. Accordingly, interleukin-13 immunoreactivities in the CA1 pyramidal neurons of CIL-pretreated animals were maintained or increased after cerebral ischemia/reperfusion. These findings indicate that the pre-treatment of CIL can attenuate neuronal damage/death in the brain after cerebral ischemia/reperfusion via an anti-inflammatory approach. PMID:27073380

  7. Neuroprotection of Chrysanthemum indicum Linne against cerebral ischemia/reperfusion injury by anti-inflammatory effect in gerbils

    PubMed Central

    Yoo, Ki-Yeon; Kim, In Hye; Cho, Jeong-Hwi; Ahn, Ji Hyeon; Park, Joon Ha; Lee, Jae-Chul; Tae, Hyun-Jin; Kim, Dae Won; Kim, Jong-Dai; Hong, Seongkweon; Won, Moo-Ho; Kang, Il Jun

    2016-01-01

    In this study, we tried to verify the neuroprotective effect of Chrysanthemum indicum Linne (CIL) extract, which has been used as a botanical drug in East Asia, against ischemic damage and to explore the underlying mechanism involving the anti-inflammatory approach. A gerbil was given CIL extract for 7 consecutive days followed by bilateral carotid artery occlusion to make a cerebral ischemia/reperfusion model. Then, we found that CIL extracts protected pyramidal neurons in the hippocampal CA1 region (CA1) from ischemic damage using neuronal nucleus immunohistochemistry and Fluoro-Jade B histofluorescence. Accordingly, interleukin-13 immunoreactivities in the CA1 pyramidal neurons of CIL-pretreated animals were maintained or increased after cerebral ischemia/reperfusion. These findings indicate that the pre-treatment of CIL can attenuate neuronal damage/death in the brain after cerebral ischemia/reperfusion via an anti-inflammatory approach. PMID:27073380

  8. [Effect of gamma-hydroxybutyric acid receptor on focal cerebral ischemia-reperfusion injury in rats].

    PubMed

    Jin, Rong; Jiang, Xin-Ying; Ma, Xing; Gu, Shu-Ling; Dai, Ti-Jun

    2007-08-01

    This study is to investigate the effect of gamma-hydroxybutyric acid receptor (GHBR) on focal cerebral ischemia-reperfusion injury in rats and its mechanism. NCS-356 (the agonist of GHBR) and NCS-382 (the antagonist of GHBR) were adopted as the tool medicine. The ripe male Sprague-Dawley rats weighing 240 - 280 g were randomly divided into seven groups: sham operation group (sham), ischemia-reperfusion group (Isc/R), NCS-356 160 microg x kg(-1) group (N1), NCS-356 320 microg x kg(-1) group (N2), NCS-356 640 microg x kg(-1) group (N3), NCS-382 640 microg x kg(-1) + NCS-356 640 microg x kg(-1) group (NCS-382 + N3), and nimodipine (Nim) 600 microg x kg(-1) group. The middle cerebral artery occlusion (MCAO) model referring to Longa's method with modifications was adopted. The effect of GHBR on behavioral consequence of MCAO rats was studied after 2 h of ischemia-reperfusion. After 24 h of ischemia-reperfusion, part of animals were used to measure the cerebral infarction volume by TTC staining; ischemic cortex of another part of animals were used to measure the content of intracellular free calcium by flow cytometry, the tNOS, iNOS activity and the content of NO by spectrophotometric method, the content of cGMP by radioimmunoassay. The neurological function score and infarction volume rate in Isc/R group rats increased significantly than that in sham group; The content of intracellular calcium ([Ca2+]) of cortex neuron and cGMP, the activities of tNOS and iNOS, and the content of NO in Isc/R group were higher than that in sham group obviously (P < 0.01); These consequence we mentioned of N1, N2, N3 and Nim group were lower than that of Isc/R. NCS-382 + N3 group could significantly antagonize the above effect of N3. Thus, NCS-356 has protective effects against ischemia-reperfusion brain injury by activating GHBR. The neuroprotective effect of GHBR is related with decreasing the content of [Ca2+]i, NO, cGMP and tNOS, iNOS activity in MCAO rats.

  9. Protective effects of lithium chloride treatment on repeated cerebral ischemia-reperfusion injury in mice.

    PubMed

    Fan, Mingyue; Song, Chunfeng; Wang, Tianjun; Li, Ling; Dong, Yanhong; Jin, Wei; Lu, Peiyuan

    2015-02-01

    Lithium is a renowned pharmacological treatment for mood disorders. Recent studies suggest that lithium chloride (LiCl) performs neuroprotective effects on cerebrovascular diseases. The present study is to investigate the protective effects of LiCl treatment on the hippocampus of mice with repeated cerebral ischemia-reperfusion (IR). Mice were subjected to IR through repeated bilateral common carotid artery occlusion. LiCl (2 mmol/kg) was administered daily postoperative until the mice were sacrificed. Swimming time was prolonged and error count increased in the model group through learning and memory tests. Pathological changes such as reduction in cell count and obvious pyknosis were seen in haematoxylin-eosin staining, and apoptosis was detected by TUNEL staining in hippocampal CA1 regions in the model group. The model animals exhibited more phospho-Akt Ser473 and phospho-GSK3β Ser9 than the sham group when measured by Western blot. LiCl treatment mitigated the prolonged swimming time and the increased error count compared with NaCl-treated group and improved the pathological changes. Meanwhile, LiCl further up-regulated phospho-Akt Ser473 and phospho-GSK3β Ser9 expression. The highest level of diversity was at 4 weeks postoperative. Therefore, repeated IR can severely damage the hippocampus and decrease the learning and memory functions in mice. Changes in the Akt and GSK3β protein activity were involved in the IR process. LiCl treatment exerted a neuroprotective effect on learning and memory by potentiating the Akt/GSK3β cell-signaling pathway.

  10. Neuroprotection by the PGE2 EP2 receptor in permanent focal cerebral ischemia.

    PubMed

    Liu, Dong; Wu, Liejun; Breyer, Richard; Mattson, Mark P; Andreasson, Katrin

    2005-05-01

    Recent studies suggest a neuroprotective function of the PGE2 EP2 receptor in excitotoxic neuronal injury. The function of the EP2 receptor was examined at time points after excitotoxicity in an organotypic hippocampal model of N-methyl-D-aspartate (NMDA) challenge and in a permanent model of focal forebrain ischemia. Activation of EP2 led to significant neuroprotection in hippocampal slices up to 3 hours after a toxic NMDA stimulus. Genetic deletion of EP2 resulted in a marked increase in stroke volume in the permanent middle cerebral artery occlusion model. These findings support further investigation into therapeutic strategies targeting the EP2 receptor in stroke.

  11. Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

    PubMed Central

    Xu, Wang-shu; Sun, Xuan; Song, Cheng-guang; Mu, Xiao-peng; Ma, Wen-ping; Zhang, Xing-hu; Zhao, Chuan-sheng

    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, bumetanide 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 findings 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. PMID:27335557

  12. Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling

    PubMed Central

    2013-01-01

    Background It has been supposed that green tea polyphenols (GTPs) have neuroprotective effects on brain damage after brain ischemia in animal experiments. Little is known regarding GTPs’ protective effects against the blood-brain barrier (BBB) disruption after ischemic stroke. We investigated the effects of GTPs on the expression of claudin-5, occludin, and ZO-1, and the corresponding cellular mechanisms involved in the early stage of cerebral ischemia. Methods Male Wistar rats were subjected to a middle cerebral artery occlusion (MCAO) for 0, 30, 60, and 120 min. GTPs (400 mg/kg/day) or vehicle was administered by intragastric gavage twice a day for 30 days prior to MCAO. At different time points, the expression of claudin-5, occludin, ZO-1, and PKCα signaling pathway in microvessel fragments of cerebral ischemic tissue were evaluated. Results GTPs reduced BBB permeability at 60 min and 120 min after ischemia as compared with the vehicle group. Transmission electron microscopy also revealed that GTPs could reverse the opening of tight junction (TJ) barrier at 60 min and 120 min after MACO. The decreased mRNA and protein expression levels of claudin-5, occludin, and ZO-1 in microvessel fragments of cerebral ischemic tissue were significantly prevented by treatment with GTPs at the same time points after ischemia in rats. Furthermore, GTPs could attenuate the increase in the expression levels of PKCα mRNA and protein caused by cerebral ischemia. Conclusions These results demonstrate that GTPs may act as a potential neuroprotective agent against BBB damage at the early stage of focal cerebral ischemia through the regulation of TJ and PKCα signaling. PMID:23870286

  13. Evaluation of the PBR/TSPO radioligand [(18)F]DPA-714 in a rat model of focal cerebral ischemia.

    PubMed

    Martín, Abraham; Boisgard, Raphaël; Thézé, Benoit; Van Camp, Nadja; Kuhnast, Bertrand; Damont, Annelaure; Kassiou, Michael; Dollé, Frédéric; Tavitian, Bertrand

    2010-01-01

    Focal cerebral ischemia leads to an inflammatory reaction involving an overexpression of the peripheral benzodiazepine receptor (PBR)/18-kDa translocator protein (TSPO) in the cerebral monocytic lineage (microglia and monocyte) and in astrocytes. Imaging of PBR/TSPO by positron emission tomography (PET) using radiolabeled ligands can document inflammatory processes induced by cerebral ischemia. We performed in vivo PET imaging with [(18)F]DPA-714 to determine the time course of PBR/TSPO expression over several days after induction of cerebral ischemia in rats. In vivo PET imaging showed significant increase in DPA (N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide) uptake on the injured side compared with that in the contralateral area on days 7, 11, 15, and 21 after ischemia; the maximal binding value was reached 11 days after ischemia. In vitro autoradiography confirmed these in vivo results. In vivo and in vitro [(18)F]DPA-714 binding was displaced from the lesion by PK11195 and DPA-714. Immunohistochemistry showed increased PBR/TSPO expression, peaking at day 11 in cells expressing microglia/macrophage antigens in the ischemic area. At later times, a centripetal migration of astrocytes toward the lesion was observed, promoting the formation of an astrocytic scar. These results show that [(18)F]DPA-714 provides accurate quantitative information of the time course of PBR/TSPO expression in experimental stroke.

  14. Myocardial perfusion imaging for detection of silent myocardial ischemia

    SciTech Connect

    Beller, G.A.

    1988-04-21

    Despite the widespread use of the exercise stress test in diagnosing asymptomatic myocardial ischemia, exercise radionuclide imaging remains useful for detecting silent ischemia in numerous patient populations, including those who are totally asymptomatic, those who have chronic stable angina, those who have recovered from an episode of unstable angina or an uncomplicated myocardial infarction, and those who have undergone angioplasty or received thrombolytic therapy. Studies show that thallium scintigraphy is more sensitive than exercise electrocardiography in detecting ischemia, i.e., in part, because perfusion defects occur more frequently than ST depression and before angina in the ischemic cascade. Thallium-201 scintigraphy can be performed to differentiate a true- from a false-positive exercise electrocardiographic test in patients with exercise-induced ST depression and no angina. The development of technetium-labeled isonitriles may improve the accuracy of myocardial perfusion imaging. 11 references.

  15. The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia.

    PubMed

    Junge, Candice E; Sugawara, Taku; Mannaioni, Guido; Alagarsamy, Sudar; Conn, P Jeffrey; Brat, Daniel J; Chan, Pak H; Traynelis, Stephen F

    2003-10-28

    The serine proteases tissue plasminogen activator, plasmin, and thrombin and their receptors have previously been suggested to contribute to neuronal damage in certain pathological situations. Here we demonstrate that mice lacking protease-activated receptor 1 (PAR1) have a 3.1-fold reduction in infarct volume after transient focal cerebral ischemia. Intracerebroventricular injection of PAR1 antagonist BMS-200261 reduced infarct volume 2.7-fold. There are no detectable differences between PAR1-/- and WT mice in cerebrovascular anatomy, capillary density, or capillary diameter, demonstrating that the neuroprotective phenotype is not likely related to congenital abnormalities in vascular development. We also show that the exogenously applied serine proteases thrombin, plasmin, and tissue plasminogen activator can activate PAR1 signaling in brain tissue. These data together suggest that if blood-derived serine proteases that enter brain tissue in ischemic situations can activate PAR1, this sequence of events may contribute to the harmful effects observed. Furthermore, PAR1 immunoreactivity is present in human brain, suggesting that inhibition of PAR1 may provide a novel potential therapeutic strategy for decreasing neuronal damage associated with ischemia and blood-brain barrier breakdown.

  16. Post-transcriptional inactivation of matrix metalloproteinase-12 after focal cerebral ischemia attenuates brain damage.

    PubMed

    Chelluboina, Bharath; Warhekar, Aditi; Dillard, Matt; Klopfenstein, Jeffrey D; Pinson, David M; Wang, David Z; Veeravalli, Krishna Kumar

    2015-05-08

    This study highlights the possible pathological role of MMP-12 in the context of ischemic stroke. Male rats were subjected to a two-hour middle cerebral artery occlusion (MCAO) procedure. MMP-12 shRNA expressing plasmid formulation was administered to these rats twenty-four hours after reperfusion. The results showed a predominant upregulation of MMP-12 (approximately 47, 58, 143, and 265 folds on days 1, 3, 5, 7 post-ischemia, respectively) in MCAO subjected rats. MMP-12 expression was localized to neurons, oligodendrocytes and microglia, but not astrocytes. Transcriptional inactivation of MMP-12 significantly reduced the infarct size. The percent infarct size was reduced from 62.87±4.13 to 34.67±5.39 after MMP-12 knockdown compared to untreated MCAO subjected rats. Expression of myelin basic protein was increased, and activity of MMP-9 was reduced in ischemic rat brains after MMP-12 knockdown. Furthermore, a significant reduction in the extent of apoptosis was noticed after MMP-12 knockdown. TNFα expression in the ipsilateral regions of MCAO-subjected rats was reduced after MMP-12 knockdown in addition to the reduced protein expression of apoptotic molecules that are downstream to TNFα signaling. Specific knockdown of MMP-12 after focal cerebral ischemia offers neuroprotection that could be mediated via reduced MMP-9 activation and myelin degradation as well as inhibition of apoptosis.

  17. Impacts of N-Butylphthalide on expression of growth factors in rats with focal cerebral ischemia

    PubMed Central

    Jiang, Yan; Sun, Leyu; Xuan, Xiaoyan; Wang, Jianping

    2016-01-01

    This study investigates the impacts of n-butylphthalide (NBP) on the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-β1 (TGF-β1) in rats with focal cerebral ischemia. The thread embolization method was used to prepare the rat model of cerebral ischemia-reperfusion (CIR). The animals were divided into a sham operation group, a model control group and NBP treatment group. The NBP group was orally administered 25 mg/kg NBP twice a day after the surgery. The immunohistochemistry and reverse transcription-polymerase chain reaction were performed to observe the protein and mRNA expressions of VEGF and TGF-β 16 hours, 1 day and 2 days after inducing CIR. The mRNA and protein expressions of VEGF and TGF-β1 in the model control group and the NBP treatment group were all increased after CIR, and those of the NBP treatment group at each post-CIR time point were higher than the model control group (p < 0.01). After CIR, the expressions of VEGF and TGF-β1 increased, suggesting that VEGF and TGF-β1 exhibited protective effects towards the ischemic brain injuries, and that NBP could upregulate the expressions of VEGF and TGF-β1 in the peri-infarcted area, thus possibly protecting the ischemic brain tissues through this mechanism. PMID:26773175

  18. Astragalus extract alleviates nerve injury after cerebral ischemia by improving energy metabolism and inhibiting apoptosis.

    PubMed

    Huang, Xiao-Ping; Tan, Hua; Chen, Bei-Yang; Deng, Chang-Qing

    2012-01-01

    This aim of this study was to explore the effects and molecular mechanisms of Astragalus extract against cerebral ischemia injury through the energy metabolism and apoptosis pathways of c‑Jun N-terminal kinase (JNK) signal transduction. After the bilateral common carotid artery of C57BL/6 mice was occluded for 20 min followed by 1-h reperfusion, the ATP content, total adenine nucleotides (TAN), energy charge (EC), and sodium potassium ATPase (Na(+)-K(+)‑ATPase) activity were decreased markedly in brain tissues. Astragalus extract markedly increased the ATP and ADP levels, EC value, and Na(+)-K(+)-ATPase activity. Twenty-four and 48 h after reperfusion, the neurocyte survival rate decreased and apoptosis rate increased, while the expression of phosphorylated JNK1/2, cytochrome c (Cyt C), and cysteine aspartic acid-specific protease (caspase)-9 and -3 were significantly enhanced in brain tissues. Astragalus extract significantly increased neurocyte survival and decreased the apoptosis rate as well as down-regulated the expression of p-JNK1/2, Cyt C, caspase-9, and caspase-3. These results suggest that Astragalus extract has neuroprotective effects against nerve injury after cerebral ischemia-reperfusion, and the underlying mechanism may be associated with improved cellular energy metabolism, inhibition of JNK signal transduction pathway activation, and then suppression of the mitochondrial apoptosis pathway.

  19. Simultaneous near-IR spectroscopy and magnetic resonance imaging to assess cerebral oxygenation and brain water during hypoxia-ischemia in two-week-old rats

    NASA Astrophysics Data System (ADS)

    Shaw, R. A.; Tuor, U. I.; Foniok, T.; Bascaramurty, S.; Ringland, K.; McKenzie, E.; Qiao, M.; Tomanek, B.; Mantsch, Henry H.

    2001-10-01

    Cerebral near-infrared spectroscopy can potentially probe several parameters related to the onset of stroke and the ensuing tissue damage. One obvious marker of ischemia is cerebral oxygenation, which can be lowered sharply in stroke-affected tissue. Also commonly assessed, though less straightforward to recover, is the redox state of the cytochrome aa3 copper center. Finally, parameters that are in principle available but seldom recovered from in vivo near-IR spectra are changes in water concentration and scattering properties of the tissue. We have evaluated the potential for near-IR spectroscopy to detect relevant changes in cerebral oxygenation, blood volume, water content, and scattering properties in an infant rat stroke model that is well characterized by magnetic resonance imaging methods. The specific aim was to acquire near-IR spectra simultaneously with MR images and to correlate stroke-associated changes detected via these two modalities prior to, during and after a hypoxia-ischemia episode within this stroke model. Presented here are results from the design and testing of a near-IR illumination/detection system that is compatible with an MR imaging system, and the recovery of trends in the near-IR spectra that complement the hypoxic-ischemic changes observed in the MR images. Unexpectedly large intensity changes observed for the in vivo near-IR water absorptions are ascribed to hypoxia-induced variations in effective optical pathlength, suggesting that the water absorptions may prove generally useful as a means to track such changes.

  20. Neuroprotective effect of s-methylisothiourea in transient focal cerebral ischemia in rat.

    PubMed

    ArunaDevi, Rathinam; Ramteke, Vinod D; Kumar, Saurabh; Shukla, Manoj K; Jaganathan, Subramani; Kumar, Dinesh; Sharma, Anil K; Tandan, Surendra K

    2010-01-01

    Over production of NO by nitric oxide synthase (NOS) in the brain parenchyma has been demonstrated to contribute to tissue damage. NO may be toxic by formation of peroxinitrite after a reaction between NO and superoxide appears to be one of the major pathways leading to cell death. Of three types of NOS, nNOS is neurotoxic in early and iNOS in late stage of transient cerebral ischemia (TFCI), while eNOS is neuroprotective in all stages. We examined the neuroprotective effect of a preferential iNOS inhibitor s-methylisothiourea (SMT) at 0, 8, 24 and 48h as multiple injections (30 and 100mg/kg, i.p.) in ischemia and reperfusion injury in a rat model of middle cerebral artery occlusion (2h) and reperfusion (72h). After 2h of ischemia and 72h of reperfusion, animals were sacrificed for studying the infarct volume, brain edema and apoptosis and neuro-behavioral abnormality was assessed at 24, 48 and 72h of reperfusion. SMT reduced significantly the infarct volume, neuro-behavioral abnormality, brain edema, number of apoptotic cells in penumbra and NOx levels in plasma and brain both at 30 and 100mg/kg in dose-dependent manner. The amount of peroxynitrite measured by rhodamine assay was significantly reduced by SMT, as compared to control group. SMT protected Neuro 2a cells against sodium azide-induced damage. It is concluded that, SMT may possibly targeting both constitutive as well as inducible NOS at varying time interval to elicit neuroprotection in TFCI rats.

  1. The nitroxide antioxidant tempol is cerebroprotective against focal cerebral ischemia in spontaneously hypertensive rats.

    PubMed

    Leker, R R; Teichner, A; Lavie, G; Shohami, E; Lamensdorf, I; Ovadia, H

    2002-08-01

    Free radicals appear to participate in the final common pathway of neuronal death in ischemia and may therefore be an adequate target for therapy. Tempol is a nitroxide antioxidant with proven protective efficacy in several animal models, including myocardial ischemia, that has not been previously tested in models of permanent cerebral ischemia. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Following dose-response and time-window-finding experiments rats were given vehicle or tempol (50 mg/kg) subcutaneously 1 h after PMCAO (n = 10/group). Five animals in each group were evaluated with a motor scale 24 h after the infarct and were then sacrificed and the injury volume was measured. The remaining animals were examined daily with the motor scale and also with a Morris water maze test on days 26-30 after PMCAO and sacrificed on day 30. Motor scores at all time points examined were significantly better in the tempol-treated animals (P < 0.05 for all). Significantly better performance in the water maze test for performance on days 26-30 was noted in the tempol group compared with the vehicle-treated group (P < 0.05). Injury volumes at days 1 and 30 were significantly reduced in the tempol group (9.83 +/- 1.05 vs 19.94 +/- 1.43% hemispheric volume, P = 0.0009, and 13.2 +/- 2.97 vs 24.4 +/- 2.38% hemispheric volume, P = 0.02, respectively). In conclusion, treatment with tempol led to significant motor and behavioral improvement and reduced injured tissue volumes both in the short and in the long term after stroke.

  2. Caffeic acid protects mice from memory deficits induced by focal cerebral ischemia.

    PubMed

    Pinheiro Fernandes, Francisco Diego; Fontenele Menezes, Ana Paula; de Sousa Neves, Julliana Catharina; Fonteles, Analu Aragão; da Silva, Ana Thais Araújo; de Araújo Rodrigues, Patrícia; Santos do Carmo, Marta Regina; de Souza, Carolina Melo; de Andrade, Geanne Matos

    2014-10-01

    Brain ischemia pathophysiology involves a complex cascade of events such as inflammation and oxidative stress that lead to neuronal loss and cognitive deficits. Caffeic acid (CA) is a natural phenolic compound with antioxidant and anti-inflammatory properties. To evaluate the neuroprotective efficacy of this compound in mice subjected to a permanent middle cerebral artery occlusion, animals were pretreated and post-treated with CA, 2, 20, and 60 mg/kg/day, intraperitoneally, at 24, 48, 72, 96, or 120 h after ischemia. Animals were evaluated at 24 h after the permanent middle cerebral artery occlusion for brain infarction and neurological deficit score. At 72 h after the occlusion, animals were evaluated for locomotor activity, working memory, and short-term aversive memory; long-term aversive memory was evaluated 24 h after the evaluation of short-term aversive memory. Finally, at 120 h after the event, spatial memory and the expression levels of synaptophysin (SYP), SNAP-25, and caspase 3 were evaluated. The treatment with CA reduced the infarcted area and improved neurological deficit scores. There was no difference in locomotor activity between groups. The working, spatial, and long-term aversive memory deficits improved with CA. Furthermore, western blotting data showed that the expression of SYP, which correlates with synaptic formation and function, decreased after ischemic insult, and CA inhibited the reduction of SYP expression. Ischemia also increased, and CA treatment decreased, caspase 3 expression. These results suggest that CA exerts neuroprotective and antidementia effects, at least in part, by preventing the loss of neural cells and synapses in ischemic brain injury. PMID:25171077

  3. Comparative analysis of autophagy and tauopathy related markers in cerebral ischemia and Alzheimer’s disease animal models

    PubMed Central

    Villamil-Ortiz, Javier G.; Cardona-Gomez, Gloria P.

    2015-01-01

    Alzheimer’s disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long-term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2-Vessel Occlusion) rat model (1,15, and 30 days post-ischemia). Our findings confirmed neuronal loss and hyperphosphorylated tau aggregation in the somatosensory cortex (SS-Cx) of the 3xTg-AD mice in the late stage (aged 18 months), which was supported by a failure in autophagy. These results were in contrast to those obtained in the SS-Cx of the CI rats, in which we detected neuronal loss and tauopathy at 1 and 15 days post-ischemia, and this phenomenon was reversed at 30 days. We proposed that this phenomenon was associated with autophagy induction in the late stage, since the data showed a decrease in p-mTOR activity, an association of Beclin-1 and Vps34, a progressive reduction in PHF-1, an increase in LC3B puncta and autophago-lysosomes formation were observed. Furthermore, the survival pathways remained unaffected. Together, our comparative study suggest that autophagy could ameliorates tauopathy in CI but not in AD, suggesting a differential temporal approach to the induction of neuroprotection and the prevention of neurodegeneration. PMID:26042033

  4. Dexmedetomidine Protects against Transient Global Cerebral Ischemia/Reperfusion Induced Oxidative Stress and Inflammation in Diabetic Rats

    PubMed Central

    Xing, Xichun; Wang, Qi; Li, Wenzhi

    2016-01-01

    Background Transient global cerebral ischemia/reperfusion (I/R) is a major perioperative complication, and diabetes increases the response of oxidative stress and inflammation induced by I/R. The objective of this study was to determine the protective effect of dexmedetomidine against transient global cerebral ischemia/reperfusion induced oxidative stress and inflammation in diabetic rats. Methods Sixty-four rats were assigned into four experimental groups: normoglycemia, normoglycemia + dexmedetomidine, hyperglycemia, and hyperglycemia + dexmedetomidine and all subsequent neurological examinations were evaluated by a blinded observer. Damage to the brain was histologically assessed using the TUNEL staining method while western blotting was used to investigate changes in the expression levels of apoptosis-related proteins as well as the microglia marker, ionized calcium-binding adapter molecule 1 (Iba1). Water content in the brain was also analyzed. In addition, hippocampal concentrations of malondialdehyde (MDA) and Nox2 (a member of the Nox family of NADPH oxidases), and the activity of superoxide dismutase and catalase were analyzed. Finally, changes in serum concentrations of tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were detected. Results Results showed that diabetes increased brain water content, the number of apoptotic neurons, early neurological deficit scores, oxidative stress (MDA and Nox2) and inflammation (pro-inflammatory cytokines including TNF-α and IL-6) levels following transient global I/R injury, but that these symptoms were attenuated following administration of dexmedetomidine. Conclusions These findings suggest that dexmedetomidine can significantly alleviate damage resulting from I/R, and this mechanism may be related to a reduction in both oxidative stress and inflammation which is normally associated with I/R. PMID:26982373

  5. Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress.

    PubMed

    Yang, Jian-Wen; Hu, Zhi-Ping

    2015-08-01

    Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway. PMID:26487850

  6. Neuroprotective effects of atorvastatin against cerebral ischemia/reperfusion injury through the inhibition of endoplasmic reticulum stress

    PubMed Central

    Yang, Jian-wen; Hu, Zhi-ping

    2015-01-01

    Cerebral ischemia triggers secondary ischemia/reperfusion injury and endoplasmic reticulum stress initiates cell apoptosis. However, the regulatory mechanism of the signaling pathway remains unclear. We hypothesize that the regulatory mechanisms are mediated by the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α in the endoplasmic reticulum stress signaling pathway. To verify this hypothesis, we occluded the middle cerebral artery in rats to establish focal cerebral ischemia/reperfusion model. Results showed that the expression levels of protein kinase-like endoplasmic reticulum kinase and caspase-3, as well as the phosphorylation of eukaryotic initiation factor 2α, were increased after ischemia/reperfusion. Administration of atorvastatin decreased the expression of protein kinase-like endoplasmic reticulum kinase, caspase-3 and phosphorylated eukaryotic initiation factor 2α, reduced the infarct volume and improved ultrastructure in the rat brain. After salubrinal, the specific inhibitor of phosphorylated eukaryotic initiation factor 2α was given into the rats intragastrically, the expression levels of caspase-3 and phosphorylated eukaryotic initiation factor 2α in the were decreased, a reduction of the infarct volume and less ultrastructural damage were observed than the untreated, ischemic brain. However, salubrinal had no impact on the expression of protein kinase-like endoplasmic reticulum kinase. Experimental findings indicate that atorvastatin inhibits endoplasmic reticulum stress and exerts neuroprotective effects. The underlying mechanisms of attenuating ischemia/reperfusion injury are associated with the protein kinase-like endoplasmic reticulum kinase/eukaryotic initiation factor 2α/caspase-3 pathway. PMID:26487850

  7. Mechanisms of Nattokinase in protection of cerebral ischemia.

    PubMed

    Ji, Hongrui; Yu, Liang; Liu, Keyu; Yu, Zhigang; Zhang, Qian; Zou, Fengjuan; Liu, Bo

    2014-12-15

    In vivo, the level of cyclic Adenosine Monophosphate (cAMP) and the pathway of the Janus Kinase1/Signal Transducers and Activators of Transcription1 (JAK1/STAT1) were studied. In vitro, the Ca(2+) mobilization in human platelet stimulated by thrombin was observed. In addition, vasomotion of vascular smooth muscle was measured by adding KCl or norepinephrine(NE) under the Ca(2+) contained bath solutions. The effect induced by NE in the presence of N-nitro-L-arginine methyl ester (L-NAME) or indometacin (Indo) was also detected. At last, the levels of tissue plasminogen activator (t-PA) and Plasminogen activator inhibitor-1 (PAI-1) in cultured supernatans in Human umbilical vein endothelial cells (Huvecs) were measured by means of ELISA kit. Results showed that Nattokinase (NK) significantly increased the cAMP level, activated the signal passage of JAK1/STAT1 in injured part and inhibited remarkably the rise of platelet intracellular Ca(2+) ([Ca(2+)]i) in human platelet. Furthermore, NK relaxed rat thoracic aortic artery in the dose-dependent manner and in the endothelium dependent manner and its effect could be attenuated by L-NAME. Also, the secretion of t-PA and PAI-1 were reduced stimulated by Adr on Huvecs. These data indicated that the neuroprotective effect of NK was associated with its antiplatelet activity by elevating cAMP level and attenuating the calcium release from calcium stores; with its anti-apoptotic effect through the activation of JAK1/STAT1 pathway; with its relaxing vascular smooth muscle by promoting synthesis and release of NO, reducing ROC calcium ion influx and with its protection on endothelial cells through increasing fibrinolytic activity and facilitating spontaneous thrombolysis.

  8. The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice

    SciTech Connect

    Hua, Fang; Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G.

    2009-12-18

    TIR domain-containing adaptor protein (TRIF) is an adaptor protein in Toll-like receptor (TLR) signaling pathways. Activation of TRIF leads to the activation of interferon regulatory factor 3 (IRF3) and nuclear factor kappa B (NF-{kappa}B). While studies have shown that TLRs are implicated in cerebral ischemia/reperfusion (I/R) injury and in neuroprotection against ischemia afforded by preconditioning, little is known about TRIF's role in the pathological process following cerebral I/R. The present study investigated the role that TRIF may play in acute cerebral I/R injury. In a mouse model of cerebral I/R induced by transient middle cerebral artery occlusion, we examined the activation of NF-{kappa}B and IRF3 signaling in ischemic cerebral tissue using ELISA and Western blots. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. NF-{kappa}B activity and phosphorylation of the inhibitor of kappa B (I{kappa}B{alpha}) increased in ischemic brains, but IRF3, inhibitor of {kappa}B kinase complex-{epsilon} (IKK{epsilon}), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-{kappa}B activity or p-I{kappa}B{alpha} induced by cerebral I/R. Moreover, although cerebral I/R induced neurological and functional impairments and brain infarction in WT mice, the deficits were not improved and brain infarct size was not reduced in TRIF knockout mice compared to WT mice. Our results demonstrate that the TRIF-dependent signaling pathway is not required for the activation of NF-{kappa}B signaling and brain injury after acute cerebral I/R.

  9. Effects of naftidrofuryl oxalate, a 5-HT2 antagonist, on neuronal damage and local cerebral blood flow following transient cerebral ischemia in gerbils.

    PubMed

    Fujikura, H; Kato, H; Araki, T; Ban, H; Hasegawa, Y; Kogure, K

    1994-02-01

    Effects of naftidrofuryl oxalate (naftidrofuryl), a 5-HT2 antagonist, on neuronal damage and local cerebral blood flow was examined in a gerbil model of transient forebrain ischemia. Effect of ketanserin tartrate (ketanserin), another 5-HT2 antagonist, on neuronal damage was also examined. Pretreatment with naftidrofuryl or ketanserin prevented hippocampal CA1 neuronal loss after 5 min of transient ischemia. Naftidrofuryl did not improve hippocampal blood flow during and 1 h after transient ischemia determined by [14C]iodoantipyrine autoradiography but increased blood flow in the caudate-putamen 1 h after transient ischemia. The results show that: (1) the 5-HT2 antagonists protect against hippocampal CA1 neuronal damage; and (2) the protective effect of naftidrofuryl may not be caused by a hemodynamic mechanism but by a direct inhibitory neuromodulation via 5-HT2 antagonistic action.

  10. Asiaticoside attenuates memory impairment induced by transient cerebral ischemia-reperfusion in mice through anti-inflammatory mechanism.

    PubMed

    Chen, She; Yin, Zhu-Jun; Jiang, Chen; Ma, Zhan-Qiang; Fu, Qiang; Qu, Rong; Ma, Shi-Ping

    2014-07-01

    Asiaticoside (AS) is isolated from Centella asiatica (L.) which has been using for a long time as a memory enhancing drug in India. This study was to investigate the effects of AS on memory impairment and inflammatory cytokines expression induced by transient cerebral ischemia and reperfusion in mice, as well as the potential signaling pathway. Transient bilateral common carotid artery occlusion (tBCCAO) induced severe memory deficits in mice according to the Morris water maze task and the step-down passive avoidance test. Meanwhile the microglial activation and the gene expression of inflammatory cytokines including interleukin (IL)-1β, interleukin (IL)-6 and tumor necrosis factor (TNF)-α were increased in the hippocampus of the mice with cerebral ischemia and reperfusion. Oral administration of AS (40 and 60 mg/kg, once per day, started the day after surgery and lasted for 7 days) significantly ameliorated the memory impairment and the inflammation. Moreover, AS (20, 40 and 60 mg/kg) markedly reduced the microglial overactivation and the phosphorylation of p38 MAPK in hippocampus compared with the transient cerebral ischemia and reperfusion group. These results suggested that AS showed the neuroprotective effect against transient cerebral ischemia and reperfusion in mice, and this effect might be associated with the anti-inflammation effect of AS via inhibiting overactivation of p38 MAPK pathway.

  11. Oleuropein, a natural extract from plants, offers neuroprotection in focal cerebral ischemia/reperfusion injury in mice.

    PubMed

    Yu, Hailong; Liu, Peipei; Tang, Hui; Jing, Jian; Lv, Xiang; Chen, Lanlan; Jiang, Li; Xu, Jun; Li, Jun

    2016-03-15

    Oleuropein (OLE) was found to have anti-inflammatory and anti-oxidant effects. The latest study has shown that it can resist myocardial injury that follows an acute myocardial infarction and can rescue impaired spinal nerve cells. In this study, we investigated the neuroprotective effects of OLE on cerebral ischemia and reperfusion injury in a middle cerebral artery occlusion model in mice.OLE (100 mg/kg) was injected intraperitoneally 1h before ischemia. We found that the volume of cerebral infarction was significantly reduced after 75 min of ischemia and 24 h of reperfusion compared with the I/R (ischemia/reperfusion) group. This protective function occurred in a dose-dependent manner. We also found that treatment with OLE could reduce the cerebral infarct volume. The neuroprotective effect was prolonged from 2 h to 4 h when we injected OLE intracerebroventricularly after reperfusion. We then found that OLE can decrease the level of cleavedcaspase-3, an important marker of apoptosis, in the ischemic mouse brain. Finally, we explored the role of OLE in providing anti-apoptotic effects through the increased expression of Bcl-2 and the decreased expression of Bax, which are important markers in apoptosis. As shown above, the function and safety of OLE in cardiovascular disease may indicate that it is a potential therapeutic for stroke. PMID:26872990

  12. Increases of Catalase and Glutathione Peroxidase Expressions by Lacosamide Pretreatment Contributes to Neuroprotection Against Experimentally Induced Transient Cerebral Ischemia.

    PubMed

    Choi, Hyun Young; Park, Joon Ha; Chen, Bai Hui; Shin, Bich Na; Lee, Yun Lyul; Kim, In Hye; Cho, Jeong-Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Won, Moo-Ho; Ahn, Ji Hyeon; Tae, Hyun-Jin; Yan, Bing Chun; Hwang, In Koo; Cho, Jun Hwi; Kim, Young-Myeong; Kim, Sung Koo

    2016-09-01

    Lacosamide is a new antiepileptic drug which is widely used to treat partial-onset seizures. In this study, we examined the neuroprotective effect of lacosamide against transient ischemic damage and expressions of antioxidant enzymes such as Zn-superoxide dismutase (SOD1), Mn-superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPX) in the hippocampal cornu ammonis 1 (CA1) region following 5 min of transient global cerebral ischemia in gerbils. We found that pre-treatment with 25 mg/kg lacosamide protected CA1 pyramidal neurons from transient global cerebral ischemic insult using hematoxylin-eosin staining and neuronal nuclear antigen immunohistochemistry. Transient ischemia dramatically changed expressions of SOD1, SOD2 and GPX, not CAT, in the CA1 pyramidal neurons. Lacosamide pre-treatment increased expressions of CAT and GPX, not SOD1 and 2, in the CA1 pyramidal neurons compared with controls, and their expressions induced by lacosamide pre-treatment were maintained after transient cerebral ischemia. In brief, pre-treatment with lacosamide protected hippocampal CA1 pyramidal neurons from ischemic damage induced by transient global cerebral ischemia, and the lacosamide-mediated neuroprotection may be closely related to increases of CAT and GPX expressions by lacosamide pre-treatment. PMID:27209305

  13. Effects of erythropoietin preconditioning on rat cerebral ischemia-reperfusion injury and the GLT-1/GLAST pathway

    PubMed Central

    YU, DAIHUA; FAN, YUANHUA; SUN, XUDE; YAO, LINONG; CHAI, WEI

    2016-01-01

    The aim of the present study was to investigate whether erythropoietin (EPO) preconditioning affects the expression of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) and protects against rat cerebral ischemia-reperfusion injury. A total of 140 Sprague Dawley rats were randomly assigned to one of the following four groups: Sham, EPO-sham, middle cerebral artery occlusion (MCAO) and EPO-MCAO. Neurological function scores were obtained 24, 36 and 72 h after reperfusion. Seventy-two hours after the induction of cerebral ischemia-reperfusion, the number of apoptotic neural cells and the cerebral infarct volume of each group were measured. The mRNA levels of GLT-1 and GLAST were determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, while the GLT-1 and GLAST protein levels were assessed using western blotting. The cerebral infarct volume was significantly increased in the MCAO group compared with that in the sham group (P<0.01); however, the infarct volume of the EPO-MCAO group was significantly lower than that of the MCAO group (P<0.01). In addition, the number of apoptotic cells found in the MCAO group was higher than that in the sham group (P<0.01), but the number of apoptotic cells in the EPO-MCAO group was significantly lower than that in the MCAO group (P<0.01). The GLT-1 and GLAST mRNA and protein levels were significantly decreased 72 h after the cerebral ischemia-reperfusion (P<0.01) compared with those in the sham group, whereas the same levels were increased significantly in the EPO-MCAO group relative to those in the MCAO group (P<0.01). In conclusion, EPO preconditioning protected against cerebral ischemia-reperfusion injury and upregulated the GLT-1 and GLAST expression. PMID:26893639

  14. Clinical Development and Implementation of an Institutional Guideline for Prospective EEG Monitoring and Reporting of Delayed Cerebral Ischemia.

    PubMed

    Muniz, Carlos F; Shenoy, Apeksha V; OʼConnor, Kathryn L; Bechek, Sophia C; Boyle, Emily J; Guanci, Mary M; Tehan, Tara M; Zafar, Sahar F; Cole, Andrew J; Patel, Aman B; Westover, Michael B; Rosenthal, Eric S

    2016-06-01

    Delayed cerebral ischemia (DCI) is the most common and disabling complication among patients admitted to the hospital for subarachnoid hemorrhage (SAH). Clinical and radiographic methods often fail to detect DCI early enough to avert irreversible injury. We assessed the clinical feasibility of implementing a continuous EEG (cEEG) ischemia monitoring service for early DCI detection as part of an institutional guideline. An institutional neuromonitoring guideline was designed by an interdisciplinary team of neurocritical care, clinical neurophysiology, and neurosurgery physicians and nursing staff and cEEG technologists. The interdisciplinary team focused on (1) selection criteria of high-risk patients, (2) minimization of safety concerns related to prolonged monitoring, (3) technical selection of quantitative and qualitative neurophysiologic parameters based on expert consensus and review of the literature, (4) a structured interpretation and reporting methodology, prompting direct patient evaluation and iterative neurocritical care, and (5) a two-layered quality assurance process including structured clinician interviews assessing events of neurologic worsening and an adjudicated consensus review of neuroimaging and medical records. The resulting guideline's clinical feasibility was then prospectively evaluated. The institutional SAH monitoring guideline used transcranial Doppler ultrasound and cEEG monitoring for vasospasm and ischemia monitoring in patients with either Fisher group 3 or Hunt-Hess grade IV or V SAH. Safety criteria focused on prevention of skin breakdown and agitation. Technical components included monitoring of transcranial Doppler ultrasound velocities and cEEG features, including quantitative alpha:delta ratio and percent alpha variability, qualitative evidence of new focal slowing, late-onset epileptiform activity, or overall worsening of background. Structured cEEG reports were introduced including verbal communication for findings concerning

  15. Clinical Development and Implementation of an Institutional Guideline for Prospective EEG Monitoring and Reporting of Delayed Cerebral Ischemia.

    PubMed

    Muniz, Carlos F; Shenoy, Apeksha V; OʼConnor, Kathryn L; Bechek, Sophia C; Boyle, Emily J; Guanci, Mary M; Tehan, Tara M; Zafar, Sahar F; Cole, Andrew J; Patel, Aman B; Westover, Michael B; Rosenthal, Eric S

    2016-06-01

    Delayed cerebral ischemia (DCI) is the most common and disabling complication among patients admitted to the hospital for subarachnoid hemorrhage (SAH). Clinical and radiographic methods often fail to detect DCI early enough to avert irreversible injury. We assessed the clinical feasibility of implementing a continuous EEG (cEEG) ischemia monitoring service for early DCI detection as part of an institutional guideline. An institutional neuromonitoring guideline was designed by an interdisciplinary team of neurocritical care, clinical neurophysiology, and neurosurgery physicians and nursing staff and cEEG technologists. The interdisciplinary team focused on (1) selection criteria of high-risk patients, (2) minimization of safety concerns related to prolonged monitoring, (3) technical selection of quantitative and qualitative neurophysiologic parameters based on expert consensus and review of the literature, (4) a structured interpretation and reporting methodology, prompting direct patient evaluation and iterative neurocritical care, and (5) a two-layered quality assurance process including structured clinician interviews assessing events of neurologic worsening and an adjudicated consensus review of neuroimaging and medical records. The resulting guideline's clinical feasibility was then prospectively evaluated. The institutional SAH monitoring guideline used transcranial Doppler ultrasound and cEEG monitoring for vasospasm and ischemia monitoring in patients with either Fisher group 3 or Hunt-Hess grade IV or V SAH. Safety criteria focused on prevention of skin breakdown and agitation. Technical components included monitoring of transcranial Doppler ultrasound velocities and cEEG features, including quantitative alpha:delta ratio and percent alpha variability, qualitative evidence of new focal slowing, late-onset epileptiform activity, or overall worsening of background. Structured cEEG reports were introduced including verbal communication for findings concerning

  16. Reconstruction of cerebral hemodynamics with dynamic contrast-enhanced time-resolved near-infrared measurements before and during ischemia

    NASA Astrophysics Data System (ADS)

    Elliott, Jonathan T.; Diop, Mamadou; Morrison, Laura B.; Lee, Ting-Yim; St. Lawrence, Keith

    2013-03-01

    We present a dynamic contrast-enhanced near-infrared (DCE-NIR) technique that is capable of non-invasive quantification of cerebral hemodynamics in adults. The challenge of removing extracerebral contamination is overcome through the use of multi-distance time-resolved DCE-NIR combined with the kinetic deconvolution optical reconstruction (KDOR) analytical method. As proof-of-principle, cerebral blood flow, cerebral blood volume and mean transit time recovered with DCE-NIR are compared with CT perfusion values in an adult pig during normocapnia, hypocapnia, and ischemia. Measurements of blood flow acquired with DCE-NIR were compared against concomitant measurements using CT Perfusion.

  17. Pravastatin acute neuroprotective effects depend on blood brain barrier integrity in experimental cerebral ischemia.

    PubMed

    Carone, D; Librizzi, L; Cattalini, A; Sala, G; Conti, E; Cuccione, E; Versace, A; Cai, R; Monza, L; de Curtis, M; Ferrarese, C; Beretta, S

    2015-07-30

    Statins have since long been reported to exert acute neuroprotection in experimental stroke models. However, crucial questions still need to be addressed as far as the timing of their cerebral effects after intravascular administration and the role played by the blood brain barrier (BBB) crossing properties. We tested the effects of an hydrophilic statin (pravastatin, 100 nM), which poorly crosses BBB under physiological conditions. Pravastatin was administered either 90 min before or immediately after transient middle cerebral artery occlusion in the in vitro isolated guinea pig brain preparation. A multi-modal outcome assessment was performed, through electrophysiological and cerebral vascular tone recordings, MAP-2 immunohistochemistry, BBB evaluation via ZO-1/FITC-albumin analysis, AKT and ERK activation and whole-cell antioxidant capacity. Pravastatin pre-ischemic administration did not produce any significant effect. Pravastatin post-ischemic administration significantly prevented MAP-2 immunoreactivity loss in ischemic areas, increased ERK phosphorylation in the ischemic hemisphere and enhanced whole-cell antioxidant capacity. Electrophysiological parameters, vascular tone and AKT signaling were unchanged. In all tested ischemic brains, ZO-1 fragmentation and FITC albumin extravasation was observed, starting 30 min from ischemia onset, indicating loss of BBB integrity. Our findings indicate that the rapid anti-ischemic effects of intravascular pravastatin are highly dependent on BBB increased permeability after stroke.

  18. Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia-Ischemia.

    PubMed

    Jantzie, Lauren L; Corbett, Christopher J; Firl, Daniel J; Robinson, Shenandoah

    2015-09-01

    Preterm birth impacts brain development and leads to chronic deficits including cognitive delay, behavioral problems, and epilepsy. Premature loss of the subplate, a transient subcortical layer that guides development of the cerebral cortex and axonal refinement, has been implicated in these neurological disorders. Subplate neurons influence postnatal upregulation of the potassium chloride co-transporter KCC2 and maturation of γ-amino-butyric acid A receptor (GABAAR) subunits. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) in Sprague-Dawley rats that mimic brain injury from extreme prematurity in humans would cause premature subplate loss and affect cortical layer IV development. Further, we predicted that the neuroprotective agent erythropoietin (EPO) could attenuate the injury. Prenatal TSHI induced subplate neuronal loss via apoptosis. TSHI impaired cortical layer IV postnatal upregulation of KCC2 and GABAAR subunits, and postnatal EPO treatment mitigated the loss (n ≥ 8). To specifically address how subplate loss affects cortical development, we used in vitro mechanical subplate ablation in slice cultures (n ≥ 3) and found EPO treatment attenuates KCC2 loss. Together, these results show that subplate loss contributes to impaired cerebral development, and EPO treatment diminishes the damage. Limitation of premature subplate loss and the resultant impaired cortical development may minimize cerebral deficits suffered by extremely preterm infants.

  19. Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury

    PubMed Central

    Hou, Shuai; Zhao, Ming-Ming; Shen, Ping-Ping; Liu, Xiu-Ping; Sun, Yuan; Feng, Jia-Chun

    2016-01-01

    This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co-administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway. PMID:27455249

  20. Neuroprotective Effect of Xueshuantong for Injection (Lyophilized) in Transient and Permanent Rat Cerebral Ischemia Model

    PubMed Central

    Wang, Xumei; Wang, Shaoxia; Wang, Jinxin; Guo, Hong; Dong, Zhaopeng; Chai, Lijuan; Hu, Limin; Zhang, Yue; Wang, Hong; Chen, Lu

    2015-01-01

    Xueshuantong for Injection (Lyophilized) (XST), a Chinese Materia Medica standardized product extracted from Panax notoginseng (Burk.), is used extensively for the treatment of cerebrovascular diseases such as acutely cerebral infarction clinically in China. In the present study, we evaluated the acute and extended protective effects of XST in different rat cerebral ischemic model and explored its effect on peroxiredoxin (Prx) 6-toll-like receptor (TLR) 4 signaling pathway. We found that XST treatment for 3 days could significantly inhibit transient middle cerebral artery occlusion (MCAO) induced infarct volume and swelling percent and regulate the mRNA expression of interleukin-1β (IL-1β), IL-17, IL-23p19, tumor necrosis factor-α (TNFα), and inducible nitric oxide synthase (iNOS) in brain. Further study demonstrated that treatment with XST suppressed the protein expression of peroxiredoxin (Prx) 6-toll-like receptor (TLR) 4 and phosphorylation level of p38 and upregulated the phosphorylation level of STAT3. In permanent MCAO rats, XST could reduce the infarct volume and swelling percent. Moreover, our results revealed that XST treatment could increase the rats' weight and improve a batch of functional outcomes. In conclusion, the present data suggested that XST could protect against ischemia injury in transient and permanent MCAO rats, which might be related to Prx6-TLR4 pathway. PMID:26681963

  1. Lateralization of the respiratory control following unilateral cerebral ischemia-reperfusion injury.

    PubMed

    Shoja, Mohammadali M; Tubbs, R Shane; Jamshidi, Masoud; Shokouhi, Ghaffar; Ansarin, Khalil

    2008-02-01

    Cerebral control of respiration has been extensively studied but at present, no evidence of cerebral laterality or dominance for respiration exists. We examined the ventilatory changes following temporary (20 min) occlusion of the right or left common carotid artery in rabbits. The corresponding groups of sham-operated rabbits were used as controls. The partial pressure of end-tidal carbon dioxide (PET(co2) ) was measured with a microstream capnograph before the operation as well as at 6h, and days 1, 4, 9 and 15 postoperation and was used to indicate the ventilatory status. The results showed that following temporary occlusion of the left common carotid artery, subjects began hypoventilation and had a progressive rise in PET(co2) on day 9 postoperation compared to the sham-operated group. However, animals that underwent occlusion of the right common carotid artery hyperventilated from as early as 6h postoperation to days 1 and 4, an effect that ceased up to day 9 postoperation. It was concluded that respiration might be under differential regulation by the two cerebral hemispheres. While the left hemispheric ischemia-reperfusion injury induced hypoventilation that of the right hemisphere resulted in hyperventilation. PMID:17981519

  2. Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia.

    PubMed

    Ahmad, Niyaz; Ahmad, Rizwan; Alam, Md Aftab; Samim, Mohd; Iqbal, Zeenat; Ahmad, Farhan Jalees

    2016-07-01

    Stroke is an important cause of deaths worldwide, resulting in an irreversible deterioration of the central nervous system. Finally, production of more free radicals. Therefore, Thymoquinone is having antioxidant property and reported to have a potential role in the amelioration of cerebral ischemia but due to low solubility and poor absorption; they exhibit low serum and tissue levels. Present work aims to prepare nanoemulsions in order enhance the bioavailability of drug and hence evaluate the drug targeting in brain via non-invasive nasal route administration. Thymoquinone Mucoadhesive Nanoemulsion (TMNE) was prepared by ionic gelation method; characterized for particles size, entrapment efficiency, zeta potential, and ex vivo permeation study. Optimized TMNE ended up with a mean globule size 94.8±6.61nm; zeta potential -13.5±1.01mV; drug content 99.86±0.35% and viscosity 110±12cp. Ultra Performance Liquid Chromatography-Photodiode Array (UPLC-PDA) based bioanalytical method was developed and validated for pharmacokinetics, biodistribution, brain-targeting efficiency (628.5786±44.79%) and brain drug-targeting potential (89.97±2.94%) studies via post intranasal administration which revealed enhanced bioavailability of TQ in brain as compared to intravenous administration. Improved neurobehavioural activity (locomotor and grip strength) was observed in middle cerebral artery occlusion induced cerebral ischemic rats after i.n. administration of TMNE. PMID:26976069

  3. Role of Rac1 GTPase in JNK signaling and delayed neuronal cell death following global cerebral ischemia.

    PubMed

    Zhang, Quan-Guang; Wang, Ruimin; Han, Dong; Dong, Yan; Brann, Darrell W

    2009-04-10

    The overall goal of this study was to determine the role of Rac1 in POSH/MLK/JNK signaling and delayed neuronal cell death following cerebral ischemia. Temporal studies revealed that Rac1 GTPase activation was significantly elevated in hippocampus CA1 at 10 min to 72 h after cerebral ischemia reperfusion, with peak levels 30 min to 6 h after reperfusion. Total Rac1 protein levels were not significantly changed following cerebral ischemia. Rac1 has been shown to interact with POSH (plenty of SH3s), a scaffold protein that binds to and regulates MLK3 and JNK activation. Co-immunoprecipitation (Co-IP) studies revealed that POSH-Rac1-MLK3 complex formation displayed a significant and prolonged elevation after reperfusion, with a correlative increase in phosphorylation/activation of MLK3 as compared to sham controls. Intracerebroventricular administration of Rac1 antisense oligonucleotides (AS-ODNs) significantly attenuated Rac1 levels and Rac1 activation at 30 min after reperfusion, with a correlated significant attenuation of POSH-MLK3-Rac1 complex formation and MLK3 activation in hippocampus CA1. Infusion of Rac1 AS-ODNs also significantly attenuated post-ischemic activation of JNK, downstream of MLK3, and strongly protected the hippocampus CA1 from ischemic damage. Missense oligos had no effect on any of the parameters measured. The Rac1 AS-ODNs results were further confirmed by administration of a Rac1 inhibitor (NSC23766), which markedly attenuated activation of Rac1 and JNK, and significantly attenuated apoptotic delayed neuronal cell death following cerebral ischemia. As a whole, these studies demonstrate an important role for Rac1 in activation of the prodeath MLK3-JNK kinase signaling pathway and delayed neuronal cell death following cerebral ischemia.

  4. Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2-related factor 2 pathway

    PubMed Central

    Han, Jing; Xiao, Qing; Lin, Yan-hua; Zheng, Zhen-zhu; He, Zhao-dong; Hu, Juan; Chen, Li-dian

    2015-01-01

    Salidroside, the main active ingredient extracted from Rhodiola crenulata, has been shown to be neuroprotective in ischemic cerebral injury, but the underlying mechanism for this neuroprotection is poorly understood. In the current study, the neuroprotective effect of salidroside on cerebral ischemia-induced oxidative stress and the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was investigated in a rat model of middle cerebral artery occlusion. Salidroside (30 mg/kg) reduced infarct size, improved neurological function and histological changes, increased activity of superoxide dismutase and glutathione-S-transferase, and reduced malon-dialdehyde levels after cerebral ischemia and reperfusion. Furthermore, salidroside apparently increased Nrf2 and heme oxygenase-1 expression. These results suggest that salidroside exerts its neuroprotective effect against cerebral ischemia through anti-oxidant mechanisms and that activation of the Nrf2 pathway is involved. The Nrf2/antioxidant response element pathway may become a new therapeutic target for the treatment of ischemic stroke. PMID:26889188

  5. Anti-inflammatory Effect of Mesenchymal Stromal Cell Transplantation and Quercetin Treatment in a Rat Model of Experimental Cerebral Ischemia.

    PubMed

    Zhang, Lan-Lan; Zhang, Hong-Tian; Cai, Ying-Qian; Han, Yan-Jiang; Yao, Fang; Yuan, Zhao-Hu; Wu, Bing-Yi

    2016-10-01

    Here, we have investigated the synergistic effect of quercetin administration and transplantation of human umbilical cord mesenchymal stromal cells (HUMSCs) following middle cerebral artery occlusion in rat. Combining quercetin treatment with delayed transplantation of HUMSCs after local cerebral ischemia significantly (i) improved neurological functional recovery; (ii) reduced proinflammatory cytokines (interleukin(IL)-1β and IL-6), increased anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor-β1), and reduced ED-1 positive areas; (iii) inhibited cell apoptosis (caspase-3 expression); and (iv) improved the survival rate of HUMSCs in the injury site. Altogether, our results demonstrate that combined HUMSC transplantation and quercetin treatment is a potential strategy for reducing secondary damage and promoting functional recovery following cerebral ischemia.

  6. Valeriana officinalis Extracts Ameliorate Neuronal Damage by Suppressing Lipid Peroxidation in the Gerbil Hippocampus Following Transient Cerebral Ischemia.

    PubMed

    Yoo, Dae Young; Jung, Hyo Young; Nam, Sung Min; Kim, Jong Whi; Choi, Jung Hoon; Kwak, Youn-Gil; Yoo, Miyoung; Lee, Sanghee; Yoon, Yeo Sung; Hwang, In Koo

    2015-06-01

    As a medicinal plant, the roots of Valeriana officinalis have been used as a sedative and tranquilizer. In the present study, we evaluated the neuroprotective effects of valerian root extracts (VE) on the hippocampal CA1 region of gerbils after 5 min of transient cerebral ischemia. Gerbils were administered VE orally once a day for 3 weeks, subjected to ischemia/reperfusion injury, and continued on VE for 3 weeks. The administration of 100 mg/kg VE (VE100 group) significantly reduced the ischemia-induced spontaneous motor hyperactivity 1 day after ischemia/reperfusion. Four days after ischemia/reperfusion, animals treated with VE showed abundant cresyl violet-positive neurons in the hippocampal CA1 region when compared to the vehicle or 25 mg/kg VE-treated groups. In addition, the VE treatment markedly decreased microglial activation in the hippocampal CA1 region 4 days after ischemia. Compared to the other groups, the VE100 group showed the lowest level of lipid peroxidation during the first 24 h after ischemia/reperfusion. In summary, the findings in this study suggest that pretreatment with VE has protective effects against ischemic injury in the hippocampal pyramidal neurons by decreasing microglial activation and lipid peroxidation. PMID:25785762

  7. Valeriana officinalis Extracts Ameliorate Neuronal Damage by Suppressing Lipid Peroxidation in the Gerbil Hippocampus Following Transient Cerebral Ischemia

    PubMed Central

    Yoo, Dae Young; Jung, Hyo Young; Nam, Sung Min; Kim, Jong Whi; Choi, Jung Hoon; Kwak, Youn-Gil; Yoo, Miyoung; Lee, Sanghee; Yoon, Yeo Sung

    2015-01-01

    Abstract As a medicinal plant, the roots of Valeriana officinalis have been used as a sedative and tranquilizer. In the present study, we evaluated the neuroprotective effects of valerian root extracts (VE) on the hippocampal CA1 region of gerbils after 5 min of transient cerebral ischemia. Gerbils were administered VE orally once a day for 3 weeks, subjected to ischemia/reperfusion injury, and continued on VE for 3 weeks. The administration of 100 mg/kg VE (VE100 group) significantly reduced the ischemia-induced spontaneous motor hyperactivity 1 day after ischemia/reperfusion. Four days after ischemia/reperfusion, animals treated with VE showed abundant cresyl violet-positive neurons in the hippocampal CA1 region when compared to the vehicle or 25 mg/kg VE-treated groups. In addition, the VE treatment markedly decreased microglial activation in the hippocampal CA1 region 4 days after ischemia. Compared to the other groups, the VE100 group showed the lowest level of lipid peroxidation during the first 24 h after ischemia/reperfusion. In summary, the findings in this study suggest that pretreatment with VE has protective effects against ischemic injury in the hippocampal pyramidal neurons by decreasing microglial activation and lipid peroxidation. PMID:25785762

  8. Neuroprotective effects of Alpinia katsumadai against neuronal damage in the gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Li, Hua; Yoo, Ki-Yeon; Lee, Choong Hyun; Choi, Jung Hoon; Hwang, In Koo; Kim, Jong-Dai; Kim, Young-Myeong; Kang, Il-Jun; Won, Moo-Ho

    2011-09-01

    Alpinia katsumadai, one of the family Zingiberaceae, contains chalcone, flavonoids, diarylheptanoids, monoterpenes, sesquiterpenoids, stilbenes, and labdanes. It has been reported that the extract of Alpinia katsumadai seed (EAKS) has antiinflammatory effects, and enhances antioxidant activities. We observed the neuroprotective effects of EAKS against ischemic damage in gerbils received oral administrations of EAKS (50 mg/kg) once a day for 7 days before transient cerebral ischemia. In the EAKS-treated ischemia group, neuronal nuclei (NeuN, a marker for neurons)-immunoreactive pyramidal neurons were abundant (68.3% of the sham group) in the hippocampal CA1 region (CA1) 4 days after ischemia/reperfusion (I/R) compared to those in the vehicle-treated ischemia group (13.18%). We also observed that EAKS treatment significantly decreased the activation of astrocytes and microglia in the CA1 compared with the vehicle-treated ischemia group 4 days postischemia. In addition, protein levels of GFAP and Iba-1 in the EAKS-treated ischemia group were much lower than those in the vehicle-treated ischemia group 4 days after I/P. Our findings indicate that the repeated supplements of EAKS could protect neurons from an ischemic damage, showing that glial activation is markedly decreased in the ischemic area.

  9. Activation of the Nrf2 defense pathway contributes to neuroprotective effects of phloretin on oxidative stress injury after cerebral ischemia/reperfusion in rats.

    PubMed

    Liu, Yu; Zhang, Lei; Liang, Jiangjiu

    2015-04-15

    Oxidative stress is considered a major contributing factor in cerebral ischemia/reperfusion injury. Phloretin, a dihydrochalcone belonging to the flavonoid family, is particularly rich in apples and apple-derived products. A large body of evidence demonstrates that phloretin exhibits anti-oxidant properties, and phloretin has potential implications for treating oxidative stress injuries in cerebral ischemia/reperfusion. Therefore, the neuroprotective and antioxidant effects of phloretin against ischemia/reperfusion injury, as well as related probable mechanisms, were investigated. The cerebral ischemic/reperfusion injury model was reproduced in male Sprague-Dawley rats through middle cerebral artery occlusion. At 24h after reperfusion, neurological score, infarct volume, and brain water content were assessed. Oxidative stress was evaluated by superoxide dismutases (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels. Nrf2 expression was measured by RT-PCR and western blot. Consequently, results showed that phloretin pretreatment for 14days significantly reduced infarct volume and brain edema, and ameliorated neurological scores in focal cerebral ischemia/reperfusion rats. SOD, GSH and GSH-Px activities were greatly decreased, and MDA levels significantly increased after ischemia/reperfusion injury. However, phloretin pretreatment dramatically suppressed these oxidative stress processes. Furthermore, phloretin upregulated Nrf2 mRNA and protein expression of in ischemia/reperfusion brain tissue. Taken together, phloretin exhibited neuroprotective effects in cerebral ischemia/reperfusion, and the mechanisms are associated with oxidative stress inhibition and Nrf2 defense pathway activation. PMID:25770876

  10. Delayed presentation of carotid dissection, cerebral ischemia, and infarction following blunt trauma: two cases.

    PubMed

    Blanco Pampín, J; Morte Tamayo, N; Hinojal Fonseca, R; Payne-James, J J; Jerreat, P

    2002-09-01

    Carotid artery dissection followed by cerebral infarction as a result of blunt trauma can occur in a number of forensically relevant situations. We describe two such cases. In the first case, a 19-year-old female was involved in a road traffic accident, when her car crashed into the rear of another car. Initially, the young woman presented a minor head injury without loss of consciousness and minor bruising to the left side of the neck. After 48 h, she had developed confusion, speech difficulties, right facial nerve paralysis, and right hemiplegia. CT scan and carotid angiography showed cerebral ischemia with infarction in the territory of the middle left cerebral artery and complete dissection of the left carotid artery. In the second case, a 33-year-old male with depression attempted to hang himself. The rope gave way and he fell down. He had also taken a paracetamol, and a non-steroidal anti-inflammatory drug overdose. He did not lose consciousness but appeared withdrawn and depressed. Approximately 6 h later, his conscious state deteriorated. A CT scan revealed thrombosis of the left internal carotid artery, extending to the middle cerebral artery. The patient died. Both cases reinforce the need for full neurological assessment and review of any individual subject to blunt trauma to the neck, whether accidental or deliberate or where the history is incomplete. In the forensic setting, in particular, RTAs, suspension by the neck, strangulation, and garotting are all instances when examination and assessment must be thorough--and clear advice given--in the absence of any immediate signs or symptoms--that any new symptoms or signs require immediate and thorough neurological investigation. There should be low threshold for prolonged neurological observation or further neurovascular investigations such as ultrasound, CT or MRI scan or angiography, to minimize the risk of developing potentially fatal or incapacitating sequelae.

  11. Ursolic acid reduces the metalloprotease/anti-metalloprotease imbalance in cerebral ischemia and reperfusion injury

    PubMed Central

    Wang, Yanzhe; He, Zhiyi; Deng, Shumin

    2016-01-01

    Background Activators of PPARs, particularly PPARγ, may be effective neuroprotective drugs against inflammatory responses in cerebral ischemia and reperfusion injury. Ursolic acid (UA) may act as a PPARγ agonist and serve as an anti-inflammatory agent. In this study, we used a rat middle cerebral artery occlusion and reperfusion model to examine how UA acts as a neuroprotective agent to modulate the metalloprotease/anti-metalloprotease balance. Methods The middle cerebral artery occlusion and reperfusion model (occlusion for 2 hours followed by reperfusion for 48 hours) was induced in male Sprague Dawley rats. UA was administered intragastrically 0.5, 24, and 47 hours after reperfusion. Bisphenol A diglycidyl ether (a PPARγ antagonist) was intraperitoneally administered 1, 24.5, and 47.5 hours after reperfusion. Forty-eight hours after reperfusion, neurological deficits and infarct volume were estimated. The PPARγ level and the metalloprotease/anti-metalloprotease balance were examined by Western blotting and immunohistochemistry. The activation of MAPK signaling pathways was also assessed. Results UA-treated (5, 10, or 20 mg/kg) rats showed significant improvement in neurological deficit score, infarct volume, and the number of intact neurons compared with control rats (P<0.01). Both the PPARγ protein level and the percentage of PPARγ-positive cells were increased in the UA-treated groups (P<0.01). Compared with the control group, the UA-treated groups exhibited reduced protein levels of MMP2, MMP9, and activated MAPKs (P<0.01) but an increased level of TIMP1 (P<0.01). UA exerted its protective effects in a dose-dependent manner. Co-treatment with UA and bisphenol A diglycidyl ether completely abolished the UA-induced changes in PPARγ expression; however UA continued to exert a significant but partial neuroprotective effect. Conclusion UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the

  12. Intraventricular brain-derived neurotrophic factor reduces infarct size after focal cerebral ischemia in rats.

    PubMed

    Schäbitz, W R; Schwab, S; Spranger, M; Hacke, W

    1997-05-01

    Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 micrograms/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls (P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 +/- 27.1 mm3 in BDNF-treated animals and 139.2 +/- 56.4 mm3 in controls (mean +/- SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 +/- 7.1 mm3 in BDNF-treated animals and 37.9 +/- 19.8 mm3 in controls (mean +/- SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal

  13. Protective effect of magnesium nitrate against neurological disorders provoked by cerebral ischemia in rats.

    PubMed

    Kuzenkov, V S; Krushinskii, A L

    2014-10-01

    The study examined effects of inorganic magnesium agents: magnesium nitrate Mg(NO3)2, magnesium sulfate MgSO4, and magnesium chloride MgCl2 on the development of neurological disorders and mortality in rats resulting from cerebral ischemia provoked by a single-stage bilateral occlusion of the common carotid arteries. The rats were injected with one of examined magnesium preparations (5 mg/1 kg body weight) 1 h prior to or 1-2 sec after occlusion. The control group rats were treated with physiological saline at the same terms. Irrespective of the moment of injection, magnesium nitrate demonstrated significant protective effect on dynamics of neurological disorders and mortality, while similar effects of magnesium sulfate and magnesium chloride were insignificant.

  14. ROCK inhibition prevents tau hyperphosphorylation and p25/CDK5 increase after global cerebral ischemia.

    PubMed

    Castro-Alvarez, John Fredy; Gutierrez-Vargas, Johanna; Darnaudéry, Muriel; Cardona-Gómez, Gloria Patricia

    2011-06-01

    Rho-kinase (ROCK) is a downstream effector of RhoA, which has been associated with growth cone collapse and retraction in neurons. ROCK inhibition has been shown to protect against ischemic damage, thereby improving short-term collateral flow, inhibiting platelet aggregation, leukocyte adhesion, and preventing neuronal death. However, little is known about the long-term effects of ROCK inhibition on behavior and neuroprotection. The consequence of ROCK inhibition on ischemic rats' learning and spatial memory after 30 days of intracerebroventricular treatment was evaluated. It was found that Y27632 (ROCK inhibitor) reduced neurodegenerative markers, such as Fluoro-Jade, PHF (paired helicoidal filaments) immunoreactivity, and p25 protein levels, in the hippocampus of ischemic animals and improved learning and spatial memory tasks. However, Y27632 alone impaired sham animals' long-term memory. These findings demonstrated the beneficial impact of ROCK inhibition on tauopathy and altered p25 protein levels following global cerebral ischemia.

  15. Inhibition on the S-nitrosylation of MKK4 can protect hippocampal CA1 neurons in rat cerebral ischemia/reperfusion.

    PubMed

    Wei, Xue Wen; Hao, Ling Yun; Qi, Su Hua

    2016-06-01

    S-nitrosylation, the nitric oxide-derived post-translational modification of proteins, plays critical roles in various physiological and pathological functions. In this present study, a rat model of cerebral ischemia and reperfusion by four-vessel occlusion was generated to assess MKK4 S-nitrosylation. Immunoprecipitation and immunoblotting were performed to evaluate MKK4 S-nitrosylation and phosphorylation. Neuronal loss was observed using histological detection. These results indicated that endogenous NO promoted the S-nitrosylation of MKK4. However, application of the exogenous NO donor S-nitrosoglutathione (GNSO), an inhibitor of the neuronal nitric oxide synthase 7-nitroindazole (7-NI), and the N-methyl-d-aspartate receptor (NMDAR) antagonist MK801 diminished I/R-induced S-nitrosylation and phosphorylation. These compounds also markedly decreased cerebral I/R-induced degeneration and death of neurons in hippocampal CA1 region in rats. Taken together, we demonstrated for the first time, that cerebral ischemia/reperfusion can induce S-nitrosylation of MKK4. We also found that inhibiting S-nitrosylation and activation of MKK4 resulted in marked decreases in neuronal degeneration and apoptosis, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stoke and the development of novel treatment strategies.

  16. Secretory phospholipase A2 inhibitor PX-18 preserves microvascular reactivity after cerebral ischemia in piglets.

    PubMed

    Domoki, Ferenc; Zimmermann, Alíz; Lenti, Laura; Tóth-Szuki, Valéria; Pardeike, Jana; Müller, Rainer H; Bari, Ferenc

    2009-09-01

    Cerebral ischemia/reperfusion (I/R) results in cellular energy failure and dysfunction of the neurovascular unit that contribute to subsequent neuronal cell death in the neonate. PX-18 is a putative neuroprotective inhibitor of secretory phospholipase A(2) (sPLA(2)) but its in vivo testing has been limited by its poor solubility. Our purpose was to assess whether PX-18 preserved neuronal-vascular reactivity to I/R-sensitive endothelium-dependent (hypercapnia, bradykinin) and/or neuron-dependent (N-methyl-D-aspartate; NMDA) stimuli. To make the drug available for in vivo studies, PX-18 was formulated as a 3% nanosuspension applying high pressure homogenization. Newborn piglets (1-day old, n=40) were anesthetized and ventilated, and cerebrovascular reactivity to the above stimuli was determined by measuring changes in pial arteriolar diameters using the closed cranial window/intravital videomicroscopy technique. Intravenous infusion of PX-18 nanosuspension (6 mg/kg, 20 min) did not affect baseline arteriolar diameters, or hypercapnia-, bradykinin-, or NMDA-induced pial arteriolar vasodilation under normoxic conditions. Global cerebral ischemia (10 min) followed by 1 h of reperfusion significantly attenuated hypercapnia-, bradykinin-, and NMDA-induced vasodilation in untreated or vehicle-treated controls. However, PX-18 resulted in nearly full preservation of cerebrovascular reactivity to all these stimuli. In conclusion, inhibition of sPLA(2) by PX-18 improves neurovascular function both at the neuronal and the microvascular level following I/R. This effect of PX-18 likely contributes to its neuroprotective effect. PMID:19555699

  17. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man.

    PubMed

    Caltagirone, Carlo; Cisari, Carlo; Schievano, Carlo; Di Paola, Rosanna; Cordaro, Marika; Bruschetta, Giuseppe; Esposito, Emanuela; Cuzzocrea, Salvatore

    2016-02-01

    Acute ischemic stroke, the most frequent cause of permanent disability in adults worldwide, results from transient or permanent reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Despite the success of experimental animal models of stroke in identifying anti-inflammatory/neuroprotective compounds, translation of these putative neuroprotectants to human clinical trials has failed to produce a positive outcome. Tissue injury and stress activate endogenous mechanisms which function to restore homeostatic balance and prevent further damage by upregulating the synthesis of lipid signaling molecules, including N-palmitoylethanolamine (PEA or palmitoylethanolamide). PEA exerts neuroprotection and reduces inflammatory secondary events associated with brain ischemia reperfusion injury (middle cerebral artery occlusion (MCAo)). Here, we examined the neuroprotective potential of a co-ultramicronized composite containing PEA and the antioxidant flavonoid luteolin (10:1 by mass), nominated co-ultraPEALut. The study consisted of two arms. In the first, rats subjected to MCAo and treated with co-ultraPEALut post-ischemia showed reduced edema and brain infract volume, improved neurobehavioral functions, and reduced expression of pro-inflammatory markers and astrocyte markers. In the second arm, a cohort of 250 stroke patients undergoing neurorehabilitation on either an inpatient or outpatient basis were treated for 60 days with a pharmaceutical preparation of co-ultraPEALut (Glialia). At baseline and after 30 days of treatment, all patients underwent a battery of evaluations to assess neurological status, impairment of cognitive abilities, the degree of spasticity, pain, and independence in daily living activities. All indices showed statistically significant gains at study end. Despite its observational nature, this represents the first description of co-ultraPEALut administration to human stroke patients and clinical improvement not

  18. Burst predicting neurons survive an in vitro glutamate injury model of cerebral ischemia

    PubMed Central

    Kuebler, Eric S.; Tauskela, Joseph S.; Aylsworth, Amy; Zhao, Xigeng; Thivierge, Jean-Philippe

    2015-01-01

    Neuronal activity in vitro exhibits network bursts characterized by brief periods of increased spike rates. Recent work shows that a subpopulation of neurons reliably predicts the occurrence of network bursts. Here, we examined the role of burst predictors in cultures undergoing an in vitro model of cerebral ischemia. Dissociated primary cortical neurons were plated on multielectrode arrays and spontaneous activity was recorded at 17 days in vitro (DIV). This activity was characterized by neuronal avalanches where burst statistics followed a power law. We identified burst predictors as channels that consistently fired immediately prior to network bursts. The timing of these predictors relative to bursts followed a skewed distribution that differed sharply from a null model based on branching ratio. A portion of cultures were subjected to an excitotoxic insult (DIV 18). Propidium iodine and fluorescence imaging confirmed cell death in these cultures. While the insult did not alter the distribution of avalanches, it resulted in alterations in overall spike rates. Burst predictors, however, maintained baseline levels of activity. The resilience of burst predictors following excitotoxic insult suggests a key role of these units in maintaining network activity following injury, with implications for the selective effects of ischemia in the brain. PMID:26648112

  19. A Possible Molecular Mechanism of Hearing loss during cerebral ischemia in mice

    PubMed Central

    Kamat, Pradip Kumar; Kalani, Anuradha; Metreveli, Naira; Tyagi, Suresh. C.; Tyagi, Neetu

    2015-01-01

    Ischemic brain stroke is a leading cause of disability, including the hearing loss. Clinical reports also suggest hearing loss in stroke patients but the mechanism is still unclear. Therefore, we hypothesize that hearing loss after cerebral ischemia may be associated with alteration in synapse, gap junctions, and sodium channel (NaC) proteins. Ischemia reperfusion injury was performed in wild type mice. Lesion volume was determined by TTC staining of the brain sections. BBB disruption was confirmed by Evans blue and BSA-FITC leakage. We found that brain edema, infarct size and permeability were increased in ischemic mice as compared to the sham. Caspase-3,-9 and TUNEL positive cells were increased in I/R mice indicates neuronal apoptosis. Moreover, increased expressions of matrix metalloprotease’s (MMP-2,-3,-9,-13), IL-6, and decreased expressions of tight junction proteins (TJP) in I/R group, as compared to the sham group signifies inflammation and BBB disruption. We also observed decreased levels of PSD95, SAP97, Connexin-43, NaC-α, NaC-β, and increased expression of Connexin-45, whereas no substantial change was observed in Connexin-26 expression in I/R group. Interestingly, auditory response was reduced in I/R mice indicates hearing loss. This data suggests that hearing loss in ischemic mice was primarily due to the alteration in connexin, synapse, and NaC channels. PMID:26034997

  20. Burst predicting neurons survive an in vitro glutamate injury model of cerebral ischemia.

    PubMed

    Kuebler, Eric S; Tauskela, Joseph S; Aylsworth, Amy; Zhao, Xigeng; Thivierge, Jean-Philippe

    2015-12-09

    Neuronal activity in vitro exhibits network bursts characterized by brief periods of increased spike rates. Recent work shows that a subpopulation of neurons reliably predicts the occurrence of network bursts. Here, we examined the role of burst predictors in cultures undergoing an in vitro model of cerebral ischemia. Dissociated primary cortical neurons were plated on multielectrode arrays and spontaneous activity was recorded at 17 days in vitro (DIV). This activity was characterized by neuronal avalanches where burst statistics followed a power law. We identified burst predictors as channels that consistently fired immediately prior to network bursts. The timing of these predictors relative to bursts followed a skewed distribution that differed sharply from a null model based on branching ratio. A portion of cultures were subjected to an excitotoxic insult (DIV 18). Propidium iodine and fluorescence imaging confirmed cell death in these cultures. While the insult did not alter the distribution of avalanches, it resulted in alterations in overall spike rates. Burst predictors, however, maintained baseline levels of activity. The resilience of burst predictors following excitotoxic insult suggests a key role of these units in maintaining network activity following injury, with implications for the selective effects of ischemia in the brain.

  1. Burst predicting neurons survive an in vitro glutamate injury model of cerebral ischemia.

    PubMed

    Kuebler, Eric S; Tauskela, Joseph S; Aylsworth, Amy; Zhao, Xigeng; Thivierge, Jean-Philippe

    2015-01-01

    Neuronal activity in vitro exhibits network bursts characterized by brief periods of increased spike rates. Recent work shows that a subpopulation of neurons reliably predicts the occurrence of network bursts. Here, we examined the role of burst predictors in cultures undergoing an in vitro model of cerebral ischemia. Dissociated primary cortical neurons were plated on multielectrode arrays and spontaneous activity was recorded at 17 days in vitro (DIV). This activity was characterized by neuronal avalanches where burst statistics followed a power law. We identified burst predictors as channels that consistently fired immediately prior to network bursts. The timing of these predictors relative to bursts followed a skewed distribution that differed sharply from a null model based on branching ratio. A portion of cultures were subjected to an excitotoxic insult (DIV 18). Propidium iodine and fluorescence imaging confirmed cell death in these cultures. While the insult did not alter the distribution of avalanches, it resulted in alterations in overall spike rates. Burst predictors, however, maintained baseline levels of activity. The resilience of burst predictors following excitotoxic insult suggests a key role of these units in maintaining network activity following injury, with implications for the selective effects of ischemia in the brain. PMID:26648112

  2. Procaspase-9 induces its cleavage by transnitrosylating XIAP via the Thioredoxin system during cerebral ischemia-reperfusion in rats

    PubMed Central

    Zhang, Dengyue; Zhao, Ningjun; Ma, Bin; Wang, Yan; Zhang, Gongliang; Yan, Xianliang; Hu, Shuqun; Xu, Tie

    2016-01-01

    Transnitrosylation is an important mechanism by which nitric oxide (NO) modulates cell signaling pathways. For instance, SNO-caspase-3 can transnitrosylate the X-linked inhibitor of apoptosis (XIAP) to enhance apoptosis. XIAP is a potent antagonist of caspase apoptotic activity. Decrease in XIAP activity via nitrosylation results in SNO-XIAP-mediated caspase activation. Considering the functional liaison of procaspase-9 and XIAP, we hypothesized that procaspase-9 nitrosylates XIAP directly. Our data confirmed that cerebral ischemia-reperfusion induced XIAP nitrosylation, procaspase-9 denitrosylation and cleavage. Interestingly, the time courses of the nitrosylation of procaspase-9 and XIAP were negatively correlated, which was more prominent after cerebral ischemia-reperfusion, suggesting a direct interaction. The nitrosylation of XIAP, as well as the denitrosylation and cleavage of procaspase-9, were inhibited by DNCB, TrxR1 AS-ODNs, or TAT-AVPY treatment. Meanwhile, DNCB, TrxR1 AS-ODNs, or TAT-AVPY also inhibited the decrease in hippocampal CA1 neurons induced by ischemia-reperfusion in rats. The denitrosylation and cleavage of procaspase-9 induced by OGD/reoxygenation in SH-SY5Y cells were inhibited when cells were co-transfected with wild-type procaspase-9 and XIAP mutant (C449G). These data suggest that cerebral ischemia-reperfusion induces a transnitrosylation from procaspase-9 to XIAP via the Trx system to consequently cause apoptosis. Additionally, Cys325 is a critical S-nitrosylation site of procaspase-9. PMID:27052476

  3. Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

    PubMed

    Davidson, Joanne O; Rout, Alexandra L; Wassink, Guido; Yuill, Caroline A; Zhang, Frank G; Green, Colin R; Bennet, Laura; Gunn, Alistair J

    2015-12-01

    Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep.

  4. Non-additive effects of delayed connexin hemichannel blockade and hypothermia after cerebral ischemia in near-term fetal sheep.

    PubMed

    Davidson, Joanne O; Rout, Alexandra L; Wassink, Guido; Yuill, Caroline A; Zhang, Frank G; Green, Colin R; Bennet, Laura; Gunn, Alistair J

    2015-12-01

    Hypothermia is partially neuroprotective after neonatal hypoxic-ischemic encephalopathy. Blockade of connexin hemichannels can improve recovery of brain activity and cell survival after ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed hypothermia with connexin hemichannel blockade with intracerebroventricular infusion of a mimetic peptide can further improve outcomes after cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8), hypothermia for 3 days (n=8), connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or hypothermia plus hemichannel blockade (n=7). After 7 days recovery, hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined hypothermia and hemichannel blockade after cerebral ischemia in near-term fetal sheep. PMID:26174327

  5. Procaspase-9 induces its cleavage by transnitrosylating XIAP via the Thioredoxin system during cerebral ischemia-reperfusion in rats.

    PubMed

    Zhang, Dengyue; Zhao, Ningjun; Ma, Bin; Wang, Yan; Zhang, Gongliang; Yan, Xianliang; Hu, Shuqun; Xu, Tie

    2016-01-01

    Transnitrosylation is an important mechanism by which nitric oxide (NO) modulates cell signaling pathways. For instance, SNO-caspase-3 can transnitrosylate the X-linked inhibitor of apoptosis (XIAP) to enhance apoptosis. XIAP is a potent antagonist of caspase apoptotic activity. Decrease in XIAP activity via nitrosylation results in SNO-XIAP-mediated caspase activation. Considering the functional liaison of procaspase-9 and XIAP, we hypothesized that procaspase-9 nitrosylates XIAP directly. Our data confirmed that cerebral ischemia-reperfusion induced XIAP nitrosylation, procaspase-9 denitrosylation and cleavage. Interestingly, the time courses of the nitrosylation of procaspase-9 and XIAP were negatively correlated, which was more prominent after cerebral ischemia-reperfusion, suggesting a direct interaction. The nitrosylation of XIAP, as well as the denitrosylation and cleavage of procaspase-9, were inhibited by DNCB, TrxR1 AS-ODNs, or TAT-AVPY treatment. Meanwhile, DNCB, TrxR1 AS-ODNs, or TAT-AVPY also inhibited the decrease in hippocampal CA1 neurons induced by ischemia-reperfusion in rats. The denitrosylation and cleavage of procaspase-9 induced by OGD/reoxygenation in SH-SY5Y cells were inhibited when cells were co-transfected with wild-type procaspase-9 and XIAP mutant (C449G). These data suggest that cerebral ischemia-reperfusion induces a transnitrosylation from procaspase-9 to XIAP via the Trx system to consequently cause apoptosis. Additionally, Cys325 is a critical S-nitrosylation site of procaspase-9. PMID:27052476

  6. Extremely low frequency magnetic field induced changes in motor behaviour of gerbils submitted to global cerebral ischemia.

    PubMed

    Rauš, Snežana; Selaković, Vesna; Radenović, Lidija; Prolić, Zlatko; Janać, Branka

    2012-03-17

    The purpose of this study was to evaluate behavioural effects of an extremely low frequency magnetic field (ELF-MF) in 3-month-old Mongolian gerbils submitted to global cerebral ischemia. After 10-min occlusion of both common carotid arteries, the gerbils were placed in the vicinity of an electromagnet and continuously exposed to ELF-MF (50Hz, 0.5mT) for 7 days. Their behaviour (locomotion, stereotypy, rotations, and immobility) was monitored on days 1, 2, 4, 7, and 14 after reperfusion for 60min in the open field. It was shown that the 10-min global cerebral ischemia per se induced a significant motor activity increase (locomotion, stereotypy and rotations), and consequently immobility decrease until day 4 after reperfusion, compared to control gerbils. Exposure to ELF-MF inhibited development of ischemia-induced motor hyperactivity during the whole period of registration, but significantly in the first 2 days after reperfusion, when the postischemic hyperactivity was most evident. Motor activity of these gerbils was still significantly increased compared to control ones, but only on day 1 after reperfusion. Our results revealed that the applied ELF-MF (50Hz, 0.5mT) decreased motor hyperactivity induced by the 10-min global cerebral ischemia, via modulation of the processes that underlie this behavioural response.

  7. Enhanced Endothelin-1 Mediated Vasoconstriction of the Ophthalmic Artery May Exacerbate Retinal Damage after Transient Global Cerebral Ischemia in Rat

    PubMed Central

    Blixt, Frank W.; Johansson, Sara Ellinor; Johnson, Leif; Haanes, Kristian Agmund; Warfvinge, Karin; Edvinsson, Lars

    2016-01-01

    Cerebral vasculature is often the target of stroke studies. However, the vasculature supplying the eye might also be affected by ischemia. The aim of the present study was to investigate if the transient global cerebral ischemia (GCI) enhances vascular effect of endothelin-1 (ET-1) and 5-hydroxytryptamine/serotonin (5-HT) on the ophthalmic artery in rats, leading to delayed retinal damage. This was preformed using myography on the ophthalmic artery, coupled with immunohistochemistry and electroretinogram (ERG) to assess the ischemic consequences on the retina. Results showed a significant increase of ET-1 mediated vasoconstriction at 48 hours post ischemia. The retina did not exhibit any morphological changes throughout the study. However, we found an increase of GFAP and vimentin expression at 72 hours and 7 days after ischemia, indicating Müller cell mediated gliosis. ERG revealed significantly decreased function at 72 hours, but recovered almost completely after 7 days. In conclusion, we propose that the increased contractile response via ET-1 receptors in the ophthalmic artery after 48 hours may elicit negative retinal consequences due to a second ischemic period. This may exacerbate retinal damage after ischemia as illustrated by the decreased retinal function and Müller cell activation. The ophthalmic artery and ET-1 mediated vasoconstriction may be a valid and novel therapeutic target after longer periods of ischemic insults. PMID:27322388

  8. Cholinergic receptor blockade by scopolamine and mecamylamine exacerbates global cerebral ischemia induced memory dysfunction in C57BL/6J mice.

    PubMed

    Ray, R S; Rai, S; Katyal, A

    2014-12-01

    Global cerebral ischemia/reperfusion (GCI/R) injury encompasses complex pathophysiological sequalae, inducing loss of hippocampal neurons and behavioural deficits. Progressive neuronal death and memory dysfunctions culminate from several different mechanisms like oxidative stress, excitotoxicity, neuroinflammation and cholinergic hypofunction. Experimental evidences point to the beneficial effects of cholinomimetic agents such as rivastigmine and galantamine in improving memory outcomes following GCI/R injury. However, the direct implications of muscarinic and nicotinic receptor blockade during global cerebral ischemia/reperfusion injury have not been investigated. Therefore, we evaluated the relative involvement of muscarinic and nicotinic receptors in spatial/associative memory functions and neuronal damage during global cerebral ischemia reperfusion injury. The outcomes of present study support the idea that preservation of both muscarinic and nicotinic receptor functions is essential to alleviate hippocampal neuronal death in CA1 region following global cerebral ischemia/reperfusion injury. PMID:25168578

  9. The rapid decrease in astrocyte-associated dystroglycan expression by focal cerebral ischemia is protease-dependent

    PubMed Central

    Milner, Richard; Hung, Stephanie; Wang, Xiaoyun; Spatz, Maria; Zoppo, Gregory J del

    2008-01-01

    During focal cerebral ischemia, the detachment of astrocytes from the microvascular basal lamina is not completely explained by known integrin receptor expression changes. Here, the impact of experimental ischemia (oxygen–glucose deprivation (OGD)) on dystroglycan expression by murine endothelial cells and astrocytes grown on vascular matrix laminin, perlecan, or collagen and the impact of middle cerebral artery occlusion on αβ-dystroglycan within cerebral microvessels of the nonhuman primate were examined. Dystroglycan was expressed on all cerebral microvessels in cortical gray and white matter, and the striatum. Astrocyte adhesion to basal lamina proteins was managed in part by α-dystroglycan, while ischemia significantly reduced expression of dystroglycan both in vivo and in vitro. Furthermore, dystroglycan and integrin α6β4 expressions on astrocyte end-feet decreased in parallel both in vivo and in vitro. The rapid loss of astrocyte dystroglycan during OGD appears protease-dependent, involving an matrix metalloproteinase-like activity. This may explain the rapid detachment of astrocytes from the microvascular basal lamina during ischemic injury, which could contribute to significant changes in microvascular integrity. PMID:18030304

  10. Blood-Spinal Cord Barrier Alterations in Subacute and Chronic Stages of a Rat Model of Focal Cerebral Ischemia.

    PubMed

    Garbuzova-Davis, Svitlana; Haller, Edward; Tajiri, Naoki; Thomson, Avery; Barretta, Jennifer; Williams, Stephanie N; Haim, Eithan D; Qin, Hua; Frisina-Deyo, Aric; Abraham, Jerry V; Sanberg, Paul R; Van Loveren, Harry; Borlongan, Cesario V

    2016-07-01

    We previously demonstrated blood-brain barrier impairment in remote contralateral brain areas in rats at 7 and 30 days after transient middle cerebral artery occlusion (tMCAO), indicating ischemic diaschisis. Here, we focused on effects of subacute and chronic focal cerebral ischemia on the blood-spinal cord barrier (BSCB). We observed BSCB damage on both sides of the cervical spinal cord in rats at 7 and 30 days post-tMCAO. Major BSCB ultrastructural changes in spinal cord gray and white matter included vacuolated endothelial cells containing autophagosomes, pericyte degeneration with enlarged mitochondria, astrocyte end-feet degeneration and perivascular edema; damaged motor neurons, swollen axons with unraveled myelin in ascending and descending tracts and astrogliosis were also observed. Evans Blue dye extravasation was maximal at 7 days. There was immunofluorescence evidence of reduction of microvascular expression of tight junction occludin, upregulation of Beclin-1 and LC3B immunoreactivities at 7 days and a reduction of the latter at 30 days post-ischemia. These novel pathological alterations on the cervical spinal cord microvasculature in rats after tMCAO suggest pervasive and long-lasting BSCB damage after focal cerebral ischemia, and that spinal cord ischemic diaschisis should be considered in the pathophysiology and therapeutic approaches in patients with ischemic cerebral infarction. PMID:27283328

  11. Down-regulated Na+/K+-ATPase activity in ischemic penumbra after focal cerebral ischemia/reperfusion in rats

    PubMed Central

    Huang, Hao; Chen, Yang-Mei; Zhu, Fei; Tang, Shi-Ting; Xiao, Ji-Dong; Li, Lv-Li; Lin, Xin-Jing

    2015-01-01

    This study was aimed to examine whether the Na+/K+ adenosine triphosphatase (Na+/K+-ATPase) activity in ischemic penumbra is associated with the pathogenesis of ischemia/reperfusion-induced brain injury. An experimental model of cerebral ischemia/reperfusion was made by transient middle cerebral artery occlusion (tMCAO) in rats and the changes of Na+/K+-ATPase activity in the ischemic penumbra was examined by Enzyme Assay Kit. Extensive infarction was observed in the frontal and parietal cortical and subcortical areas at 6 h, 24 h, 48 h, 3 d and 7 d after tMCAO. Enzyme Assay analyses revealed the activity of Na+/K+-ATPase was decreased in the ischemic penumbra of model rats after focal cerebral ischemia/reperfusion compared with sham-operated rats, and reduced to its minimum at 48 h, while the infarct volume was enlarged gradually. In addition, accompanied by increased brain water content, apoptosis-related bcl-2 and Bax proteins, apoptotic index and neurologic deficits Longa scores, but fluctuated the ratio of bcl-2/Bax. Correlation analysis showed that the infarct volume, apoptotic index, neurologic deficits Longa scores and brain water content were negatively related with Na+/K+-ATPase activity, while the ratio of bcl-2/Bax was positively related with Na+/K+-ATPase activity. Our results suggest that down-regulated Na+/K+-ATPase activity in ischemic penumbra might be involved in the pathogenesis of cerebral ischemia/reperfusion injury presumably through the imbalance ratio of bcl-2/Bax and neuronal apoptosis, and identify novel target for neuroprotective therapeutic intervention in cerebral ischemic disease. PMID:26722460

  12. Neuroprotective Effect of 6-Paradol in Focal Cerebral Ischemia Involves the Attenuation of Neuroinflammatory Responses in Activated Microglia

    PubMed Central

    Park, Sung Hyuk; Chun, Kwang-Hoon; Kim, Sun Yeou; Shin, Dong Yun; Choi, Ji Woong

    2015-01-01

    Paradols are non-pungent and biotransformed metabolites of shogaols and reduce inflammatory responses as well as oxidative stress as shogaols. Recently, shogaol has been noted to possess therapeutic potential against several central nervous system (CNS) disorders, including cerebral ischemia, by reducing neuroinflammation in microglia. Therefore, paradol could be used to improve neuroinflammation-associated CNS disorders. Here, we synthesized paradol derivatives (2- to 10-paradols). Through the initial screening for anti-inflammatory activities using lipopolysaccharide (LPS)-stimulated BV2 microglia, 6-paradol was chosen to be the most effective compound without cytotoxicity. Pretreatment with 6-paradol reduced neuroinflammatory responses in LPS-stimulated BV2 microglia by a concentration-dependent manner, which includes reduced NO production by inhibiting iNOS upregulation and lowered secretion of proinflammatory cytokines (IL-6 and TNF-α). To pursue whether the beneficial in vitro effects of 6-paradol leads towards in vivo therapeutic effects on transient focal cerebral ischemia characterized by neuroinflammation, we employed middle cerebral artery occlusion (MCAO)/reperfusion (M/R). Administration of 6-paradol immediately after reperfusion significantly reduced brain damage in M/R-challenged mice as assessed by brain infarction, neurological deficit, and neural cell survival and death. Furthermore, as observed in cultured microglia, 6-paradol administration markedly reduced neuroinflammation in M/R-challenged brains by attenuating microglial activation and reducing the number of cells expressing iNOS and TNF-α, both of which are known to be produced in microglia following M/R challenge. Collectively, this study provides evidences that 6-paradol effectively protects brain after cerebral ischemia, likely by attenuating neuroinflammation in microglia, suggesting it as a potential therapeutic agent to treat cerebral ischemia. PMID:25789481

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

    PubMed Central

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

    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 improve functional outcome after global cerebral ischemia. Incomplete global cerebral ischemia was induced in Wistar rats and the time-course of enhanced contractile responses and the effect of U0126 in cerebral arteries were studied by wire myography and the neuronal cell death by TUNEL. The expression of ETB and 5-HT1B receptors was determined by immunofluorescence. Results Enhanced vasoconstriction peaked in fore- and midbrain arteries 3 days after ischemia. Neuronal cell death appeared initially in the hippocampus 3 days after ischemia and gradually increased until 7 days post-ischemia. Treatment with U0126 normalised cerebrovascular ETB and 5-HT1B receptor expression and contractile function, reduced hippocampal cell death and improved survival rate compared to vehicle treated animals. Conclusions Excessive cerebrovascular expression of contractile ETB and 5-HT1B receptors is a delayed response to global cerebral ischemia peaking 3 days after the insult, which likely contributes to the development of delayed neuronal damage. The enhanced cerebrovascular contractility can be

  14. Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells.

    PubMed

    Schock, Sarah C; Edrissi, Hamidreza; Burger, Dylan; Cadonic, Robert; Hakim, Antoine; Thompson, Charlie

    2014-07-18

    Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry. When MPs were added to cultured endothelial cells or normal rat kidney cells they induced cell death in a time and dose dependent manner. Analysis of pellets by electron microscopy indicates that cell death signals are carried by particles in the range of 400 nm in diameter or less. Cell death involved the activation of caspase 3 and was not a consequence of oxidative stress. Inhibition of the Fas/FasL signaling pathway also did not improve cell survival. MPs were found to contain caspase 3 and treating the MPs with a caspase 3 inhibitor significantly reduced cell death. A TNF-α receptor blocker and a TRAIL neutralizing antibody also significantly reduced cell death. Levels of circulating MPs are elevated in a rodent model of chronic cerebral ischemia. MPs with a diameter of 400 nm or less activate the TNF-α and TRAIL signaling pathways and may deliver caspase 3 to cultured cells. PMID:24976400

  15. The neuroprotective effects of intravascular low level laser irradiation on cerebral ischemia rats

    NASA Astrophysics Data System (ADS)

    Qiu, Yongming; Lu, Zhaofeng; Wang, Zhongguang; Jiang, Jiyao

    2005-07-01

    The effects of intravascular low level laser irradiation of He-Ne on rat MCAo-induced cerebral injury were studied. The results showed that control rats (subjected to MCAo injury without laser treatment) at 7d exhibited striatal and cortical brain infarction in the right hemisphere from approximately 3 to 11mm from the front pole. the total infarct volume in this group was 34.5+/-8.1mm3. For experimental rats (with laser management), the total infarct volume was 29.0+/-9.0mm3. P was gained less than 0.05. The neurological score of control group was 4.7+/-0.6 and it was 5.2+/-1.0 in experimental group, comparison by statistical analysis showed P less than 0.05. The cerebral pathological damages in the control group were more severe than in experimental group. We concluded that the intravascular low level laser irradiation has no remarked complication and is helpful to reduce ischemic damage. There is clinically potential for the application of intravascular He-Ne low level laser irradiation in ischemia stroke.

  16. Combination of HBO and Memantine in Focal Cerebral Ischemia: Is There a Synergistic Effect?

    PubMed

    Wang, Feng; Liang, Wei; Lei, Chong; Kinden, Renee; Sang, Hanfei; Xie, Yaning; Huang, Yi; Qu, Yan; Xiong, Lize

    2015-12-01

    Hyperbaric oxygen (HBO) therapy and memantine, a non-competitive NMDA antagonist, are both promising treatment strategies for improving stroke prognosis. However, HBO's narrow therapeutic time window (<6 h post-stroke) and the adverse effect of high-dose MEM administration limits the use of these therapeutic interventions. In this study, we investigated whether or not MEM could prolong the narrow therapeutic window of HBO treatment. Transient focal cerebral ischemia was induced in male Sprague-Dawley rats by middle cerebral artery occlusion (MCAO) for 120 min. MCAO produced neurobehavioral deficits, increased infarction volume, increased Evans blue (EB) content and levels of pro-inflammatory factors, as well as depleted glutathione (GSH), and reduced catalase (CAT) and superoxide dismutase (SOD) activity in the ischemic ipsilateral hemisphere. The combination of 5 mg/kg MEM treatment 15 min after the onset of ischemic event and HBO therapy 12 h post-reperfusion significantly restored neurologic scores, EB concentration and IL-10 levels, as well as significantly decreased infarct volume and increased antioxidant activity. These results imply that the combination of MEM and HBO therapy not only prolongs the therapeutic window of HBO treatment, but also lowers the dosage requirement of MEM. The mechanism underlying the neuroprotective effects of the combined treatment may lie in alleviated blood-brain barrier (BBB) permeability, inhibited inflammatory response, and up-regulation of the antioxidant enzyme activity.

  17. Autophagy Upregulation and Apoptosis Downregulation in DAHP and Triptolide Treated Cerebral Ischemia

    PubMed Central

    Yang, Yang; Gao, Keqiang; Hu, Zhiying; Li, Weiyun; Davies, Henry; Ling, Shucai; Rudd, John A.; Fang, Marong

    2015-01-01

    It has previously been demonstrated that ischemic stroke activates autophagy pathways; however, the mechanism remains unclear. The aim of this study is to further investigate the role that autophagy plays in cerebral ischemia. 2, 4-diamino-6-hydroxy-pyrimidine (DAHP), for its nitric oxide synthase (NOS) inhibiting neuroprotective effect, and triptolide (TP), for its anti-inflammatory property, were selected to administer pre middle cerebral artery occlusion (MCAO). The drugs were administered 12 hours prior to MCAO. Both magnetic resonance imaging (MRI) and 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the drugs reduce the area of infarction. Immunoblotting analysis revealed increases in Beclin-1 and myeloid cell leukelia-1(Mcl-1) in treated rats. This could be a contributing factor to the reduction in autophagy induced damage. Immunochemistry and western blot showed that mTOR expression in treated rats was marginally different 24 h after injury, and this could also be significant in the mechanism. Furthermore, terminal deoxynucleotidyl transferase- (TdT-) mediated dUTP nick end labeling (TUNEL) staining proved that the drugs are effective in reducing apoptosis. The upregulation of Beclin-1 and Mcl-1 and downregulation of Bcl-2, caspase-3, and the Bcl-2/Beclin-1 ratio infer that the neuroprotective effect of DAHP and TP act via the mediation of autophagy and apoptosis pathways. PMID:25729215

  18. Effects of high and low 17β-estradiol doses on focal cerebral ischemia in rats

    PubMed Central

    Ingberg, Edvin; Theodorsson, Elvar; Theodorsson, Annette; Ström, Jakob O.

    2016-01-01

    The majority of the numerous animal studies of the effects of estrogens on cerebral ischemia have reported neuroprotective results, but a few have shown increased damage. Differences in hormone administration methods, resulting in highly different 17β-estradiol levels, may explain the discrepancies in previously reported effects. The objective of the present study was to test the hypothesis that it is the delivered dose per se, and not the route and method of administration, that determines the effect, and that high doses are damaging while lower doses are protective. One hundred and twenty ovariectomized female Wistar rats (n = 40 per group) were randomized into three groups, subcutaneously administered different doses of 17β-estradiol and subjected to transient middle cerebral artery occlusion. The modified sticky tape test was performed after 24 h and the rats were subsequently sacrificed for infarct size measurements. In contrast to our hypothesis, a significant negative correlation between 17β-estradiol dose and infarct size was found (p = 0.018). Thus, no support was found for the hypothesis that 17β-estradiol can be both neuroprotective and neurotoxic merely depending on dose. In fact, on the contrary, the findings indicate that the higher the dose of 17β-estradiol, the smaller the infarct. PMID:26839007

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

    PubMed Central

    Kim, Hyun Ah; Whittle, Stephanie C.; Lee, Seyoung; Chu, Hannah X.; Zhang, Shenpeng R.; Wei, Zihui; Arumugam, Thiruma V.; Vinh, Anthony; Drummond, Grant R.; Sobey, Christopher G.

    2014-01-01

    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. PMID:25477780

  20. Study of Protein Expresion in Peri-Infarct Tissue after Cerebral Ischemia

    PubMed Central

    Brea, David; Agulla, Jesús; Staes, An; Gevaert, Kris; Campos, Francisco; Sobrino, Tomás; Blanco, Miguel; Dávalos, Antoni; Castillo, José; Ramos-Cabrer, Pedro

    2015-01-01

    In this work, we report our study of protein expression in rat peri-infarct tissue, 48 h after the induction of permanent focal cerebral ischemia. Two proteomic approaches, gel electrophoresis with mass spectrometry and combined fractional diagonal chromatography (COFRADIC), were performed using tissue samples from the periphery of the induced cerebral ischemic lesions, using tissue from the contra-lateral hemisphere as a control. Several protein spots (3408) were identified by gel electrophoresis, and 11 showed significant differences in expression between peri-infarct and contra-lateral tissues (at least 3-fold, p < 0.05). Using COFRADIC, 5412 proteins were identified, with 72 showing a difference in expression. Apart from blood-related proteins (such as serum albumin), both techniques showed that the 70 kDa family of heat shock proteins were highly expressed in the peri-infarct tissue. Further studies by 1D and 2D western blotting and immunohistochemistry revealed that only one member of this family (the inducible form, HSP72 or HSP70i) is specifically expressed by the peri-infarct tissue, while the majority of this family (the constitutive form, HSC70 or HSP70c) is expressed in the whole brain. Our data support that HSP72 is a suitable biomarker of peri-infarct tissue in the ischemic brain. PMID:26153530

  1. Current management of delayed cerebral ischemia: update from results of recent clinical trials.

    PubMed

    Brathwaite, Shakira; Macdonald, R Loch

    2014-04-01

    Subarachnoid hemorrhage (SAH) accounts for 5-7% of all strokes worldwide and is associated with high mortality and morbidity. Even after surgical intervention, approximately 30% of patients develop long-term cognitive and neurological deficits that significantly affect their capacity to return to work or daily life unassisted. Much of this stems from a secondary ischemic phenomenon referred to as delayed cerebral ischemia (DCI). While DCI has been historically attributed to the narrowing of the large basal cerebral arteries, it is now recognized that numerous pathways contribute to its pathogenesis, including microcirculatory dysfunction, microthrombosis, cortical spreading depression, and early brain injury. This paper seeks to summarize some of the key pathophysiological events that are associated with poor outcome after SAH, provide a general overview of current methods of treating SAH patients, and review the results of recent clinical trials directed at improving outcome after SAH. The scientific basis of these studies will be discussed, in addition to the available results and recommendations for effective patient management. Therapeutic methods under current clinical investigation will also be addressed. In particular, the mechanisms by which they are expected to elicit improved outcome will be investigated, as well as the specific study designs and anticipated time lines for completion.

  2. Acetylcholine- and sodium hydrosulfide-induced endothelium-dependent relaxation and hyperpolarization in cerebral vessels of global cerebral ischemia-reperfusion rat.

    PubMed

    Han, Jun; Chen, Zhi-Wu; He, Guo-Wei

    2013-01-01

    We investigated the effects of endothelium-derived hyperpolarizing factor (EDHF) and the role of hydrogen sulphide (H2S) in the cerebral vasorelaxation induced by acetylcholine (ACh) in global cerebral ischemia-reperfusion (CIR) rats. CIR was induced by occlusion of bilateral carotid and vertebral arteries. Isolated arterial segments from the cerebral basilar (CBA) and middle artery (MCA) of CIR rats were studied in a pressurized chamber. Transmembrane potential was recorded using glass microelectrodes to evaluate hyperpolarization. In the CIR CBAs and MCAs preconstricted by 30 mM KCl, ACh induced concentration-dependent vasorelaxation and hyperpolarization that were partially attenuated by NG-nitro-l-arginine methyl ester (l-NAME, 30 μM) and l-NAME plus indomethacin (10 μM). The residual responses were abolished by the H2S inhibitor dl-propargylglycine (PPG, 100 μM). The H2S donor NaHS and l-Cys, the substrate of endogenous H2S synthase, elicited similar responses to ACh and was inhibited by tetraethylamonine (1 mM) or PPG. ACh induces EDHF-mediated vasorelaxation and hyperpolarization in rat cerebral arteries. These responses are up-regulated by ischemia-reperfusion while NO-mediated responses are down-regulated. Further, the ACh-induced, EDHF-mediated relaxation, and hyperpolarization and the inhibition of these responses are similar to the H2S-induced responses, suggesting that H2S is a possible candidate for EDHF in rat cerebral vessels.

  3. The Effects of Antecedent Exercise on Motor Function Recovery and Brain-derived Neurotrophic Factor Expression after Focal Cerebral Ischemia in Rats

    PubMed Central

    Kim, Gyeyeop; Kim, Eunjung

    2013-01-01

    [Purpose] In the present study, we investigated the effect of antecedent exercise on functional recovery and brain-derived neurotrophic factor (BDNF) expression following focal cerebral ischemia injury. [Subjects] The rat middle cerebral artery occlusion (MCAO) model was employed. Adult male Sprague-Dawley rats were randomly divided into 4 groups. Group I included untreated normal rats (n=10); Group II included untreated rats with focal cerebral ischemia (n=10); Group III included rats that performed treadmill exercise (20 m/min) training after focal cerebral ischemia (n=10); and Group IV included rats that performed antecedent treadmill exercise (20 m/min) training before focal cerebral ischemia (n=10) as well as treadmill exercise after ischemia. At different time points (1, 7, 14, and 21 days) Garcia’s score, and the hippocampal expressions level of BDNF were examined. [Results] In the antecedent exercise group, improvements in the motor behavior index (Garcia’s score) were observed and hippocampal BDNF protein expression levels increased. [Conclusion] These results indicate that antecedent treadmill exercise, before permanent brain ischemia exerts a neuroprotective effect against ischemia brain injury by improving motor performance and increasing the level of BDNF expression. Furthermore, the antecedent treadmill exercise of appropriate intensity is critical for post-stroke rehabilitation. PMID:24259800

  4. Permanent middle cerebral artery occlusion in sheep: a novel large animal model of focal cerebral ischemia.

    PubMed

    Boltze, Johannes; Förschler, Annette; Nitzsche, Björn; Waldmin, Daniela; Hoffmann, Anke; Boltze, Christiane M; Dreyer, Antje Y; Goldammer, Axel; Reischauer, Anne; Härtig, Wolfgang; Geiger, Kathrin D; Barthel, Henryk; Emmrich, Frank; Gille, Uwe

    2008-12-01

    As effective stroke treatment by thrombolysis is bound to a narrow time window excluding most patients, numerous experimental treatment strategies have been developed to gain new options for stroke treatment. However, all approaches using neuroprotective agents that have been successfully evaluated in rodents have subsequently failed in clinical trials. Existing large animal models are of significant scientific value, but sometimes limited by ethical drawbacks and mostly do not allow for long-term observation. In this study, we are introducing a simple, but reliable stroke model using permanent middle cerebral artery occlusion in sheep. This model allows for control of ischemic lesion size and subsequent neurofunctional impact, and it is monitored by behavioral phenotyping, magnetic resonance imaging, and positron emission tomography. Neuropathologic and (immuno)histologic investigations showed typical ischemic lesion patterns whereas commercially available antibodies against vascular, neuronal, astroglial, and microglial antigens were feasible for ovine brain specimens. Based on absent mortality in this study and uncomplicated species-appropriate housing, long-term studies can be realized with comparatively low expenditures. This model could be used as an alternative to existing large animal models, especially for longitudinal analyses of the safety and therapeutic impact of novel therapies in the field of translational stroke research.

  5. Diosgenin attenuates the brain injury induced by transient focal cerebral ischemia-reperfusion in rats.

    PubMed

    Zhang, Xinxin; Xue, Xuanji; Zhao, Jing; Qian, Chunxiang; Guo, Zengjun; Ito, Yoichiro; Sun, Wenji

    2016-09-01

    The aim of the present study is to explore the potential cerebroprotection of diosgenin against the transient focal cerebral ischemia-reperfusion (I/R) injury and its possible underlying mechanisms. The diosgenin at two dose levels, namely 100 and 200mgkg(-1), was intragastrically administrated once daily for 7-day period prior to the surgery. Then, the rats were subjected to middle cerebral artery occlusion (MCAO) using the intraluminal thread for 90min. After 24h reperfusion, several diagnostic indicators were evaluated and all animals were sacrificed to harvest their brains and blood for subsequent biochemical analyses. The results indicated that diosgenin treatment significantly inhibited the death rate and improved the impaired neurological functions along with neurological deficit scores and cerebral infarct size as compared with the rats exposed to I/R insult without agents administration. The increase in the number of apoptotic cells determined by TUNEL in the hippocampus CA1 and cortex was also apparently attenuated in the diosgenin treatment group, which was closely correlated with suppression of Caspase-3 activity and Bax/Bcl-2 ratio. In addition the elevated concentrations of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in blood serum of the I/R treated rats were reduced almost to their normal level. Further results obtained from the Western blotting analysis revealed that the protein expression of IκBα in the injured brain was up-regulated, while the p65 subunit of NF-κB was down-regulated in nucleus after the treatment. Collectively, this neuroprotection of diosgenin against I/R injury may be attained through its anti-apoptosis, anti-inflammation and intervening the NF-κB signal pathway properties. Due to the satisfactory findings, diosgenin might be a powerful therapeutic agent to combat the similar disease in future clinic. PMID:27425638

  6. Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice.

    PubMed

    Sun, Jing; Wang, Fangyan; Li, Haixiao; Zhang, Huiqing; Jin, Jiangtao; Chen, Wenqian; Pang, Mengqi; Yu, Junjie; He, Yiwen; Liu, Jiaming; Liu, Chunfeng

    2015-01-01

    Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1β, TNF-α, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti-inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect.

  7. Effects of Shaoyao-Gancao Decoction on Infarcted Cerebral Cortical Neurons: Suppression of the Inflammatory Response following Cerebral Ischemia-Reperfusion in a Rat Model

    PubMed Central

    Jia, Xinling; Yang, Jian; Li, Qing; Yan, Guofeng; Xu, Zhongju; Wang, Jingye

    2016-01-01

    The mechanisms by which Shaoyao-Gancao decoction (SGD) inhibits the production of inflammatory cytokines in serum and brain tissue after cerebral ischemia-reperfusion (CI-RP) in rats were investigated. A right middle cerebral artery occlusion was used to induce CI-RP after which the rats were divided into model (n = 39), SGD (n = 28), clopidogrel (n = 25) and sham operated (n = 34) groups. The Bederson scale was used to evaluate changes in behavioral indices. The levels of IL-1β, TNF-α, MCP-1, IL-10, RANTES, VEGF, and TGF-β1 in the serum and infarcted brain tissues were measured. Nissl body and immunohistochemical staining methods were used to detect biochemical changes in neurons, microglial cells, and astrocytes. Serum levels of VEGF, TNF-α, MCP-1, IL-1β, and IL-10 increased significantly 24 h after CI-RP. In brain tissue, levels of TNF-α and IL-1β significantly increased 24 h after CI-RP, whereas levels of TGF-β1 and MCP-1 were significantly higher 96 h after CI-RP (P < 0.05). SGD or clopidogrel after CI-RP reduced TNF-α and IL-1β levels in brain tissue and serum levels of MCP-1, IL-1β, and IL-10. SGD increased the number of NeuN-positive cells in infarcted brain tissue and reduced the number of IBA1-positive and GFAP-positive cells. The efficacy of SGD was significantly higher than that of clopidogrel. PMID:27413737

  8. YiQiFuMai Powder Injection Ameliorates Cerebral Ischemia by Inhibiting Endoplasmic Reticulum Stress-Mediated Neuronal Apoptosis

    PubMed Central

    Hu, Yang

    2016-01-01

    YiQiFuMai (YQFM) powder injection as a modern preparation derived from Sheng Mai San, a traditional Chinese medicine, has been widely used in the treatment of cardiovascular and cerebrovascular diseases. However, its neuroprotective effect and underlying mechanism in cerebral ischemia remain to be explored. The present study was designed to investigate the neuroprotective effect of YQFM on endoplasmic reticulum (ER) stress-mediated neuronal apoptosis in the permanent middle cerebral artery occlusion- (MCAO-) injured mice and the oxygen-glucose deprivation- (OGD-) induced pheochromocytoma (PC12) cells. The results showed that single administration of YQFM (1.342 g/kg, i.p.) could reduce the brain infarction and improve the neurological deficits and the cerebral blood flow (CBF) after MCAO for 24 h in mice. Moreover, incubation with YQFM (100, 200, and 400 μg/mL) could increase the cell viability, decrease the caspase-3 activity, and inhibit the cell apoptosis in OGD-induced PC12 cells for 12 h. In addition, YQFM treatment could significantly modulate cleaved caspase-3 and Bcl-2 expressions and inhibit the expressions of ER stress-related marker proteins and signaling pathways in vivo and in vitro. In conclusion, our findings provide the first evidence that YQFM ameliorates cerebral ischemic injury linked with modulating ER stress-related signaling pathways, which provided some new insights for its prevention and treatment of cerebral ischemia diseases. PMID:27087890

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

    PubMed

    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.

  10. Correlation of clinical and angiographic findings in brain ischemia with regional cerebral blood flow measured by the xenon inhalation technique

    SciTech Connect

    Awad, I.; Little, J.R.; Furlan, A.J.; Weinstein, M.

    1982-07-01

    Eighty-eight patients with brain ischemia underwent cerebral angiography and measurement of regional cerebral blood flow (rCBF) after /sup 133/Xe inhalation. A fast compartment flow rate and an initial slope index were computed for each detector and for each hemisphere. The clinical presentation, angiographic findings, and rCBF results were then examined for significant correlations. Patients with hemispheric infarction most frequently showed bilateral diffusely decreased rCBF. In patients with transient ischemic attacks, no specific pattern emerged. Patients with unilateral internal carotid artery occlusion frequently hd bilateral diffusely decreased rCBF. Patients with severe internal carotid artery stenosis were more likely to show decreased rCBF than were patients with mild or moderate stenosis. The initial slope index seemed to be a more sensitive indicator of brain ischemia than the fast compartment flow rate. The possible pathophysiological significance and relationship to patient management of the various rCBF patterns are discussed.

  11. [Studying the neuroprotective effect of the novel glutamic acid derivative neiroglutam on focal cerebral ischemia in rats].

    PubMed

    Tiurenkov, I N; Kurkin, D V; Bakulin, D A; Volotova, E V

    2014-01-01

    We have studied the neuroprotective effect of the novel glutamic acid derivative neiroglutam on reversible focal cerebral ischemia in rats. The neuroprotective drug action was assessed by the ability to reduce the severity of neurological deficit (1, 2, 3, 5 and 7 days), forelimb fine-motor disorders (in the ladder test), hind limb motor activity (beam-walking test), and volume of the infarct zone upon 7-day pathologic exposure. It was found that the therapeutic administration of neiroglutam (26 mg/kg, i.p., for 7 days) reduces the volume of necrosis of cerebral tissues in case of focal brain ischemia in animals (on the average by 38%, (p < 0.05) and decreases the severity of motor disorders, which indicates the presence of neuroprotective effect of this compound. PMID:25365863

  12. Analysis of the endothelial nitric oxide synthase gene as a modifier of the cerebral response to ischemia.

    PubMed

    Dutra, Ana Virginia; Lin, Hsiu-Fen; Juo, Suh-Hang Hank; Boyadjis, Melanie; Moussouttas, Michael; Reddy, P Leema; Grewal, Raji Paul

    2006-01-01

    We studied the endothelial nitric oxide synthase (eNOS or NOS-3) gene as a potential modifier of the cerebral response to ischemia by investigating the association of two common polymorphisms with ischemic stroke volume. We genotyped an intronic variable number tandem repeat and a single nucleotide polymorphism, G894T, in 132 patients with nonlacunar ischemic strokes in whom clinical data and stroke lesion volume were recorded. Our results show that all genotypes are in Hardy-Weinberg equilibrium. After adjustment of covariates, neither of the NOS-3 polymorphisms showed significant differences comparing the genotypes and mean stroke volume (analysis of variance). Our results do not suggest a major gene effect of the NOS-3 gene as a modifier of the cerebral response to ischemia. PMID:17904064

  13. [Activation of autophagy pathway in hippocampus and deterioration of learning and memory ability by intermittent hypoxia in rats after cerebral ischemia].

    PubMed

    Guo, Xiangfei; Zhao, Yaning; Li, Jianmin; Liu, Wenqian; Chen, Changxiang

    2016-09-01

    Objective To investigate the effects of different duration of intermittent hypoxia on the autophagy pathway in the hippocampus and the learning and memory ability after cerebral ischemia in rats. Methods 100 male Wistar rats were randomly divided into sham operation (SO) group, ischemia/reperfusion (I/R) group, intermittent hypoxia for 7 days combined with ischemia/reperfusion (IH7-I/R) group, intermittent hypoxia for 14 days combined with ischemia/reperfusion (IH14-I/R) group, intermittent hypoxia for 21 days combined with ischemia/reperfusion (IH21-I/R) group, n =20 in each group. The rats in IH7-I/R group, IH14-I/R group and IH21-I/R group were respectively subjected to intermittent hypoxia for 7, 14 and 21 days prior to I/R modeling by improved Pulsinelli four-vessel occlusion (4-VO). The morphological changes of nerve cells in the hippocampus of rat brain were detected by HE staining; the levels of mammalian target of rapamycin (mTOR) and beclin 1 mRNA in the hippocampus were determined by quantitative real-time PCR; the distribution of mTOR and beclin 1 in the hippocampus was observed by immunohistochemistry; the learning and memory ability of rats was assessed by the Morris water maze test. Results Compared with the SO group, the never cell morphology was damaged, the number of survival neurons in the hippocampus was reduced, the expressions of mTOR and beclin 1 in the hippocampus were strengthened, and the learning and memory ability declined in the I/R group. Compared with the I/R group, the never cell morphology was damaged seriously, the number of survival neurons in the hippocampus decreased, the expressions of mTOR and beclin 1 in the hippocampus increased, and the learning and memory ability dropped in the intermittent hypoxia groups. What's more, the above changes were dependent on the duration of intermittent hypoxia. Conclusion Intermittent hypoxia aggravates the dysfunction of learning and memory after cerebral ischemia and the damages increase

  14. Postischemic, systemic administration of polyamine-modified superoxide dismutase reduces hippocampal CA1 neurodegeneration in rat global cerebral ischemia.

    PubMed

    Wengenack, T M; Curran, G L; Poduslo, J F

    1997-04-18

    Antioxidant enzymes such as superoxide dismutase (SOD) have shown neuroprotective effects in animal models of cerebral ischemia, but only at very high doses. Modifications to increase the plasma half-life or blood-brain barrier (BBB) permeability of SOD have resulted in limited neuroprotective effects. No one has demonstrated neuroprotection with postischemic administration. The specific aim of the present study was to administer systemically a polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, following global cerebral ischemia in rats and analyze the effects on the selective vulnerability of CA1 hippocampal neurons. Following 12 min of four-vessel occlusion, global cerebral ischemia, male Wistar rats were dosed (i.v.) with either saline, native SOD (5000 U/kg), polyamine-modified SOD (5000 U/kg), or enzymatically inactive, polyamine-modified SOD (2.1 mg/kg) twice daily for 3 days. Neuroprotective effects on hippocampal CA1 neurons were assessed using standard histological methods. Saline-treated animals had very few remaining CA1 neurons (1.44 +/- 0.60 neurons/reticle; x +/- S.E.M.) compared to sham rats (58.57 +/- 0.69). Native (10.38 +/- 2.96) or inactive, polyamine-modified SOD (7.32 +/- 2.68) did not show significant neuroprotective effects. Polyamine-modified SOD, however, resulted in the survival of significantly more CA1 neurons (24.61 +/- 5.90; P < 0.01). Postischemic, systemic administration of polyamine-modified SOD, having increased BBB permeability and preserved enzymatic activity, significantly reduced hippocampal CA1 neuron loss following global cerebral ischemia. Similar modification of other antioxidant enzymes and neurotrophic factors with polyamines may provide a useful technique for the systemic delivery of therapeutic proteins across the BBB for the treatment of stroke and other neurodegenerative disorders. PMID:9134958

  15. Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia.

    PubMed

    Wakita, H; Tomimoto, H; Akiguchi, I; Kimura, J

    1998-05-01

    Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agents in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immunosuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rats received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macrophage was investigated with immunohistochemistry for leukocyte common antigen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefaction and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there was persistent and extensive activation of the microglia/macrophages and astroglia in the white matter, including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. In the FK506-treated rats, the number of activated microglia/macrophages was significantly reduced in a dose-dependent manner (p<0.01) as compared to the vehicle-treated rats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p<0. 01). Thus, a clinically-relevant dosage of FK506 attenuated both glial activation and white matter changes in chronic cerebral ischemia in the rat. These results indicate a potential use for FK506 in cerebrovascular diseases.

  16. Comparison of antioxidant activity of hydroethanolic fresh and aged garlic extracts and their effects on cerebral ischemia.

    PubMed

    Cervantes, Maria Isabel; de Oca Balderas, Pavel Montes; de Jesús Gutiérrez-Baños, José; Orozco-Ibarra, Marisol; Fernández-Rojas, Berenice; Medina-Campos, Omar Noel; Espinoza-Rojo, Mónica; Ruiz-Tachiquín, Martha; Ortiz-Plata, Alma; Salazar, Ma Isabel; Rubio-Osornio, Moisés; Castañeda-Saucedo, Eduardo; Pedraza-Chaverri, José; Calzada, Fernando; Aguilera, Penélope

    2013-09-01

    Antioxidant properties and protective effect of aged garlic extract (AGE) and of 20% hydroethanolic fresh extracts from garlic clove (GCE) and skin (GSE) on cerebral ischemia were evaluated by administering extracts at the beginning of reperfusion in a rat model of stroke. All three extracts scavenged superoxide anion, peroxynitrite anion, and peroxyl radicals, but with different efficiencies; furthermore, GCE and GSE scavenged hydroxyl radicals and GSE scavenged singlet oxygen. These extracts significantly prevented reduction of neuronal nuclear antigen in the infarcted area, although no improvement in neurological function was observed. Importantly, GCE and GSE contained S-allylcystein, a compound associated with AGE's neuroprotective effect against damage induced by cerebral ischemia. Extracts decreased mRNA expression of NR1- and NR2B-NMDA-receptor subunits and prevented ischemia-induced reduction in mitochondrial potential and in ATP synthesis. These results indicate that antioxidants present in garlic extracts may regulate ROS concentrations during ischemia, favour pro-survival pathways, and attenuate mitochondrial dysfunction. PMID:23578652

  17. Sex differences in brain proteomes of neuron-specific STAT3-null mice after cerebral ischemia/reperfusion.

    PubMed

    Di Domenico, Fabio; Casalena, Gabriella; Jia, Jia; Sultana, Rukhsana; Barone, Eugenio; Cai, Jian; Pierce, William M; Cini, Chiara; Mancuso, Cesare; Perluigi, Marzia; Davis, Catherine M; Alkayed, Nabil J; Butterfield, D Allan; Butterfield, Allan D

    2012-05-01

    Signal transduction and activator of transcription-3 (STAT3) plays an important role in neuronal survival, regeneration and repair after brain injury. We previously demonstrated that STAT3 is activated in brain after cerebral ischemia specifically in neurons. The effect was sex-specific and modulated by sex steroids, with higher activation in females than males. In the current study, we used a proteomics approach to identify downstream proteins affected by ischemia in male and female wild-type (WT) and neuron-specific STAT3 knockout (KO) mice. We established four comparison groups based on the transgenic condition and the hemisphere analyzed, respectively. Moreover, the sexual variable was taken into account and male and female animals were analyzed independently. Results support a role for STAT3 in metabolic, synaptic, structural and transcriptional responses to cerebral ischemia, indeed the adaptive response to ischemia/reperfusion injury is delayed in neuronal-specific STAT3 KO mice. The differences observed between males and females emphasize the importance of sex-specific neuronal survival and repair mechanisms, especially those involving antioxidant and energy-related activities, often caused by sex hormones.

  18. Evaluation the development of focal cerebral ischemia in rats by optical imaging based on the spreading depression signals

    NASA Astrophysics Data System (ADS)

    Chen, Shangbin; Feng, Zhe; Zeng, Shaoqun; Luo, Qingming; Li, Pengcheng

    2007-02-01

    Spreading depression (SD) has been found involved in focal cerebral ischemia which may result in severe or lethal neurological deficits. Electrical recording of SD has been used for acute and long term monitoring of focal cerebral ischemia but with an inherently low resolution. Here, we presented optical intrinsic signal imaging (OISI) to characterize the spontaneous SD waves following permanent middle cerebral artery occlusion (MCAO) in rats with high spatial resolution. During each SD episode, the measured optical reflectance varied regionally: decreased (-12.5+/-2.8%) in the area near the midline, remained flat (3.1+/-2.5%) in the lateral region, and increased (12.1+/-3.6%) in the intermediate cortex. The three types of changes yielded identifications for three biological relevant zones: nonischemic cortex, penumbra and infarct core. Accompanying recurrent SD waves, the suggested penumbral area reduced by about 6.4+/-2.5% of the whole imaged area per SD event, indicating a growth of the infracted area. Staining with 2% 2,3,5-triphenyltetrazolium chloride (TTC) 4 h post-occlusion proved the infarct cortex to be consistent with the lateral region where the final SD wave did not invade (r=0.86+/-0.10). The results suggest that OISI based on SD can effectively used to distinguish nonischemic cortex, penumbra and infarct core in the ischemic hemisphere and monitor the development of ischemia with high spatial resolution.

  19. Targeting Glial Mitochondrial Function for Protection from Cerebral Ischemia: Relevance, Mechanisms, and the Role of MicroRNAs

    PubMed Central

    Li, Le

    2016-01-01

    Astrocytes and microglia play crucial roles in the response to cerebral ischemia and are effective targets for stroke therapy in animal models. MicroRNAs (miRs) are important posttranscriptional regulators of gene expression that function by inhibiting the translation of select target genes. In astrocytes, miR expression patterns regulate mitochondrial function in response to oxidative stress via targeting of Bcl2 and heat shock protein 70 family members. Mitochondria play an active role in microglial activation, and miRs regulate the microglial neuroinflammatory response. As endogenous miR expression patterns can be altered with exogenous mimics and inhibitors, miR-targeted therapies represent a viable intervention to optimize glial mitochondrial function and improve clinical outcome following cerebral ischemia. In the present article, we review the role that astrocytes and microglia play in neuronal function and fate following ischemic stress, discuss the relevance of mitochondria in the glial response to injury, and present current evidence implicating miRs as critical regulators in the glial mitochondrial response to cerebral ischemia. PMID:27777645

  20. Unique action mechanisms of tramadol in global cerebral ischemia-induced mechanical allodynia.

    PubMed

    Matsuura, Wataru; Kageyama, Erika; Harada, Shinichi; Tokuyama, Shogo

    2016-06-15

    Central poststroke pain is associated with specific somatosensory abnormalities, such as neuropathic pain syndrome. Although central poststroke pain is a serious condition, details pertaining to underlying mechanisms are not well established, making current standard treatments only partially effective. Here, we assessed the effects of tramadol, an analgesic drug mediated by opioid receptors, using a mouse model of global cerebral ischemia. Ischemia was induced by bilateral carotid artery occlusion (30 min) in male ddY mice. Development of hind-paw mechanical allodynia was measured 3 days after bilateral carotid artery occlusion using the von Frey test. Mechanical allodynia was significantly and dose dependently suppressed by intraperitoneal tramadol (10 or 20 mg/kg). These effects, which peaked at 10 min and continued for at least 60 min, were inhibited by naloxone (nonselective opioid receptor antagonist, 1 mg/kg, intraperitoneal). Tramadol antinociception was significantly negated by β-funaltrexamine (selective μ-opioid receptor antagonist, 20 mg/kg, intraperitoneal), but not naltrindole (selective δ-opioid receptor antagonist, 5 mg/kg, intraperitoneal) or nor-binaltorphimine (selective κ-opioid receptor antagonist, 10 mg/kg, intraperitoneal) after 5 min, by β-funaltrexamine and nor-binaltorphimine but not naltrindole after 10 min, and by all selective opioid receptor antagonists at 15 and 30 min after tramadol treatment. These results suggested that antinociception induced by tramadol through various opioid receptors was time dependent. Furthermore, it is possible that the opioid receptors involved in tramadol-induced antinociception change over time with the metabolism of this drug.

  1. The protective effect of qiancao naomaitong mixture on neuronal damage and cerebral ischemia/reperfusion injury.

    PubMed

    Lu, Juan; Li, Yi-Hang; Zhan, Xia; Li, Guang; Chen, Zhe; Chen, Xi

    2016-10-01

    Context Qiancao Naomaitong Mixture (QNM) is mainly used to treat ischemic stroke patients in the clinic. Objective This study evaluates the protective effect of QNM on neuronal damage in vitro, and clarifies the underlying mechanism against cerebral ischemia-reperfusion (I/R) injury in vivo. Materials and methods Activity assay of caspase 3 (C-3) and caspase 8 (C-8) were measured with microplate reader and cell apoptosis was investigated. Cerebral I/R injury was induced by MCAO model. QNM groups were given at 0.27, 0.54 and 1.08 mL/100 g body weight. The weight ratio of cerebral infarction tissue was obtained. The cytokine levels in serum and brain tissue were measured using ELISA. Results Compared with the OGD group (C-3: 29.69 ± 5.63, C-8: 74.05 ± 6.86), 100 mg/mL QNM (C-3: 19.80 ± 2.62, C-8: 48.94 ± 6.41) and 200 mg/mL QNM (C-3: 16.28 ± 4.55, C-8: 41.08 ± 4.05) treatments decreased C-3 and C-8 activities significantly, and inhibited apoptosis of SH-SY5Y cells. The weight ratios of cerebral tissues in low, medium and high dose groups were 17.33 ± 5.1%, 17.78 ± 5.4% and 14.25 ± 4.2%, respectively, significantly lower than in control group. QNM also improved the cytokine levels in serum and brain tissue. In addition, histological examination indicated that dense neuropil and largely surviving neurons were seen in treated rats. Conclusion QNM exerted protective effect by inhibiting the cell apoptosis in vitro. The protective mechanisms of QNM were associated with its properties of anti-apoptosis and antioxidation as well as improved neuronal nutrition in I/R rats. PMID:26987389

  2. Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats.

    PubMed

    Liang, Hao; Liu, Ping; Wang, Yunshan; Song, Shuliang; Ji, Aiguo

    2011-07-15

    The neuronal damage following cerebral ischemia is a serious risk to stroke patients. The aim of this study was to investigate the neuroprotective effects of alkaloid extract from Leonurus heterophyllus (LHAE) on cerebral ischemic injury. After 24 h of reperfusion following ischemia for 2 h induced by middle cerebral artery occlusion (MCAO), some rats were intraperitoneally administered different doses of LHAE (3.6, 7.2, 14.4 mg/kg, respectively). Neurological examination was measured in all animals. Infarct volume, myeloperoxidase (MPO) activity, levels of nitrate/nitrite metabolite (NO) and apoptosis ratio of nerve fiber in brain were determined. The results showed that LHAE at 7.2 mg/kg or 14.4 mg/kg exerted significantly decreasing neurological deficit scores and reducing the infarct volume on rats with focal cerebral ischemic injury (p<0.05). At those dose, the MPO content were significantly decreased in ischemic brain as compared with model group (p<0.05). LHAE at 14.4 mg/kg significantly decreased the NO level compared with the model group (p<0.05). In addition, LHAE significantly decreased the apoptosis ratio of nerve fiber compared with the model group (p<0.05). This study suggests that LHAE may be used for treatment of ischemic stroke as a neuroprotective agent. Further studies are warranted to assess the efficacy and safety of LHAE in patients.

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

    PubMed Central

    YU, JINGWEI; BAO, CUIFEN; DONG, YANRU; LIU, XIA

    2015-01-01

    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. PMID:26018745

  4. Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid.

    PubMed

    Narasimhan, P; Sklar, R; Murrell, M; Swanson, R A; Sharp, F R

    1996-11-15

    Differential screening of gerbil brain hippocampal cDNA libraries was used to search for genes expressed in ischemic, but not normal, brain. The methylmalonyl-CoA mutase (MCM) cDNA was highly expressed after ischemia and showed a 95% similarity to mouse and 91% similarity to the human MCM cDNAs. Transient global ischemia induced a fourfold increase in MCM mRNA on Northern blots from both hippocampus and whole forebrain. MCM protein exhibited a similar induction on Western blots of gerbil cerebral cortex 8 and 24 hr after ischemia. Treatment of primary brain astrocytes with either the branched-chain amino acid (BCAA) isoleucine or the BCAA metabolite, propionate, induced MCM mRNA fourfold. Increased concentrations of BCAAs and odd-chain fatty acids, both of which are metabolized to propionate, may contribute to inducing the MCM gene during ischemia. Methylmalonic acid, which is formed from the MCM substrate methylmalonyl-CoA and which inhibits succinate dehydrogenase (SDH), produced dose-related cell death when injected into the basal ganglia of adult rat brain. This neurotoxicity is similar to that of structurally related mitochondrial SDH inhibitors, malonate and 3-nitropropionic acid. Methylmalonic acid may contribute to neuronal injury in human conditions in which it accumulates, including MCM mutations and B12 deficiency. This study shows that methylmalonyl-CoA mutase is induced by several stresses, including ischemia, and would serve to decrease the accumulation of an endogenous cellular mitochondrial inhibitor and neurotoxin, methylmalonic acid.

  5. Synergic Effect of Borneol and Ligustrazine on the Neuroprotection in Global Cerebral Ischemia/Reperfusion Injury: A Region-Specificity Study

    PubMed Central

    Ruan, Ming; Zhang, Zhen-Nian

    2016-01-01

    The cooperation of ligustrazine (LI) and borneol was proved to be much better than each of them in treating cerebral ischemia. However, the mechanism of their synergic therapy is unclear till now. Moreover, whether their cooperation brought different degrees of protection among different brain regions was also unclear. In the present study, the effects of LI, borneol, and their mixture were observed in global cerebral ischemia-reperfusion (GCIR) injury by detecting microcirculation, expressions of caspase-3 and p53, levels of IL-1β, IL-6, and TNF-α, and contents of SOD, GSH-Px, and MDA in cortex, hippocampus, hypothalamus, and striatum, respectively. Furthermore, Nissl bodies were scored also. Monotherapy of LI or borneol showed obvious improvements in the four regions, specially in cortex and hippocampus. Interestingly, the cooperation of LI and borneol brought some new improvements, specially in hypothalamus and striatum. Thus, the synergic effect of the two drugs showed region-specificity in GCIR injury except the expressions of caspase-3 and p53. PMID:27547227

  6. Synergic Effect of Borneol and Ligustrazine on the Neuroprotection in Global Cerebral Ischemia/Reperfusion Injury: A Region-Specificity Study.

    PubMed

    Yu, Bin; Ruan, Ming; Zhang, Zhen-Nian; Cheng, Hai-Bo; Shen, Xiang-Chun

    2016-01-01

    The cooperation of ligustrazine (LI) and borneol was proved to be much better than each of them in treating cerebral ischemia. However, the mechanism of their synergic therapy is unclear till now. Moreover, whether their cooperation brought different degrees of protection among different brain regions was also unclear. In the present study, the effects of LI, borneol, and their mixture were observed in global cerebral ischemia-reperfusion (GCIR) injury by detecting microcirculation, expressions of caspase-3 and p53, levels of IL-1β, IL-6, and TNF-α, and contents of SOD, GSH-Px, and MDA in cortex, hippocampus, hypothalamus, and striatum, respectively. Furthermore, Nissl bodies were scored also. Monotherapy of LI or borneol showed obvious improvements in the four regions, specially in cortex and hippocampus. Interestingly, the cooperation of LI and borneol brought some new improvements, specially in hypothalamus and striatum. Thus, the synergic effect of the two drugs showed region-specificity in GCIR injury except the expressions of caspase-3 and p53. PMID:27547227

  7. Lipoic acid protects against reperfusion injury in the early stages of cerebral ischemia.

    PubMed

    Connell, Barry J; Saleh, Monique; Khan, Bobby V; Saleh, Tarek M

    2011-02-23

    Lipoic acid (LA) is a known antioxidant currently used as a therapy in patients with vascular and metabolic disorders. We tested the hypothesis that lipoic acid is protective against the cell death observed following stroke. Lipoic acid was administered 30minutes prior to, or immediately following removal of sutures used to occlude the middle cerebral artery (MCA) in male Sprague-Dawley rats. Following removal of the sutures, the MCA territory was allowed to undergo 5.5hrs of reperfusion. This ischemia/reperfusion (I/R) resulted in a focal infarct restricted to the prefrontal cortex (24±3mm(3)). Pretreatment with LA 30minutes prior to occlusion resulted in a dose-dependent reduction in infarct volume. This reduction in infarct volume was not observed when the LA was administered immediately prior to reperfusion (30minutes post-occlusion). To investigate a potential hemodynamic mechanism for this LA-induced neuroprotection, blood pressure, heart rate and baroreceptor reflex sensitivity (BRS) were measured. Intravenous administration of LA did not result in any significant changes in any of these parameters compared to saline-treated rats. Similarly, there was no significant contribution of systemic nitric oxide or alteration in cerebral perfusion measured following pretreatment with lipoic acid or during the course of occlusion and reperfusion compared with saline-treated rats. Western blot analysis of tissue from the ischemic cortex showed an increase in protein expression of superoxide dismutase (SOD2), but not SOD1, in LA pretreated rats. This suggests a potential mechanism of action contributing to the LA-induced neuroprotection observed. Furthermore, the data in the present investigation suggest the potential use of LA pretreatment as a neuroprotectant in stroke patients. PMID:21172313

  8. Rodent Hypoxia-Ischemia Models for Cerebral Palsy Research: A Systematic Review.

    PubMed

    Rumajogee, Prakasham; Bregman, Tatiana; Miller, Steven P; Yager, Jerome Y; Fehlings, Michael G

    2016-01-01

    Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5-3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice-Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury. PMID:27199883

  9. Rodent Hypoxia–Ischemia Models for Cerebral Palsy Research: A Systematic Review

    PubMed Central

    Rumajogee, Prakasham; Bregman, Tatiana; Miller, Steven P.; Yager, Jerome Y.; Fehlings, Michael G.

    2016-01-01

    Cerebral palsy (CP) is a complex multifactorial disorder, affecting approximately 2.5–3/1000 live term births, and up to 22/1000 prematurely born babies. CP results from injury to the developing brain incurred before, during, or after birth. The most common form of this condition, spastic CP, is primarily associated with injury to the cerebral cortex and subcortical white matter as well as the deep gray matter. The major etiological factors of spastic CP are hypoxia/ischemia (HI), occurring during the last third of pregnancy and around birth age. In addition, inflammation has been found to be an important factor contributing to brain injury, especially in term infants. Other factors, including genetics, are gaining importance. The classic Rice–Vannucci HI model (in which 7-day-old rat pups undergo unilateral ligation of the common carotid artery followed by exposure to 8% oxygen hypoxic air) is a model of neonatal stroke that has greatly contributed to CP research. In this model, brain damage resembles that observed in severe CP cases. This model, and its numerous adaptations, allows one to finely tune the injury parameters to mimic, and therefore study, many of the pathophysiological processes and conditions observed in human patients. Investigators can recreate the HI and inflammation, which cause brain damage and subsequent motor and cognitive deficits. This model further enables the examination of potential approaches to achieve neural repair and regeneration. In the present review, we compare and discuss the advantages, limitations, and the translational value for CP research of HI models of perinatal brain injury. PMID:27199883

  10. Proinflammatory cytokines in the embolic model of cerebral ischemia in rat.

    PubMed

    Jafarinaveh, Hamid Reza; Allahtavakoli, Mohammad; Rezazadeh, Hossein; Kazemi Arababadi, Mohammad; Taghavi, Mohammad Mohsen; Shamsizadeh, Ali; Rahmani, Mohammad Reza

    2014-04-01

    Increased levels of proinflammatory cytokines have been recorded after the onset of transient or permanent brain ischemia and are usually associated with exacerbation of ischemic injury. Embolic stroke model is more relevant to the pathophysiological situation in such patients, because the majority of ischemic injuries in humans are induced by old thrombi that originate from the heart and carotid arteries. Therefore, the aim of the present study was to investigate changes of inflammatory cytokines after embolic stroke. Rats were subjected to embolic stroke, induced by a natural old clot which was injected in Middle Cerebral Artery (MCA), or sham stroke, which the same volume of saline was injected into the MCA. At 48 h after stroke induction, the levels of 5 cytokines (IL-1α and β, IL-6, IFN-γ and TNF-α) were determined in 500 µg of total protein using the Bio-Plex Rat Cytokine Array (BioRad), according to the manufacturer's instructions in ischemic and non-ischemic cortices. While stroke animals showed infarctions and neurological deficits, we did not observe any cerebral infarction and neurological deficits in sham-operated animals. The levels of IL-1α (p=0.000) and -β (p =0.004), IL-6 (p =0.008), TNF-α (p =0.000) and IFN-γ (p =0.044) were significantly increased compared to sham treated animals. The findings of the present study suggest that part of ischemic injury in the embolic stroke may be mediated through the increased levels of inflammatory cytokines. PMID:24338258

  11. [Practical value of the detection of silent myocardial ischemia in patients with coronary disease using Holters].

    PubMed

    Jan, F; Monin, J L; Leichter, S; Pochmalicki, G

    1994-02-01

    The prognosis of painless myocardial ischemia is similar to that of symptomatic ischemia. The Holter technique (and solid memory Holter in particular) is a simple method of detection which, taken together with exercise testing, enables the identification among coronary disease patients of a high risk group in whom effort ischemia is accompanied by episodes of ischemia under everyday conditions and in whom additional investigations (exercise thallium scan then coronary arteriography) and appropriate treatment, including transluminal angioplasty and aorto-coronary bypass if necessary, may be required. The role of drug treatment in silent ischemia has not yet been clearly defined. While electrical ischemia regresses significantly with the majority of standard drug regimens, and beta-blockers in particular, none has yet been confirmed as having a preventive effect against serious events following on from silent myocardial ischemia.

  12. Urgent endarterectomy using pretreatment with free radical scavenger, edaravone, and early clamping of the parent arteries for cervical carotid artery stenosis with crescendo transient ischemic attacks caused by mobile thrombus and hemodynamic cerebral ischemia. Case report.

    PubMed

    Kobayashi, Masakazu; Ogasawara, Kuniaki; Inoue, Takashi; Saito, Hideo; Komoribayashi, Nobukazu; Suga, Yasunori; Ogawa, Akira

    2007-03-01

    A 68-year-old man with left cervical internal carotid artery stenosis suffered crescendo transient ischemic attacks caused by mobile thrombus detected by carotid echography and secondary impairment of cerebral hemodynamic reserve demonstrated by positron emission tomography. Urgent carotid endarterectomy (CEA) was performed following pretreatment with edaravone and early clamping of the carotid arteries without intraluminal shunting. The postoperative course was uneventful, and postoperative magnetic resonance imaging and single-photon emission computed tomography revealed no new cerebral ischemic lesions and no findings of cerebral hyperperfusion, respectively. The risks associated with CEA are higher for patients with evolving stroke or crescendo transient ischemic attacks than that for patients with stable disease. This case demonstrates that urgent endarterectomy for cervical carotid artery stenosis with crescendo transient ischemic attacks caused by mobile thrombi and hemodynamic cerebral ischemia can be successfully performed following pretreatment with edaravone and early clamping of the carotid arteries.

  13. Hippo/MST1 signaling mediates microglial activation following acute cerebral ischemia-reperfusion injury.

    PubMed

    Zhao, Siqi; Yin, Jie; Zhou, Lujun; Yan, Feng; He, Qing; Huang, Li; Peng, Shengyi; Jia, Junying; Cheng, Jinbo; Chen, Hong; Tao, Wufan; Ji, Xunming; Xu, Yun; Yuan, Zengqiang

    2016-07-01

    Cerebral ischemia-reperfusion injury is a major public health concern that causes high rates of disability and mortality in adults. Microglial activation plays a crucial role in ischemic stroke-induced alteration of the immune microenvironment. However, the mechanism underlying the triggering of microglial activation by ischemic stroke remains to be elucidated. Previously, we demonstrated that the protein kinase Hippo/MST1 plays an important role in oxidative stress-induced cell death in mammalian primary neurons and that the protein kinase c-Abl phosphorylates MST1 at Y433, which increases MST1 kinase activity. Microglial activation has been implicated as a secondary detrimental cellular response that contributes to neuronal cell death in ischemic stroke. Here, we are the first, to our knowledge, to demonstrate that MST1 mediates stroke-induced microglial activation by directly phosphorylating IκBα at residues S32 and S36. We further demonstrate that Src kinase functions upstream of MST1-IκB signaling during microglial activation. Specific deletion of MST1 in microglia mitigates stroke-induced brain injury. Therefore, we propose that Src-MST1-IκB signaling plays a critical role in stroke-induced microglial activation. Together with our previous work demonstrating that MST1 is important for oxidative stress-induced neuronal cell death, our results indicate that MST1 could represent a potent therapeutic target for ischemic stroke.

  14. Neuronal NAMPT is released after cerebral ischemia and protects against white matter injury

    PubMed Central

    Jing, Zheng; Xing, Juan; Chen, Xinzhi; Stetler, Ruth A; Weng, Zhongfang; Gan, Yu; Zhang, Feng; Gao, Yanqin; Chen, Jun; Leak, Rehana K; Cao, Guodong

    2014-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) has been implicated in neuroprotection against ischemic brain injury, but the mechanism underlying its protective effect remains largely unknown. To further examine the protective effect of NAMPT against ischemic stroke and its potential mechanism of action, we generated a novel neuron-specific NAMPT transgenic mouse line. Transgenic mice and wild-type littermates were subjected to transient occlusion of the middle cerebral artery (MCAO) for 60 minutes. Neuron-specific NAMPT overexpression significantly reduced infarct volume by 65% (P=0.018) and improved long-term neurologic outcomes (P≤0.05) compared with littermates. Interestingly, neuronal overexpression of NAMPT increased the area of myelinated fibers in the striatum and corpus callosum, indicating that NAMPT protects against white matter injury. The mechanism of protection appeared to be through extracellular release of NAMPT. First, NAMPT was secreted into the extracellular medium by primary cortical neurons exposed to ischemia-like oxygen–glucose deprivation (OGD) in vitro. Second, conditioned medium from NAMPT-overexpressing neurons exposed to OGD protected cultured oligodendrocytes from OGD. Third, the protective effects of conditioned medium were abolished by antibody-mediated NAMPT depletion, strongly suggesting that the protective effect is mediated by the extracellular NAMPT released into in the medium. These data suggest a novel neuroprotective role for secreted NAMPT in the protection of white matter after ischemic injury. PMID:25005877

  15. Assessment transcallosal Diaschisis in a model of focal cerebral ischemia in rats

    PubMed Central

    Muñoz Ospina, Beatriz Elena; Castaño, Daniel Manrique; Potes, Laura; Umbarila Prieto, John

    2016-01-01

    Objective: To evaluate transcallosal changes after a local ischemic injury in rats by using the monoclonal marker anti-NeuN (Mouse anti-neuronal nuclei). Methods: Twenty-eight adult, male, Wistar rats were subjected to focal injury in the right hemisphere. The technique used was the experimental model of focal ischemic injury through intraluminal suture of the middle cerebral artery. Analyses were made for the five groups: after the lesion (control), at 24 h, 96 h, 10 days and 20 days. Exofocal neuronal damage was inferred from neuronal immunoreactivity changes to NeuN. Results: In the cortex contralateral to the lesion, immunoreactivity was diminished. This finding was most notable in the supra-granular sheets 24 h post ischemia. After 96 h, there was a generalized diminishment of the inmmunoreactivity in the supra and infra-granular sheets. At 10 and 20 days, the tissue recovered some immunoreactivity to NeuN, but there were some changes in the VI layer. Conclusion: The immunoreactive changes to NeuN support the process of inter-hemispheric diaschisis. Changes in immunoreactivity could indicate metabolic stress secondary to the disruption in connectivity to the site of lesion. PMID:27546930

  16. Epidemiology and risk factors of cerebral ischemia and ischemic heart diseases: similarities and differences.

    PubMed

    Soler, Ernest Palomeras; Ruiz, Virgina Casado

    2010-08-01

    Cerebral ischemia and ischemic heart diseases, common entities nowadays, are the main manifestation of circulatory diseases. Cardiovascular diseases, followed by stroke, represent the leading cause of mortality worldwide. Both entities share risk factors, pathophisiology and etiologic aspects by means of a main common mechanism, atherosclerosis. However, each entity has its own particularities. Ischemic stroke shows a variety of pathogenic mechanisms not present in ischemic heart disease. An ischemic stroke increases the risk of suffering a coronary heart disease, and viceversa. The aim of this chapter is to review data on epidemiology, pathophisiology and risk factors for both entities, considering the differences and similarities that could be found in between them. We discuss traditional risk factors, obtained from epidemiological data, and also some novel ones, such as hyperhomocisteinemia or sleep apnea. We separate risk factors, as clasically, in two groups: nonmodifiables, which includes age, sex, or ethnicity, and modifiables, including hypertension, dyslipidemia or diabetis, in order to discuss the role of each factor in both ischemic events, ischemic stroke and coronary heart disease.

  17. Epidemiology and Risk Factors of Cerebral Ischemia and Ischemic Heart Diseases: Similarities and Differences

    PubMed Central

    Soler, Ernest Palomeras; Ruiz, Virgina Casado

    2010-01-01

    Cerebral ischemia and ischemic heart diseases, common entities nowadays, are the main manifestation of circulatory diseases. Cardiovascular diseases, followed by stroke, represent the leading cause of mortality worldwide. Both entities share risk factors, pathophisiology and etiologic aspects by means of a main common mechanism, atherosclerosis. However, each entity has its own particularities. Ischemic stroke shows a variety of pathogenic mechanisms not present in ischemic heart disease. An ischemic stroke increases the risk of suffering a coronary heart disease, and viceversa. The aim of this chapter is to review data on epidemiology, pathophisiology and risk factors for both entities, considering the differences and similarities that could be found in between them. We discuss traditional risk factors, obtained from epidemiological data, and also some novel ones, such as hyperhomocisteinemia or sleep apnea. We separate risk factors, as clasically, in two groups: nonmodifiables, which includes age, sex, or ethnicity, and modifiables, including hypertension, dyslipidemia or diabetis, in order to discuss the role of each factor in both ischemic events, ischemic stroke and coronary heart disease. PMID:21804773

  18. Impact of Reperfusion after 3 Hours of Symptom Onset on Tissue Fate in Acute Cerebral Ischemia

    PubMed Central

    Bang, Oh Young; Liebeskind, David S.; Buck, Brian H.; Yoon, Sa Rah; Alger, Jeffry R.; Ovbiagele, Bruce; Saver, Jeffrey L.

    2009-01-01

    BACKGROUND Reperfusion of penumbral tissue is a promising strategy for treatment of acute cerebral ischemia more than 3 hours from symptom onset. However, there has been only sparse direct evidence that reperfusion after 3 hours prevents infarct growth. METHODS We analyzed clinical and serial magnetic resonance imaging (MRI) data on patients who received endovascular recanalization therapy 3–12 hours after last known well time. Multimodal MRIs were acquired pretreatment, early (1–20 hours), and late (2–7 days) after treatment. Degree of recanalization was assessed on end of procedure catheter angiogram, degree of reperfusion on early posttreatment perfusion MRI, and infarct growth by analysis of diffusion lesion volumes on pretreatment and late MRIs. RESULTS Twenty-seven (12 men, 15 women) underwent endovascular recanalization procedures at 6.0 ± 2.1 hours (range, 3.0–11.5 hours) after last known well time. Immediate posttreatment perfusion lesion (Tmax ≥4 seconds) volume correlated strongly with infarct growth (r = .951, P < .001), exceeding the correlations of vessel recanalization score (r = −.198, P = .446) and pretreatment diffusion-perfusion mismatch volume (r = .518, P = .033). Without reperfusion, enlargement of DWI lesion volume was observed in all patients, and extent of enlargement depended on volume of immediate posttreatment perfusion defects. CONCLUSION Our data indicate that posttreatment reperfusion is the major determinant of threatened tissue outcome, and suggest reperfusion even after 3 hours of symptom onset can alter tissue fate over a wide range of mismatch volumes. PMID:19021836

  19. Comparative pharmacokinetics of five rhubarb anthraquinones in normal and thrombotic focal cerebral ischemia-induced rats.

    PubMed

    Feng, Su-xiang; Li, Jian-sheng; Qu, Ling-bo; Shi, Yan-mei; Zhao, Di

    2013-10-01

    A comparative oral pharmacokinetic study of five anthraquinones (aloe-emodin, emodin, rhein, chrysophanol and physcion) from the extract of Rheum palmatum L. was performed in normal and thrombotic focal cerebral ischemia (TFCI)-induced rats. The plasma samples were clarified through solid phase extraction prior to simultaneous determination of the anthraquinones with a validated high-performance liquid chromatography-fluorescence system. The results indicated that the Cmax, t(1/2) and AUC(0-t), of aloe-emodin, rhein, emodin and chrysophanol in TFCI-induced rats were nearly double, whereas the CL values were remarkably decreased (p < 0.05) over those of the normal rats. The plasma drug concentration-time data of five anthraquinones to rats fitted a two-compartment open model. The five anthraquinones in rat plasma were absorbed quickly and eliminated slowly in both groups. The obtained results could be helpful for evaluating the impact of the efficacy and safety of the drug in clinical applications.

  20. Carbonic anhydrase inhibition for the management of cerebral ischemia: in vivo evaluation of sulfonamide and coumarin inhibitors.

    PubMed

    Di Cesare Mannelli, Lorenzo; Micheli, Laura; Carta, Fabrizio; Cozzi, Andrea; Ghelardini, Carla; Supuran, Claudiu T

    2016-12-01

    Ischemia of brain areas is a global health problem, causing death or long-term disability. Current pharmacological options have limited impact on ischemic damages. Recently, a relationship between hypoxia and carbonic anhydrase (CA) over-expression has been highlighted suggesting CA inhibition as a possible target. This study aimed to evaluate the pharmacological profile of sulfonamide and coumarin CA inhibitors in rats underwent permanent middle cerebral artery occlusion (pMCAO). The neurological score of pMCAO rats was dramatically reduced 24 h after occlusion. Repeated subcutaneous injections of the CA inhibitors 4 and 7 (1 mg kg(-1)) were able to increase the neurological score by 40%. Compound 7 showed the tendency to reduce the volume of hemisphere infarction. The standard CA inhibitor acetazolamide was ineffective. The properties of novel CA inhibitors to improve neurological functionalities after cerebral ischemic insult are shown. The CA involvement in cerebral hypoxic phenomena deserves deeper investigations.

  1. Quantitative T(1rho) and magnetization transfer magnetic resonance imaging of acute cerebral ischemia in the rat.

    PubMed

    Mäkelä, Heidi I; Kettunen, Mikko I; Gröhn, Olli H J; Kauppinen, Risto A

    2002-05-01

    It has been previously shown that T1 in the rotating frame (T(1rho)) is a very sensitive and early marker of cerebral ischemia and that, interestingly, it can provide prognostic information about the degree of subsequent neuronal damage. In the present study the authors have quantified T(1rho) together with the rate and other variables of magnetization transfer (MT) associated with spin interactions between the bulk and semisolid macromolecular pools by means of Z spectroscopy, to examine the possible overlap of mechanisms affecting these magnetic resonance imaging contrasts. Substantial prolongation of cerebral T(1rho) was observed minutes after induction of ischemia, this change progressing in a time-dependent manner. Difference Z spectra (contralateral nonischemic minus ischemic brain tissue) showed a significant positive reminder in the time points from 0.5 to 3 hours after induction of ischemia, the polarity of this change reversing by 24 hours. Detailed analysis of the MT variables showed that the initial Z spectral changes were due to concerted increase in the maximal MT (+3%) and amount of MT (+4%). Interestingly, the MT rates derived either from the entire frequency range of Z spectra or the time constant for the first-order forward exchange (k(sat)) were unchanged at this time, these variables reducing only one day after induction of ischemia. The authors conclude that T(1rho) changes in the acute phase of ischemia coincide with both elevated maximal MT and amount of MT. These changes occur independent of the overall MT rate and in the absence of net water gain to the tissue, whereas in the consolidating infarction the decrease in the rate and amount of MT, as well as the extensive prolongation of T(1rho), are associated with water accumulation. PMID:11973427

  2. Soluble epoxide hydrolase gene deletion improves blood flow and reduces infarct size after cerebral ischemia in reproductively senescent female mice

    PubMed Central

    Zuloaga, Kristen L.; Zhang, Wenri; Roese, Natalie E.; Alkayed, Nabil J.

    2015-01-01

    Soluble epoxide hydrolase (sEH), a key enzyme in the metabolism of vasodilatory epoxyeicosatrienoic acids (EETs), is sexually dimorphic, suppressed by estrogen, and contributes to underlying sex differences in cerebral blood flow and injury after cerebral ischemia. We tested the hypothesis that sEH inhibition or gene deletion in reproductively senescent (RS) female mice would increase cerebral perfusion and decrease infarct size following stroke. RS (15–18 month old) and young (3–4 month old) female sEH knockout (sEHKO) mice and wild type (WT) mice were subjected to 45 min middle cerebral artery occlusion (MCAO) with laser Doppler perfusion monitoring. WT mice were treated with vehicle or a sEH inhibitor t-AUCB at the time of reperfusion and every 24 h thereafter for 3 days. Differences in regional cerebral blood flow were measured in vivo using optical microangiography (OMAG). Infarct size was measured 3 days after reperfusion. Infarct size and cerebral perfusion 24 h after MCAO were not altered by age. Both sEH gene deletion and sEH inhibition increased cortical perfusion 24 h after MCAO. Neither sEH gene deletion nor sEH inhibition reduced infarct size in young mice. However, sEH gene deletion, but not sEH inhibition of the hydrolase domain of the enzyme, decreased infarct size in RS mice. Results of these studies show that sEH gene deletion and sEH inhibition enhance cortical perfusion following MCAO and sEH gene deletion reduces damage after ischemia in RS female mice; however this neuroprotection in absent is young mice. PMID:25642188

  3. Electroacupuncture attenuates cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive rats

    PubMed Central

    TAN, FENG; CHEN, JIE; LIANG, YANGUI; GU, MINHUA; LI, YANPING; WANG, XUEWEN; MENG, DI

    2014-01-01

    Cerebral ischemia induces injury, not only in the ischemic core and surrounding penumbra tissues, but also in remote areas such as the cervical spinal cord. The aim of the present study was to determine the effects of electroacupuncture (EA) on cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive (RHRSP) rats. The results demonstrated that neuronal loss, which was assayed by Nissl staining in the cervical spinal cords of RHRSP rats subjected to transient middle cerebral artery occlusion (MCAO), was markedly decreased by EA stimulation at the GV20 (Baihui) and GV14 (Dazhui) acupoints compared with that in rats undergoing sham stimulation. Quantitative polymerase chain reaction and western blot analysis demonstrated that EA stimulation blocked the MCAO-induced elevated protein expression levels of glial fibrillary acidic protein and amyloid precursor protein in the cervical spinal cord at days 24 and 48. To further investigate the mechanism underlying the neuroprotective role of EA stimulation, the protein expression levels of Nogo-A and Nogo-66 receptor-1 (NgR1), two key regulatory molecules for neurite growth, were recorded in each group. The results revealed that EA stimulation reduced the MCAO-induced elevation of Nogo-A and NgR1 protein levels at day 14 and 28 in RHRSP rats. Therefore, the results demonstrated that EA reduced cervical spinal cord injury following cerebral ischemia in RHRSP rats, indicating that EA has the potential to be developed as a therapeutic treatment agent for cervical spinal cord injury following stroke. PMID:24926338

  4. Protective effect of α-terpineol against impairment of hippocampal synaptic plasticity and spatial memory following transient cerebral ischemia in rats

    PubMed Central

    Moghimi, Mahsa; Parvardeh, Siavash; Zanjani, Taraneh Moini; Ghafghazi, Shiva

    2016-01-01

    Objective(s): Cerebral ischemia is often associated with cognitive impairment. Oxidative stress has a crucial role in the memory deficit following ischemia/reperfusion injury. α-Terpineol is a monoterpenoid with anti-inflammatory and antioxidant effects. This study was carried out to investigate the effect of α-terpineol against memory impairment following cerebral ischemia in rats. Materials and Methods: Cerebral ischemia was induced by transient bilateral common carotid artery occlusion in male Wistar rats. The rats were allocated to sham, ischemia, and α-terpineol-treated groups. α-Terpineol was given at doses of 50, 100, and 200 mg/kg, IP once daily for 7 days post ischemia. Morris water maze (MWM) test was used to assess spatial memory and in vivo extracellular recording of long-term potentiation (LTP) in the hippocampal dentate gyrus was carried out to evaluate synaptic plasticity. Malondialdehyde (MDA) was measured to assess the extent of lipid peroxidation in the hippocampus. Results: In MWM test, α-terpineol (100 mg/kg, IP) significantly decreased the escape latency during training trials (P<0.01). In addition, α-terpineol increased the number of crossings over the platform location and decreased average proximity to the target in probe trial (P<0.05). In electrophysiological recording, α-terpineol (100 mg/kg) facilitated the induction of LTP in the hippocampus which was persistent over 2 hr. α-Terpineol (100 and 200 mg/kg) also significantly lowered hippocampal MDA levels in rats subjected to cerebral ischemia. Conclusion: These findings indicate that α-terpineol improves cerebral ischemia-related memory impairment in rats through the facilitation of LTP and suppression of lipid peroxidation in the hippocampus. PMID:27803783

  5. Targeting Mannose Binding Lectin Confers Long Lasting Protection with a Surprisingly Wide Therapeutic Window in Cerebral Ischemia

    PubMed Central

    Orsini, Franca; Villa, Pia; Parrella, Sara; Zangari, Rosalia; Zanier, Elisa R.; Gesuete, Raffaella; Stravalaci, Matteo; Fumagalli, Stefano; Ottria, Roberta; Reina, Josè J.; Paladini, Alessandra; Micotti, Edoardo; Ribeiro-Viana, Renato; Rojo, Javier; Pavlov, Vasile I.; Stahl, Gregory L.; Bernardi, Anna; Gobbi, Marco; De Simoni, Maria-Grazia

    2012-01-01

    Background The involvement of complement system in brain injury has been scarcely investigated. Here we document the pivotal role of mannose binding lectin (MBL), one of the recognition molecules of the lectin complement pathway, in brain ischemic injury. Methods and Results Focal cerebral ischemia was induced in mice (by permanent or transient middle cerebral artery occlusion) and rats (by 3-vessels occlusion). We first observed that MBL is deposited on ischemic vessels up to 48h after injury and that functional MBL/MASP2 complexes are increased. Next we demonstrated that: 1) MBL−/− mice are protected from both transient and permanent ischemic injury; 2) Polyman2, the newly synthesized mannosylated molecule selected for its binding to MBL, improves neurological deficits and infarct volume when given up to 24h after ischemia in mice; 3) anti-MBL-A antibody improves neurological deficits and infarct volume when given up to 18h after ischemia, as assessed following 28d in rats. Conclusions Our data show an important role for MBL in the pathogenesis of brain ischemic injury and provide a strong support to the concept that MBL inhibition may be a relevant therapeutic target in humans, one with a wide therapeutic window of application. PMID:22879370

  6. PET imaging of serotoninergic neurotransmission with [11C]DASB and [18F]altanserin after focal cerebral ischemia in rats

    PubMed Central

    Martín, Abraham; Szczupak, Boguslaw; Gómez-Vallejo, Vanessa; Plaza, Sandra; Padró, Daniel; Cano, Ainhoa; Llop, Jordi

    2013-01-01

    The use of selective serotonin reuptake inhibitors has shown functional improvement after stroke. Despite this, the role of serotoninergic neurotransmission after cerebral ischemia evolution and its involvement in functional recovery processes are still largely unknown. For this purpose, we performed in parallel in vivo magnetic resonance imaging and positron emission tomography (PET) with [11C]DASB and [18F]altanserin at 1, 3, 7, 14, 21, and 28 days after middle cerebral artery occlusion (MCAO) in rats. In the ischemic territory, PET with [11C]DASB and [18F]altanserin showed a dramatic decline in serotonin transporter (SERT) and 5-HT2A binding potential in the cortex and striatum after cerebral ischemia. Interestingly, a slight increase in [11C]DASB binding was observed from days 7 to 21 followed by the uppermost binding at day 28 in the ipsilateral midbrain. In contrast, no changes were observed in the contralateral hemisphere by using both radiotracers. Likewise, both functional and behavior testing showed major impaired outcome at day 1 after ischemia onset followed by a recovery of the sensorimotor function and dexterity from day 21 to day 28 after cerebral ischemia. Taken together, these results might evidence that SERT changes in the midbrain could have a key role in the functional recovery process after cerebral ischemia. PMID:23982048

  7. Extracranial-Intracranial Bypass Surgery for Stroke Prevention in Hemodynamic Cerebral Ischemia: The Carotid Occlusion Surgery Study: A Randomized Trial

    PubMed Central

    Powers, William J.; Clarke, William R.; Grubb, Robert L.; Videen, Tom O; Adams, Harold P.; Derdeyn, Colin P.

    2013-01-01

    Context Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. Objective Test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. Design Parallel group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002–2010. Setting 49 clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. Participants Arteriographically-confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. 195 were randomized: 97 to surgery and 98 to no surgery. Follow-up for the primary endpoint until occurrence, 2 years, or end of trial was 99% complete. No participant withdrew because of adverse events. Interventions Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Anti-thrombotic therapy and risk factor intervention were recommended for all. Main Outcome Measure For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days post surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery was the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within two years of randomization. Results The trial was terminated early for futility. Two-year rates for the primary endpoint were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group

  8. Absolute Cerebral Blood Flow Infarction Threshold for 3-Hour Ischemia Time Determined with CT Perfusion and 18F-FFMZ-PET Imaging in a Porcine Model of Cerebral Ischemia

    PubMed Central

    Cockburn, Neil; Kovacs, Michael

    2016-01-01

    CT Perfusion (CTP) derived cerebral blood flow (CBF) thresholds have been proposed as the optimal parameter for distinguishing the infarct core prior to reperfusion. Previous threshold-derivation studies have been limited by uncertainties introduced by infarct expansion between the acute phase of stroke and follow-up imaging, or DWI lesion reversibility. In this study a model is proposed for determining infarction CBF thresholds at 3hr ischemia time by comparing contemporaneously acquired CTP derived CBF maps to 18F-FFMZ-PET imaging, with the objective of deriving a CBF threshold for infarction after 3 hours of ischemia. Endothelin-1 (ET-1) was injected into the brain of Duroc-Cross pigs (n = 11) through a burr hole in the skull. CTP images were acquired 10 and 30 minutes post ET-1 injection and then every 30 minutes for 150 minutes. 370 MBq of 18F-FFMZ was injected ~120 minutes post ET-1 injection and PET images were acquired for 25 minutes starting ~155–180 minutes post ET-1 injection. CBF maps from each CTP acquisition were co-registered and converted into a median CBF map. The median CBF map was co-registered to blood volume maps for vessel exclusion, an average CT image for grey/white matter segmentation, and 18F-FFMZ-PET images for infarct delineation. Logistic regression and ROC analysis were performed on infarcted and non-infarcted pixel CBF values for each animal that developed infarct. Six of the eleven animals developed infarction. The mean CBF value corresponding to the optimal operating point of the ROC curves for the 6 animals was 12.6 ± 2.8 mL·min-1·100g-1 for infarction after 3 hours of ischemia. The porcine ET-1 model of cerebral ischemia is easier to implement then other large animal models of stroke, and performs similarly as long as CBF is monitored using CTP to prevent reperfusion. PMID:27347877

  9. Absolute Cerebral Blood Flow Infarction Threshold for 3-Hour Ischemia Time Determined with CT Perfusion and 18F-FFMZ-PET Imaging in a Porcine Model of Cerebral Ischemia.

    PubMed

    Wright, Eric A; d'Esterre, Christopher D; Morrison, Laura B; Cockburn, Neil; Kovacs, Michael; Lee, Ting-Yim

    2016-01-01

    CT Perfusion (CTP) derived cerebral blood flow (CBF) thresholds have been proposed as the optimal parameter for distinguishing the infarct core prior to reperfusion. Previous threshold-derivation studies have been limited by uncertainties introduced by infarct expansion between the acute phase of stroke and follow-up imaging, or DWI lesion reversibility. In this study a model is proposed for determining infarction CBF thresholds at 3hr ischemia time by comparing contemporaneously acquired CTP derived CBF maps to 18F-FFMZ-PET imaging, with the objective of deriving a CBF threshold for infarction after 3 hours of ischemia. Endothelin-1 (ET-1) was injected into the brain of Duroc-Cross pigs (n = 11) through a burr hole in the skull. CTP images were acquired 10 and 30 minutes post ET-1 injection and then every 30 minutes for 150 minutes. 370 MBq of 18F-FFMZ was injected ~120 minutes post ET-1 injection and PET images were acquired for 25 minutes starting ~155-180 minutes post ET-1 injection. CBF maps from each CTP acquisition were co-registered and converted into a median CBF map. The median CBF map was co-registered to blood volume maps for vessel exclusion, an average CT image for grey/white matter segmentation, and 18F-FFMZ-PET images for infarct delineation. Logistic regression and ROC analysis were performed on infarcted and non-infarcted pixel CBF values for each animal that developed infarct. Six of the eleven animals developed infarction. The mean CBF value corresponding to the optimal operating point of the ROC curves for the 6 animals was 12.6 ± 2.8 mL·min-1·100g-1 for infarction after 3 hours of ischemia. The porcine ET-1 model of cerebral ischemia is easier to implement then other large animal models of stroke, and performs similarly as long as CBF is monitored using CTP to prevent reperfusion. PMID:27347877

  10. Time-course of protection by the selective A2A receptor antagonist SCH58261 after transient focal cerebral ischemia.

    PubMed

    Melani, Alessia; Dettori, Ilaria; Corti, Francesca; Cellai, Lucrezia; Pedata, Felicita

    2015-08-01

    Evidence indicates that the adenosine A2A receptor subtype is of critical importance in stroke. In previous studies, in the model of permanent middle cerebral artery occlusion (pMCAo), the adenosine A2A receptor antagonist, SCH58261, administered soon after ischemia, proved protective against excessive glutamate outflow in the first 4 h after ischemia and against neurological deficit and tissue damage evaluated 24 h after pMCAo. In the present work, we investigated if neuroprotective effect of SCH58261 was maintained 7 days after transient MCAo (tMCAo). SCH58261 (0.01 mg/kg, i.p.), administered twice/day for 7 days, protected from neurological deficit 1 day after tMCAo, but no more after 5 and 7 days. Two days after tMCAo, SCH58261 did not reduce blood cell infiltration, evaluated as HIS-48 positive cells, into ischemic striatal and cortical tissue. Moreover, 7 days after tMCAo, SCH58261 has not protected ischemic areas from damage and has not ameliorated myelin organization into the ischemic striatum. Protection by the A2A receptor antagonist 24 h after ischemia is attributable to reduced excitotoxicity. Seven days after ischemia the early protective effect of the A2A receptor antagonist likely has been overwhelmed by a secondary damage due to blood cell infiltration and neuroinflammation.

  11. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.

    PubMed

    Nada, Shadia E; Tulsulkar, Jatin; Raghavan, Aparna; Hensley, Kenneth; Shah, Zahoor A

    2012-12-01

    Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation. PMID:23036362

  12. A derivative of the CRMP2 binding compound lanthionine ketimine provides neuroprotection in a mouse model of cerebral ischemia.

    PubMed

    Nada, Shadia E; Tulsulkar, Jatin; Raghavan, Aparna; Hensley, Kenneth; Shah, Zahoor A

    2012-12-01

    Lanthionines are novel neurotrophic and neuroprotective small molecules that show promise for the treatment of neurodegenerative diseases. In particular, a recently developed, cell permeable lanthionine derivative known as LKE (lanthionine ketimine 5-ethyl ester) promotes neurite growth at low nanomolar concentrations. LKE also has neuroprotective, anti-apoptotic, and anti-inflammatory properties. Its therapeutic potential in cerebral ischemia and its mechanisms of neurotrophic action remain to be fully elucidated. Here, we hypothesize that the neuroprotective actions of LKE could result from induction or modulation of CRMP2. We found that treating primary cultured mouse neurons with LKE provided significant protection against t-butyl hydroperoxide-induced neuronal death possibly through CRMP2 upregulation. Similarly, in vivo studies showed that LKE pre and/or post-treatment protects mice against permanent distal middle cerebral artery occlusion (p-MCAO) as evidenced by lower stroke lesions and improved functional outcomes in terms of rotarod, grip strength and neurologic deficit scores in treated groups. Protein expression levels of CRMP2 were higher in brain cortices of LKE pretreated mice, suggesting that LKE's neuroprotective activity may be CRMP2 dependent. Lower activity of cleaved PARP-1 and higher activity of SIRT-1 was also observed in LKE treated group suggesting its anti-apoptotic properties. Our results suggest that LKE has potential as a therapeutic intervention in cerebral ischemia and that part of its protective mechanism may be attributed to CRMP2 mediated action and PARP-1/SIRT-1 modulation.

  13. The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury

    PubMed Central

    Iadecola, Costantino; Salkowski, Cindy A.; Zhang, Fangyi; Aber, Tracy; Nagayama, Masao; Vogel, Stefanie N.; Elizabeth Ross, M.

    1999-01-01

    The transcription factor interferon regulatory factor 1 (IRF-1) is involved in the molecular mechanisms of inflammation and apoptosis, processes that contribute to ischemic brain injury. In this study, the induction of IRF-1 in response to cerebral ischemia and its role in ischemic brain injury were investigated. IRF-1 gene expression was markedly upregulated within 12 h of occlusion of the middle cerebral artery in C57BL/6 mice. The expression reached a peak 4 d after ischemia (6.0 ± 1.8-fold; P < 0.001) and was restricted to the ischemic regions of the brain. The volume of ischemic injury was reduced by 23 ± 3% in IRF-1+/− and by 46 ± 9% in IRF-1−/− mice (P < 0.05). The reduction in infarct volume was paralleled by a substantial attenuation in neurological deficits. Thus, IRF-1 is the first nuclear transacting factor demonstrated to contribute directly to cerebral ischemic damage and may be a novel therapeutic target in ischemic stroke. PMID:9989987

  14. Lactulose ameliorates cerebral ischemia-reperfusion injury in rats by inducing hydrogen by activating Nrf2 expression.

    PubMed

    Zhai, Xiao; Chen, Xiao; Shi, Jiazi; Shi, Duo; Ye, Zhouheng; Liu, Wenwu; Li, Ming; Wang, Qijin; Kang, Zhimin; Bi, Hongda; Sun, Xuejun

    2013-12-01

    Molecular hydrogen has been proven effective in ameliorating cerebral ischemia/reperfusion (I/R) injury by selectively neutralizing reactive oxygen species. Lactulose can produce a considerable amount of hydrogen through fermentation by the bacteria in the gastrointestinal tract. To determine the neuroprotective effects of lactulose against cerebral I/R injury in rats and explore the probable mechanisms, we carried out this study. The stroke model was produced in Sprague-Dawley rats through middle cerebral artery occlusion. Intragastric administration of lactulose substantially increased breath hydrogen concentration. Behavioral and histopathological verifications matched biochemical findings. Behaviorally, rats in the lactulose administration group won higher neurological scores and showed shorter escape latency time in the Morris test. Morphologically, 2,3,5-triphenyltetrazolium chloride showed smaller infarction volume; Nissl staining manifested relatively clear and intact neurons and TUNEL staining showed fewer apoptotic neurons. Biochemically, lactulose decreased brain malondialdehyde content, caspase-3 activity, and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine concentration and increased superoxide dismutase activity. The effects of lactulose were superior to those of edaravone. Lactulose orally administered activated the expression of NF-E2-related factor 2 (Nrf2) in the brain as verified by RT-PCR and Western blot. The antibiotics suppressed the neuroprotective effects of lactulose by reducing hydrogen production. Our study for the first time demonstrates a novel therapeutic effect of lactulose on cerebral ischemia/reperfusion injury and the probable underlying mechanisms. Lactulose intragastrically administered possessed neuroprotective effects on cerebral I/R injury in rats, which could be attributed to hydrogen production by the fermentation of lactulose through intestinal bacteria and Nrf2 activation.

  15. Impaired vascular remodeling after endothelial progenitor cell transplantation in MMP9-deficient mice suffering cortical cerebral ischemia

    PubMed Central

    Morancho, Anna; Ma, Feifei; Barceló, Verónica; Giralt, Dolors; Montaner, Joan; Rosell, Anna

    2015-01-01

    Endothelial progenitor cells (EPCs) are being investigated for advanced therapies, and matrix metalloproteinase 9 (MMP9) has an important role in stroke recovery. Our aim was to determine whether tissue MMP9 influences the EPC-induced angiogenesis after ischemia. Wild-type (WT) and MMP9-deficient mice (MMP9/KO) were subjected to cerebral ischemia and treated with vehicle or outgrowth EPCs. After 3 weeks, we observed an increase in the peri-infarct vessel density in WT animals but not in MMP9/KO mice; no differences were found in the vehicle-treated groups. Our data suggest that tissue MMP9 has a crucial role in EPC-induced vascular remodeling after stroke. PMID:26219597

  16. Ischemia detection by electrocardiogram in wavelet domain using entropy measure

    PubMed Central

    Rabbani, Hossein; Mahjoob, Mohammad Parsa; Farahabadi, Eiman; Farahabadi, Amin; Dehnavi, Alireza Mehri

    2011-01-01

    BACKGROUND: Ischemic heart disease is one of the common fatal diseases in advanced countries. Because signal perturbation in healthy people is less than signal perturbation in patients, entropy measure can be used as an appropriate feature for ischemia detection. METHODS: Four entropy-based methods comprising of using electrocardiogram (ECG) signal directly, wavelet sub-bands of ECG signals, extracted ST segments and reconstructed signal from time-frequency feature of ST segments in wavelet domain were investigated to distinguish between ECG signal of healthy individuals and patients. We used exercise treadmill test as a gold standard, with a sample of 40 patients who had ischemic signs based on initial diagnosis of medical practitioner. RESULTS: The suggested technique in wavelet domain resulted in the highest discrepancy between healthy individuals and patients in comparison to other methods. Specificity and sensitivity of this method were 95% and 94% respectively. CONCLUSIONS: The method based on wavelet sub-bands outperformed the others. PMID:22973350

  17. Improvement in Regional CBF by L-Serine Contributes to Its Neuroprotective Effect in Rats after Focal Cerebral Ischemia

    PubMed Central

    Jiang, Zheng-Lin; Wang, Guo-Hua; Sun, Li; Jiang, Rui; Zhao, Guang-Wei; Han, Le-Yang

    2013-01-01

    To investigate the mechanisms underlying the neuroprotective effect of L-serine, permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery while monitoring cerebral blood flow (CBF). Rats were divided into control and L-serine-treated groups after middle cerebral artery occlusion. The neurological deficit score and brain infarct volume were assessed. Nissl staining was used to quantify the cortical injury. L-serine and D-serine levels in the ischemic cortex were analyzed with high performance liquid chromatography. We found that L-serine treatment: 1) reduced the neurological deficit score, infarct volume and cortical neuron loss in a dose-dependent manner; 2) improved CBF in the cortex, and this effect was inhibited in the presence of apamin plus charybdotoxin while the alleviation of both neurological deficit score and infarct volume was blocked; and 3) increased the amount of L-serine and D-serine in the cortex, and inhibition of the conversion of L-serine into D-serine by aminooxyacetic acid did not affect the reduction of neurological deficit score and infarct volume by L-serine. In conclusion, improvement in regional CBF by L-serine may contribute to its neuroprotective effect on the ischemic brain, potentially through vasodilation which is mediated by the small- and intermediate-conductance Ca2+-activated K+ channels on the cerebral blood vessel endothelium. PMID:23825613

  18. Adenosine triphosphate stress echocardiography in the detection of myocardial ischemia.

    PubMed

    Fukai, T; Koyanagi, S; Tashiro, H; Ichiki, T; Tsutsui, H; Matsumoto, T; Takeshita, A

    1995-10-01

    The purpose of this study was to assess feasibility and safety in the diagnosis of coronary artery in the diagnosis of coronary artery disease and myocardial ischemia using adenosine triphosphate (ATP) stress echocardiography. ATP, a product of human myocardial tissue, is more potent than adenosine in increasing coronary blood flow. Like adenosine, ATP also has a short half-life (<10 s). Left ventricular echocardiograms were recorded during step-wise infusions of ATP in 86 patients who underwent coronary angiography and stress thallium 201 scintigraphy. No serious complications occurred with ATP infusion and most of the side effects were mild and transient. Significant coronary artery disease (>75% diameter stenosis) was present in 34 of 48 patients who had normal echocardiograms at rest. The sensitivity and specificity of ATP-induced wall motion abnormalities for coronary artery disease was 65% (22 of 34) and 100% (14 of 14), respectively. The sensitivity was 50% (10 of 20) in those with one-vessel disease and 86% (12 of 14) in those with multivessel disease (P < .05). In patients with normal echocardiograms at rest and without prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of myocardial ischemia assessed by 201Tl single proton emission computed tomography was 58%, with a specificity of 76%, and a diagnostic accuracy of 66%. The sensitivity was 43% in those with one-vessel disease, and 86% in those with multivessel disease (P = .05). In patients with prior myocardial infarction, the sensitivity of ATP stress echocardiography for the detection of viable but jeopardized myocardium was 81%, with a specificity of 91%. The patients with well-developed collateral circulation had a higher incidence of developing wall motion abnormality than those without collaterals (70% v 40%, P < .01). ATP stress echocardiography is valuable for the assessment of coronary artery disease in patients with multivessel disease, coronary

  19. Transcutaneous auricular vagus nerve stimulation regulates expression of growth differentiation factor 11 and activin-like kinase 5 in cerebral ischemia/reperfusion rats.

    PubMed

    Ma, Jingxi; Zhang, Lina; He, Guoqian; Tan, Xiaodan; Jin, Xinhao; Li, Changqing

    2016-10-15

    Growth differentiation factor 11 (GDF11), as a rejuvenation factor in heterochronic parabiosis, can increase proliferation of primary brain capillary endothelial cells (ECs). However, the angiogenic role of GDF11 in ischemia-induced brain injury is still unclear. There are no previous reports on the spatiotemporal expression of GDF11 in cerebral ischemia/reperfusion (I/R) rats. Our recent work has strongly suggested that transcutaneous auricular vagus nerve stimulation (ta-VNS) reduces infarct size and induces angiogenesis in focal cerebral I/R rats. This study focused on expression of GDF11 and activin-like kinase 5 (ALK5) and the effects of ta-VNS in a rat cerebral I/R model. For ta-VNS, electrical stimulation of the left cavum concha (1h duration) using percutaneous needles was initiated 30min after induction of ischemia. Expression of GDF11 was analyzed by enzyme-linked immunosorbent assay, immunohistochemistry, real-time polymerase chain reaction, and western blot 24h, 3d, and 7d after reperfusion. In addition, neurobehavioral function, EC proliferation, and expression of ALK5 in ECs in the peri-infarct cortex were measured. Results showed that levels of GDF11 were significantly elevated after cerebral I/R, both in plasma and the peri-infarct cerebral cortex. Interestingly, splenic GDF11 levels decreased after ischemia. ALK5 was expressed in ECs in the peri-infarct cerebral cortex where active vessel remodeling was noted. ta-VNS improved neurobehavioral recovery, upregulated cerebral GDF11 and downregulated splenic GDF11, indicating a brain-spleen communication during stroke. ta-VNS also increased expression of ALK5 in ECs and stimulated proliferation of ECs. These results suggest that, after cerebral ischemia, GDF11 redistributes and participates in angiogenesis as an angiogenic factor that acts at least in part through ALK5. GDF11/ALK5 may represent a new potential therapy target for stroke. PMID:27653860

  20. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus.

    PubMed

    Bae, Eun Joo; Chen, Bai Hui; Yan, Bing Chun; Shin, Bich Na; Cho, Jeong Hwi; Kim, In Hye; Ahn, Ji Hyeon; Lee, Jae Chul; Tae, Hyun-Jin; Hong, Seongkweon; Kim, Dong Won; Cho, Jun Hwi; Lee, Yun Lyul; Won, Moo-Ho; Park, Joon Ha

    2015-06-01

    The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1-3) between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults. PMID:26199612

  1. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

    PubMed Central

    Bae, Eun Joo; Chen, Bai Hui; Yan, Bing Chun; Shin, Bich Na; Cho, Jeong Hwi; Kim, In Hye; Ahn, Ji Hyeon; Lee, Jae Chul; Tae, Hyun-Jin; Hong, Seongkweon; Kim, Dong Won; Cho, Jun Hwi; Lee, Yun Lyul; Won, Moo-Ho; Park, Joon Ha

    2015-01-01

    The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1–3) between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults. PMID:26199612

  2. Short-Term Sleep Deprivation Stimulates Hippocampal Neurogenesis in Rats Following Global Cerebral Ischemia/Reperfusion

    PubMed Central

    Cheng, Oumei; Li, Rong; Zhao, Lei; Yu, Lijuan; Yang, Bin; Wang, Jia; Chen, Beibei; Yang, Junqing

    2015-01-01

    Background Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR). Methods One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d. Results The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects. Conclusions Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process. PMID:26039740

  3. Unsupervised nonlinear dimensionality reduction machine learning methods applied to multiparametric MRI in cerebral ischemia: preliminary results

    NASA Astrophysics Data System (ADS)

    Parekh, Vishwa S.; Jacobs, Jeremy R.; Jacobs, Michael A.

    2014-03-01

    The evaluation and treatment of acute cerebral ischemia requires a technique that can determine the total area of tissue at risk for infarction using diagnostic magnetic resonance imaging (MRI) sequences. Typical MRI data sets consist of T1- and T2-weighted imaging (T1WI, T2WI) along with advanced MRI parameters of diffusion-weighted imaging (DWI) and perfusion weighted imaging (PWI) methods. Each of these parameters has distinct radiological-pathological meaning. For example, DWI interrogates the movement of water in the tissue and PWI gives an estimate of the blood flow, both are critical measures during the evolution of stroke. In order to integrate these data and give an estimate of the tissue at risk or damaged; we have developed advanced machine learning methods based on unsupervised non-linear dimensionality reduction (NLDR) techniques. NLDR methods are a class of algorithms that uses mathematically defined manifolds for statistical sampling of multidimensional classes to generate a discrimination rule of guaranteed statistical accuracy and they can generate a two- or three-dimensional map, which represents the prominent structures of the data and provides an embedded image of meaningful low-dimensional structures hidden in their high-dimensional observations. In this manuscript, we develop NLDR methods on high dimensional MRI data sets of preclinical animals and clinical patients with stroke. On analyzing the performance of these methods, we observed that there was a high of similarity between multiparametric embedded images from NLDR methods and the ADC map and perfusion map. It was also observed that embedded scattergram of abnormal (infarcted or at risk) tissue can be visualized and provides a mechanism for automatic methods to delineate potential stroke volumes and early tissue at risk.

  4. Poppy seed oil protection of the hippocampus after cerebral ischemia and re-perfusion in rats.

    PubMed

    Cevik-Demirkan, A; Oztaşan, N; Oguzhan, E O; Cil, N; Coskun, S

    2012-11-01

    The brain is highly sensitive to hypoxia; this is true particularly of parts that are crucial for cognitive function. The effects of hypoxia are especially dramatic in the hippocampus. We evaluated the potential protective effects of poppy seed oil on the number of hippocampus cells and the serum antioxidant/oxidant status after cerebral ischemia and re-perfusion (CIR). Eighteen rats were divided into three equal groups. Group 1 served as the control group without CIR. Group 2 received poppy seed oil daily by oral gavage at a dose of 0.4 ml/kg, while group 3 was given 0.4 ml/kg saline solution by oral gavage per day; these treatments were continued for one month. Groups 2 and 3 were subjected to CIR induced by clamps on two points of both of the carotid arteries for 45 min followed by 45 min re-perfusion. There were significant decreases in the number of hippocampus cells between groups 1 and 2, and between groups 1 and 3. The mean cell number in group 2 was not significantly different from that of group 3. The serum nitric oxide levels in CIR groups were elevated significantly compared to controls, and were significantly higher in group 2 than in group 3. The glutathione levels were increased significantly in the poppy seed oil treated group compared to the saline CIR groups. The malondialdehyde levels were markedly increased in group 3 compared to both groups 1 and 2. Our study suggests that poppy seed oil can improve antioxidant defense capacity after CIR, although this treatment did not alter significantly the frequency of cell death.

  5. Transthyretin provides trophic support via megalin by promoting neurite outgrowth and neuroprotection in cerebral ischemia

    PubMed Central

    Gomes, J R; Nogueira, RS; Vieira, M; Santos, SD; Ferraz-Nogueira, J P; Relvas, J B; Saraiva, M J

    2016-01-01

    Transthyretin (TTR) is a protein whose function has been associated to binding and distribution of thyroid hormones in the body and brain. However, little is known regarding the downstream signaling pathways triggered by wild-type TTR in the CNS either in neuroprotection of cerebral ischemia or in physiological conditions. In this study, we investigated how TTR affects hippocampal neurons in physiologic/pathologic conditions. Recombinant TTR significantly boosted neurite outgrowth in mice hippocampal neurons, both in number and length, independently of its ligands. This TTR neuritogenic activity is mediated by the megalin receptor and is lost in megalin-deficient neurons. We also found that TTR activates the mitogen-activated protein kinase (MAPK) pathways (ERK1/2) and Akt through Src, leading to the phosphorylation of transcription factor CREB. In addition, TTR promoted a transient rise in intracellular calcium through NMDA receptors, in a Src/megalin-dependent manner. Moreover, under excitotoxic conditions, TTR stimulation rescued cell death and neurite loss in TTR KO hippocampal neurons, which are more sensitive to excitotoxic degeneration than WT neurons, in a megalin-dependent manner. CREB was also activated by TTR under excitotoxic conditions, contributing to changes in the balance between Bcl2 protein family members, toward anti-apoptotic proteins (Bcl2/BclXL versus Bax). Finally, we clarify that TTR KO mice subjected to pMCAO have larger infarcts than WT mice, because of TTR and megalin neuronal downregulation. Our results indicate that TTR might be regarded as a neurotrophic factor, because it stimulates neurite outgrowth under physiological conditions, and promotes neuroprotection in ischemic conditions. PMID:27518433

  6. Influence of age on the cerebral lesions in an immature rat model of cerebral hypoxia-ischemia: a light microscopic study.

    PubMed

    Towfighi, J; Mauger, D; Vannucci, R C; Vannucci, S J

    1997-06-18

    The most frequently used model of neonatal cerebral hypoxia-ischemia consists of a 7-day postnatal rat model with combined common carotid artery ligation and hypoxemia. Neuropathologic studies have shown major differences between this 7-day postnatal rat model and a similar adult model in regard to overall cerebral vulnerability, type and distribution of lesions. It is not clear how and when during animals' development these changes in cerebral vulnerability take place. To determine this we studied groups of rats of 2 to 30 postnatal days. The animals underwent unilateral common carotid artery ligation followed by breathing in 8% oxygen for 30, 60, 90, or 120 min and their brains were examined at 24- or 72-h recovery intervals. Due to resistance of 2-3-day-old rats to develop cerebral hypoxic-ischemic damage, 5% O2 was used instead of 8% O2. The results indicate that: (i) There is an overall increase in severity of cerebral lesions on the side of common carotid artery ligation between 2 and 7 postnatal days. There is also an increase in the frequency of cerebral lesions in developing animals with increasing age. (ii) Hippocampus is remarkably resistant to hypoxic-ischemic insult at 2-3 postnatal days but becomes progressively vulnerable, and by age 13 postnatal days hippocampal vulnerability far exceeds that of cortex. (iii) Cortical lesions change from predominantly columnar cell death to laminar selective neuronal death at age 13 postnatal days. (iv) Also significant changes occur in relative vulnerability of various hippocampal regions during development. During the first 5 postnatal days relative vulnerability of hippocampal regions is similar, but as the animals' development proceeds and hippocampal vulnerability increases lesions tend to involve specific regions while sparing others. By age 13 postnatal days CA1 and lateral CA3 develop increased vulnerability while medial CA3 and fascia dentata become relatively resistant and by 21 postnatal days adult

  7. Hydrogen sulfide protects the brain against ischemic reperfusion injury in a transient model of focal cerebral ischemia.

    PubMed

    Gheibi, Sevda; Aboutaleb, Nahid; Khaksari, Mehdi; Kalalian-Moghaddam, Hamid; Vakili, Abedin; Asadi, Yasin; Mehrjerdi, Fatemeh Zare; Gheibi, Azam

    2014-01-01

    Hydrogen sulfide (H(2)S), a well-known toxic gas, is regarded as endogenous neuromodulator and plays multiple roles in the central nervous system under physiological and pathological states, especially in secondary neuronal injury. Recent studies have shown relatively high concentrations of hydrogen sulfide (H(2)S) in the brain and also cytoprotective effects of endogenous and exogenous H(2)S in models of in vitro and in vivo ischemic injury. H(2)S protects neurons by functioning as an anti-oxidant, anti-inflammatory, and anti-apoptotic mediator and by improving neurological function. Moreover, it protects neurons from glutamate toxicity. Therefore, the present study aimed to determine whether H(2)S provides protection in transient focal cerebral ischemia. Focal ischemia was induced by 60-min middle cerebral artery occlusion (MCAO), followed by 23-h reperfusion. Saline as a vehicle and NaHS (H(2)S donor; 1 and 5 mg) were intraperitoneally injected (IP) at the beginning of ischemia. Infarct volume, brain edema, and apoptosis were assessed 24 h after MCAO.Treatment with NaHS at doses of 1 and 5 mg markedly reduced total infarct volumes by 29 and 51 %, respectively (P < 0.001). In addition, NaHS at doses of 1 and 5 mg reduced brain edema (P < 0.05) and inhibited apoptosis by decreasing positive TUNEL cells (P < 0.001).The present study shows that treatment with H(2)S reduces brain injuries and postischemic cerebral edema in a dose-dependent manner likely through the blocking programmed cell death.We propose that H(2)S might be a promising therapeutic target for stroke, although more researches are necessary to take into account the potential therapeutic effects of H(2)S in stroke patients.

  8. Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury.

    PubMed

    Zhu, Haibo; He, Jie; Ye, Liang; Lin, Fei; Hou, Jian; Zhong, Yan; Jiang, Wanglin

    2015-11-01

    Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood-brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression.

  9. Levallorphan and dynorphin improve motor dysfunction in Mongolian gerbils with unilateral carotid occlusion: the first application of the inclined plane method in the experimental cerebral ischemia.

    PubMed

    Handa, N; Matsumoto, M; Kitagawa, K; Uehara, A; Ogawa, S; Etani, H; Yoneda, S; Kimura, K; Kamada, T

    1988-01-01

    Levallorphan and dynorphin were effective on the motor dysfunction in the gerbil model of unilateral cerebral ischemia. The effect of opioids, levallorphan (mixed agonist-antagonist), dynorphin (kappa-receptor agonist) and naloxone (mu-receptor antagonist), on neurological impairment was evaluated using the unilateral cerebral ischemia model of gerbil. Motor function was evaluated quantitatively by using the inclined plane method. Both levallorphan-treated group and dynorphin-treated group showed a significant improvement of the motor dysfunction compared with saline-control group. On the other hand, naloxone-treated group did not differ from saline-control group. The beneficial effect of these opioids on motor dysfunction might be mediated by the kappa-opioid receptor. This study also showed the potential usefulness of the inclined plane method for the investigation on the cerebral ischemia.

  10. Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: the possible molecular mechanism.

    PubMed

    Yu, Kewei; Wu, Yi; Hu, Yongshan; Zhang, Qi; Xie, Hongyu; Liu, Gang; Chen, Yao; Guo, Zhenzhen; Jia, Jie

    2013-11-13

    Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. Recent studies have demonstrated that animals housed in an enriched environment condition after an experimental stroke obtained a better functional outcome than those housed in a standard condition. However, little is known about the underlying mechanisms of neuroprotective effects of enriched environment exposure prior to injury. The current study examined the neuroprotective effects of prior enriched environment exposure after transient middle cerebral artery occlusion (MCAO) in rats. Male Sprague Dawley (SD) rats, weighing 55-65g at the beginning of the experiment, were randomly assigned to a pre-ischemic enriched environment (PIEE) or pre-ischemic standard condition (PISC) group for 1 month. They were weighed on days1, 7, 18, and 28, and their locomotor activity was tracked during the period between 9:00am and 3:00pm daily. After 1 month, ischemia was induced by occluding the middle cerebral artery for 90min, followed by reperfusion. After approximately 24h of the operation, functional outcomes were assessed using the beam-walking test and a neurological evaluation scale in all rats. We measured the expression of extracellular signal regulated protein kinases1/2 (ERK1/2) by western blotting and gene expression levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthasen (iNOS) by Real-Time PCR in the cortical area affected by ischemia. Finally, we measured the level of malondialdehyde (MDA) content, which is a biomarker of oxidative stress. The results showed that rats in the PIEE group had lighter weight than those in the PISC group. The functional outcomes of rats in the PIEE group were better than those in the PISC group, and substances associated with inflammation, such as MDA, nNOS, iNOS, and phospho-ERK1/2, were lower in the PIEE group compared with the PISC group. These results

  11. Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: the possible molecular mechanism.

    PubMed

    Yu, Kewei; Wu, Yi; Hu, Yongshan; Zhang, Qi; Xie, Hongyu; Liu, Gang; Chen, Yao; Guo, Zhenzhen; Jia, Jie

    2013-11-13

    Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. Recent studies have demonstrated that animals housed in an enriched environment condition after an experimental stroke obtained a better functional outcome than those housed in a standard condition. However, little is known about the underlying mechanisms of neuroprotective effects of enriched environment exposure prior to injury. The current study examined the neuroprotective effects of prior enriched environment exposure after transient middle cerebral artery occlusion (MCAO) in rats. Male Sprague Dawley (SD) rats, weighing 55-65g at the beginning of the experiment, were randomly assigned to a pre-ischemic enriched environment (PIEE) or pre-ischemic standard condition (PISC) group for 1 month. They were weighed on days1, 7, 18, and 28, and their locomotor activity was tracked during the period between 9:00am and 3:00pm daily. After 1 month, ischemia was induced by occluding the middle cerebral artery for 90min, followed by reperfusion. After approximately 24h of the operation, functional outcomes were assessed using the beam-walking test and a neurological evaluation scale in all rats. We measured the expression of extracellular signal regulated protein kinases1/2 (ERK1/2) by western blotting and gene expression levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthasen (iNOS) by Real-Time PCR in the cortical area affected by ischemia. Finally, we measured the level of malondialdehyde (MDA) content, which is a biomarker of oxidative stress. The results showed that rats in the PIEE group had lighter weight than those in the PISC group. The functional outcomes of rats in the PIEE group were better than those in the PISC group, and substances associated with inflammation, such as MDA, nNOS, iNOS, and phospho-ERK1/2, were lower in the PIEE group compared with the PISC group. These results

  12. Monitoring cerebral oxygenation in a pediatric patient undergoing surgery for vascular ring.

    PubMed

    Joshi, Reena K; Motta, Pablo; Horibe, Mayumi; Mossad, Emad

    2006-02-01

    Regional cerebral oxygenation can be monitored using near-infrared spectroscopy (NIRS). Inadequacy of collateral cerebral circulation and regional cerebral ischemia during cardiac and vascular surgery may be detected by the use of NIRS monitoring. We report a 2-year-old child who underwent surgical repair of vascular ring and subclavian reimplantation, where use of NIRS helped in early detection and timely intervention to prevent prolonged cerebral ischemia. PMID:16430416

  13. Core-shell hybrid liposomal vesicles loaded with panax notoginsenoside: preparation, characterization and protective effects on global cerebral ischemia/reperfusion injury and acute myocardial ischemia in rats

    PubMed Central

    Zhang, Jing; Han, Xizhen; Li, Xiang; Luo, Yun; Zhao, Haiping; Yang, Ming; Ni, Bin; Liao, Zhenggen

    2012-01-01

    Purpose: Novel panax notoginsenoside-loaded core-shell hybrid liposomal vesicles (PNS-HLV) were developed to resolve the restricted bioavailability of PNS and to enhance its protective effects in vivo on oral administration. Methods: Physicochemical characterizations of PNS-HLV included assessment of morphology, particle size and zeta potential, encapsulation efficiency (EE%), stability and in vitro release study. In addition, to evaluate its oral treatment potential, we compared the effect of PNS-HLV on global cerebral ischemia/reperfusion and acute myocardial ischemia injury with those of PNS solution, conventional PNS-loaded nanoparticles, and liposomes. Results: In comparison with PNS solution, conventional PNS-loaded nanoparticles and liposomes, PNS-HLV was stable for at least 12 months at 4°C. Satisfactory improvements in the EE% of notoginsenoside R1, ginsenoside Rb1, and ginsenoside Rg1 were shown with the differences in EE% shortened and the greater controlled drug release profiles were exhibited from PNS-HLV. The improvements in the physicochemical properties of HLV contributed to the results that PNS-HLV was able to significantly inhibit the edema of brain and reduce the infarct volume, while it could markedly inhibit H2O2, modified Dixon agar, and serum lactate dehydrogenase, and increase superoxide dismutase (P < 0.05). Conclusion: The results of the present study imply that HLV has promising prospects for improving free drug bioactivity on oral administration. PMID:22915851

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

    PubMed

    Sun, Fen; Jin, Kunlin; Uteshev, Victor V

    2013-01-01

    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. PMID:23951360

  15. Effects of ischemic preconditioning on VEGF and pFlk-1 immunoreactivities in the gerbil ischemic hippocampus after transient cerebral ischemia.

    PubMed

    Park, Yoo Seok; Cho, Jun Hwi; Kim, In Hye; Cho, Geum-Sil; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Shin, Myoung Cheol; Tae, Hyun-Jin; Cho, Young Shin; Lee, Yun Lyul; Kim, Young-Myeong; Won, Moo-Ho; Lee, Jae-Chul

    2014-12-15

    Ischemia preconditioning (IPC) displays an important adaptation of the CNS to sub-lethal ischemia. In the present study, we examined the effect of IPC on immunoreactivities of VEGF-, and phospho-Flk-1 (pFlk-1) following transient cerebral ischemia in gerbils. The animals were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+) sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to 2 min of ischemia followed by 1 day of recovery. In the ischemia-operated-group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) alone 5 days after ischemia-reperfusion, however, in all the IPC+ischemia-operated-groups, pyramidal neurons in the SP were well protected. In immunohistochemical study, VEGF immunoreactivity in the ischemia-operated-group was increased in the SP at 1 day post-ischemia and decreased with time. Five days after ischemia-reperfusion, strong VEGF immunoreactivity was found in non-pyramidal cells, which were identified as pericytes, in the stratum oriens (SO) and radiatum (SR). In the IPC+sham-operated- and IPC+ischemia-operated-groups, VEGF immunoreactivity was significantly increased in the SP. pFlk-1 immunoreactivity in the sham-operated- and ischemia-operated-groups was hardly found in the SP, and, from 2 days post-ischemia, pFlk-1 immunoreactivity was strongly increased in non-pyramidal cells, which were identified as pericytes. In the IPC+sham-operated-group, pFlk-1 immunoreactivity was significantly increased in both pyramidal and non-pyramidal cells; in the IPC+ischemia-operated-groups, the similar pattern of VEGF immunoreactivity was found in the ischemic CA1, although the VEGF immunoreactivity was strong in non-pyramidal cells at 5 days post-ischemia. In brief, our findings show that IPC dramatically augmented the induction of VEGF and pFlk-1 immunoreactivity in the pyramidal cells of the CA1 after ischemia

  16. Effects of ischemic preconditioning on VEGF and pFlk-1 immunoreactivities in the gerbil ischemic hippocampus after transient cerebral ischemia.

    PubMed

    Park, Yoo Seok; Cho, Jun Hwi; Kim, In Hye; Cho, Geum-Sil; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Shin, Myoung Cheol; Tae, Hyun-Jin; Cho, Young Shin; Lee, Yun Lyul; Kim, Young-Myeong; Won, Moo-Ho; Lee, Jae-Chul

    2014-12-15

    Ischemia preconditioning (IPC) displays an important adaptation of the CNS to sub-lethal ischemia. In the present study, we examined the effect of IPC on immunoreactivities of VEGF-, and phospho-Flk-1 (pFlk-1) following transient cerebral ischemia in gerbils. The animals were randomly assigned to four groups (sham-operated-group, ischemia-operated-group, IPC plus (+) sham-operated-group, and IPC+ischemia-operated-group). IPC was induced by subjecting gerbils to 2 min of ischemia followed by 1 day of recovery. In the ischemia-operated-group, a significant loss of neurons was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) alone 5 days after ischemia-reperfusion, however, in all the IPC+ischemia-operated-groups, pyramidal neurons in the SP were well protected. In immunohistochemical study, VEGF immunoreactivity in the ischemia-operated-group was increased in the SP at 1 day post-ischemia and decreased with time. Five days after ischemia-reperfusion, strong VEGF immunoreactivity was found in non-pyramidal cells, which were identified as pericytes, in the stratum oriens (SO) and radiatum (SR). In the IPC+sham-operated- and IPC+ischemia-operated-groups, VEGF immunoreactivity was significantly increased in the SP. pFlk-1 immunoreactivity in the sham-operated- and ischemia-operated-groups was hardly found in the SP, and, from 2 days post-ischemia, pFlk-1 immunoreactivity was strongly increased in non-pyramidal cells, which were identified as pericytes. In the IPC+sham-operated-group, pFlk-1 immunoreactivity was significantly increased in both pyramidal and non-pyramidal cells; in the IPC+ischemia-operated-groups, the similar pattern of VEGF immunoreactivity was found in the ischemic CA1, although the VEGF immunoreactivity was strong in non-pyramidal cells at 5 days post-ischemia. In brief, our findings show that IPC dramatically augmented the induction of VEGF and pFlk-1 immunoreactivity in the pyramidal cells of the CA1 after ischemia

  17. Prophylactic volume expansion therapy for the prevention of delayed cerebral ischemia after early aneurysm surgery. Results of a preliminary trial.

    PubMed

    Solomon, R A; Fink, M E; Lennihan, L

    1988-03-01

    From June 1986 to June 1987, 47 consecutive patients with ruptured intracranial aneurysms were treated with immediate aneurysm surgery and prophylactic volume expansion therapy for ten to 14 days after subarachnoid hemorrhage (SAH). Twenty-four patients were admitted within three days of SAH. Twenty-three of these patients had an excellent result, and one patient died. There were no cases of delayed cerebral infarction. In 18 of 23 patients admitted more than three days after SAH, there was an excellent result. The other five patients had permanent morbidity related to the original SAH. These preliminary data suggest that immediate aneurysm surgery and aggressive postoperative prophylactic volume expansion in all patients can substantially reduce rebleeding and delayed cerebral ischemia, potential causes of morbidity, after aneurysmal subarachnoid hemorrhage. A more extensive prospective trial of this approach will be required to test this hypothesis. PMID:3277601

  18. Decreased light attenuation in cerebral cortex during cerebral edema detected using optical coherence tomography

    PubMed Central

    Rodriguez, Carissa L. R.; Szu, Jenny I.; Eberle, Melissa M.; Wang, Yan; Hsu, Mike S.; Binder, Devin K.; Park, B. Hyle

    2014-01-01

    Abstract. Cerebral edema develops in response to a variety of conditions, including traumatic brain injury and stroke, and contributes to the poor prognosis associated with these injuries. This study examines the use of optical coherence tomography (OCT) for detecting cerebral edema in vivo. Three-dimensional imaging of an in vivo water intoxication model in mice was performed using a spectral-domain OCT system centered at 1300 nm. The change in attenuation coefficient was calculated and cerebral blood flow was analyzed using Doppler OCT techniques. We found that the average attenuation coefficient in the cerebral cortex decreased over time as edema progressed. The initial decrease began within minutes of inducing cerebral edema and a maximum decrease of 8% was observed by the end of the experiment. Additionally, cerebral blood flow slowed during late-stage edema. Analysis of local regions revealed the same trend at various locations in the brain, consistent with the global nature of the cerebral edema model used in this study. These results demonstrate that OCT is capable of detecting in vivo optical changes occurring due to cerebral edema and highlights the potential of OCT for precise spatiotemporal detection of cerebral edema. PMID:25674578

  19. Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

    PubMed Central

    Wang, Peng-qian; Li, Bing; Liu, Jun; Zhang, Ying-ying; Yu, Ya-nan; Zhang, Xiao-xu; Yuan, Ye; Guo, Zhi-li; Wu, Hong-li; Li, Hai-xia; Dang, Hai-xia; Guo, Shan-shan; Wang, Zhong

    2015-01-01

    Aim: Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds. Methods: Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis. Results: In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function. Conclusion: The pure synergism between UA and JA underlies 10 new core pathways and 3 new core functions, which are involved in inflammation, immune responses, apoptosis and nervous system development. PMID:25960134

  20. Therapeutic time window of neuroprotection by non-competitive AMPA antagonists in transient and permanent focal cerebral ischemia in rats.

    PubMed

    Matucz, Eva; Móricz, Krisztina; Gigler, Gábor; Benedek, Angéla; Barkóczy, József; Lévay, György; Hársing, László G; Szénási, Gábor

    2006-12-01

    EGIS-8332 and GYKI 53405 are selective, non-competitive AMPA (2-amino-3[3-hydroxy-5-methyl-4-isoxazolyl] propionic acid) antagonists that effectively protected against tissue injury caused by global and focal cerebral ischemia in laboratory animals. This study evaluated the therapeutic time window of neuroprotection by EGIS-8332 and GYKI 53405 in permanent and transient middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. Infarct size was measured by TTC staining 48 h after permanent MCAO (electrocoagulation), and 24 h after reperfusion following a 1-h transient MCAO carried out using the intraluminal filament technique. Treatment with EGIS-8332 (10 mg/kg, i.p.) 60 or 120 min after permanent MCAO, decreased infarct size by 30% and 36%, respectively, and the effect of GYKI 53405 (10 mg/kg, i.p.) was similar (30% and 33%, respectively; p<0.01 all). Neither compound was effective if administered 180 or 240 min after permanent MCAO. Both EGIS-8332 and GYKI 53405 (20 mg/kg, i.p.) reduced the core and total (core plus penumbra) volumes of tissue injury in the whole brain and the cerebral cortex when administered 120 or 180 min after transient MCAO. The compounds did not alter tissue damage in the striatum. No neuroprotective effect was obtained at 240 min after transient MCAO. In conclusion, the therapeutic time window of neuroprotection by EGIS-8332 and GYKI 53405 was 2 h in permanent and 3 h in transient focal cerebral ischemia in rats. The results suggest that treatment with non-competitive AMPA antagonists can only be expected to produce a neuroprotective action in humans if administered shortly after the appearance of stroke symptoms.

  1. Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-κB/PUMA signal in rats.

    PubMed

    Zhang, Bin; Song, Cunfeng; Feng, Bo; Fan, Weibing

    2016-01-01

    Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent antitumor activity. Recently, triptolide was found to have protective effects against acute cerebral ischemia/reperfusion (I/R) injury through inhibition of cell apoptosis. However, the regulatory mechanism of the effect remains unclear. We hypothesize that the regulatory mechanisms of triptolide are mediated by nuclear factor κB (NF-κB) and p53-upregulated-modulator-of-apoptosis signal inhibition. To verify this hypothesis, we occluded the middle cerebral artery in male rats to establish focal cerebral I/R model. The rats received triptolide or vehicle at the onset of reperfusion following middle cerebral artery occlusion. At 24 hours after reperfusion, neurological deficits, infarct volume, and cell apoptosis were evaluated. The expression levels of NF-κBp65, PUMA, and caspase-3 were determined by Western blot. Real-time polymerase chain reaction was used to determine the levels of NF-κBp65 mRNA, PUMA mRNA, and caspase-3 mRNA. NF-κB activity was determined by electrophoretic mobility shift assay. Apoptotic cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In I/R group, neurological deficit scores, cerebral infarct volume, expression of NF-κBp65, PUMA, caspase-3, NF-κB activity, and TUNEL-positive cells were found to be increased at 24 hours after I/R injury. The I/R/triptolide rats showed significantly better neurological deficit scores, decreased neural apoptosis, and reduced cerebral infarct volume. In addition, the expression of NF-κBp65, PUMA, caspase-3, and NF-κB activity was suppressed in the I/R/triptolide rats. These results indicate that the neuroprotective effects of triptolide during acute cerebral I/R injury are possibly related to the inhibition of apoptosis through suppression of NF-κB/PUMA signaling pathway.

  2. Neuroprotection by triptolide against cerebral ischemia/reperfusion injury through the inhibition of NF-κB/PUMA signal in rats.

    PubMed

    Zhang, Bin; Song, Cunfeng; Feng, Bo; Fan, Weibing

    2016-01-01

    Triptolide, an active compound extracted from the Chinese herb thunder god vine (Tripterygium wilfordii Hook F.), has potent antitumor activity. Recently, triptolide was found to have protective effects against acute cerebral ischemia/reperfusion (I/R) injury through inhibition of cell apoptosis. However, the regulatory mechanism of the effect remains unclear. We hypothesize that the regulatory mechanisms of triptolide are mediated by nuclear factor κB (NF-κB) and p53-upregulated-modulator-of-apoptosis signal inhibition. To verify this hypothesis, we occluded the middle cerebral artery in male rats to establish focal cerebral I/R model. The rats received triptolide or vehicle at the onset of reperfusion following middle cerebral artery occlusion. At 24 hours after reperfusion, neurological deficits, infarct volume, and cell apoptosis were evaluated. The expression levels of NF-κBp65, PUMA, and caspase-3 were determined by Western blot. Real-time polymerase chain reaction was used to determine the levels of NF-κBp65 mRNA, PUMA mRNA, and caspase-3 mRNA. NF-κB activity was determined by electrophoretic mobility shift assay. Apoptotic cells were detected using terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. In I/R group, neurological deficit scores, cerebral infarct volume, expression of NF-κBp65, PUMA, caspase-3, NF-κB activity, and TUNEL-positive cells were found to be increased at 24 hours after I/R injury. The I/R/triptolide rats showed significantly better neurological deficit scores, decreased neural apoptosis, and reduced cerebral infarct volume. In addition, the expression of NF-κBp65, PUMA, caspase-3, and NF-κB activity was suppressed in the I/R/triptolide rats. These results indicate that the neuroprotective effects of triptolide during acute cerebral I/R injury are possibly related to the inhibition of apoptosis through suppression of NF-κB/PUMA signaling pathway. PMID:27307742

  3. Dioscin ameliorates cerebral ischemia/reperfusion injury through the downregulation of TLR4 signaling via HMGB-1 inhibition.

    PubMed

    Tao, Xufeng; Sun, Xiance; Yin, Lianhong; Han, Xu; Xu, Lina; Qi, Yan; Xu, Youwei; Li, Hua; Lin, Yuan; Liu, Kexin; Peng, Jinyong

    2015-07-01

    We previously reported the promising effect of dioscin against hepatic ischemia/reperfusion (I/R) injury, but its effect on cerebral I/R injury remains unknown. In this work, an in vitro oxygen-glucose deprivation and reoxygenation (OGD/R) model and an in vivo middle cerebral artery occlusion (MCAO) model were used. The results indicated that dioscin clearly protected PC12 cells and primary cortical neurons against OGD/R insult and significantly prevented cerebral I/R injury. Further research demonstrated that dioscin-induced neuroprotection was accompanied by a significant inhibition in the expression and the nuclear to cytosolic translocation of HMGB-1, reflected by decreased TLR4 expression. Blockade of the TLR4/MyD88/TRAF6 signaling pathway by dioscin inhibited NF-κB and AP-1 transcriptional activities, MAPK and STAT3 phosphorylation, and pro-inflammatory cytokine responses, and upregulated the levels of anti-inflammatory factors. In addition, small interfering RNA (siRNA) and overexpressed genes of HMGB-1 and TLR4 were applied in in vitro experiments, respectively, and the results further confirmed that dioscin showed an efficient neuroprotection because of its inhibiting effects on HMGB-1/TLR4 signaling and subsequent suppressing inflammation. These findings provide new insights that will aid in elucidating the effect of dioscin against cerebral I/R injury and support the development of dioscin as a potential treatment for ischemic stroke. PMID:25772012

  4. Changes in number of synapses and mitochondria in presynaptic terminals in the dentate gyrus following cerebral ischemia and rehabilitation training.

    PubMed

    Briones, Teresita L; Suh, Eugene; Jozsa, Lauren; Rogozinska, Magdalena; Woods, Julie; Wadowska, Maggie

    2005-02-01

    Damage to the adult brain can result in adaptive plasticity in regions adjacent to the site of the principal insult and that the plastic changes may be modulated by post-injury rehabilitation training. In this study, we examined the effects of rehabilitation training on synaptic morphology in the dentate gyrus following transient global cerebral ischemia and the metabolic correlates of the ultrastructural changes. Forty adult male Wistar rats were included in the study and assigned to either ischemia or sham group. Following ischemic or sham surgery, rats were randomized to either complex environment housing (EC), exercise (EX), or social condition (SC, paired housing) group. Electron microscopy and unbiased stereological methods were used to evaluate synaptic plasticity and the number and size of mitochondria in synaptic axon terminals. Increased number of granule neurons was seen in all ischemic groups and in the sham EC rats. Changes in the number of synapses per neuron in the outer and inner molecular layers of the dentate gyrus parallel those seen in granule neurons. Similarly, ischemia and behavioral experience in EC independently increased the number of synaptic mitochondria in presynaptic terminals in both the outer and inner molecular layers; however, no significant changes were seen in mitochondrial size. These data suggest a link between behavioral training and synaptic plasticity in the region adjacent to the injury and that the likely metabolic correlate of this synaptic plasticity is increased number of mitochondria at synaptic axon terminals.

  5. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window

    PubMed Central

    Yrjänheikki, Juha; Tikka, Tiina; Keinänen, Riitta; Goldsteins, Gundars; Chan, Pak H.; Koistinaho, Jari

    1999-01-01

    The only treatment of patients with acute ischemic stroke is thrombolytic therapy, which benefits only a fraction of stroke patients. Both human and experimental studies indicate that ischemic stroke involves secondary inflammation that significantly contributes to the outcome after ischemic insult. Minocycline is a semisynthetic second-generation tetracycline that exerts antiinflammatory effects that are completely separate from its antimicrobial action. Because tetracycline treatment is clinically well tolerated, we investigated whether minocycline protects against focal brain ischemia with a wide therapeutic window. Using a rat model of transient middle cerebral artery occlusion, we show that daily treatment with minocycline reduces cortical infarction volume by 76 ± 22% when the treatment is started 12 h before ischemia and by 63 ± 35% when started even 4 h after the onset of ischemia. The treatment inhibits morphological activation of microglia in the area adjacent to the infarction, inhibits induction of IL-1β-converting enzyme, and reduces cyclooxygenase-2 expression and prostaglandin E2 production. Minocycline had no effect on astrogliosis or spreading depression, a wave of ionic transients thought to contribute to enlargement of cortical infarction. Treatment with minocycline may act directly on brain cells, because cultured primary neurons were also salvaged from glutamate toxicity. Minocycline may represent a prototype of an antiinflammatory compound that provides protection against ischemic stroke and has a clinically relevant therapeutic window. PMID:10557349

  6. Asiatic Acid, a Pentacyclic Triterpene From Centella asiatica, Is Neuroprotective in a Mouse Model of Focal Cerebral Ischemia

    PubMed Central

    Krishnamurthy, Rajanikant G.; Senut, Marie-Claude; Zemke, Daniel; Min, Jiangyong; Frenkel, Mark B.; Greenberg, Eric J.; Yu, Seong-Woon; Ahn, Nick; Goudreau, John; Kassab, Mounzer; Panickar, Kiran S.; Majid, Arshad

    2010-01-01

    Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or β-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood–brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood–brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia. PMID:19382233

  7. Improving Active and Passive Avoidance Memories Deficits Due to Permanent Cerebral Ischemia by Pomegranate Seed Extract in Female Rats

    PubMed Central

    Sarkaki, Alireza; Rezaiei, Moslem; Gharib naseri, MohammadKazem; Rafieirad, Maryam

    2013-01-01

    Background: This study aimed to evaluate the effect of two weeks oral administration of pomegranate seed extract (PGSE) on active and passive avoidance memories after permanent bilateral common carotid arteries occlusion (2CCAO) to induce permanent cerebral ischemia in adult female rats. Methods: Seventy adult female Wistar rats (250 ± 20 g) were used. Animals were divided randomly into seven groups with 10 in each: 1) Sham-operated; 2) Ischemic; 3–6) Ischemic received PGSE (100, 200, 400, and 800 mg/2mL/kg, orally) for 14 days; 7) Ischemic received vehicle. In order to create 2CCAO, carotid arteries were ligatured and then cut bilaterally. Active and passive avoidance task were measured using criterion condition responses (CCRs) in Y-maze and step-through latency (STL) in two-way shuttle box in all female rats. Results: Both active and passive avoidance memories were significantly impaired in rats after cerebral hypoxia-ischemia (CHI) (P < 0.001). PGSE treatment significantly improved passive and active memory impairments with 2CCAO (P < 0.05, P < 0.01, and P < 0.001). No toxicity was observed even with high-dose PGSE consumption (800 mg/kg, for 14 days). Conclusion: PGSE exhibits therapeutic potential for avoidance memories, which is most likely related at least in part to its antioxidative and free radical scavenging actions. PMID:23983574

  8. Anti-Inflammatory Effects of Traditional Chinese Medicines against Ischemic Injury in In Vivo Models of Cerebral Ischemia

    PubMed Central

    2016-01-01

    Inflammation plays a crucial role in the pathophysiology of acute ischemic stroke. In the ischemic cascade, resident microglia are rapidly activated in the brain parenchyma and subsequently trigger inflammatory mediator release, which facilitates leukocyte-endothelial cell interactions in inflammation. Activated leukocytes invade the endothelial cell junctions and destroy the blood-brain barrier integrity, leading to brain edema. Toll-like receptors (TLRs) stimulation in microglia/macrophages through the activation of intercellular signaling pathways secretes various proinflammatory cytokines and enzymes and then aggravates cerebral ischemic injury. The secreted cytokines activate the proinflammatory transcription factors, which subsequently regulate cytokine expression, leading to the amplification of the inflammatory response and exacerbation of the secondary brain injury. Traditional Chinese medicines (TCMs), including TCM-derived active compounds, Chinese herbs, and TCM formulations, exert neuroprotective effects against inflammatory responses by downregulating the following: ischemia-induced microglial activation, microglia/macrophage-mediated cytokine production, proinflammatory enzyme production, intercellular adhesion molecule-1, matrix metalloproteinases, TLR expression, and deleterious transcription factor activation. TCMs also aid in upregulating anti-inflammatory cytokine expression and neuroprotective transcription factor activation in the ischemic lesion in the inflammatory cascade during the acute phase of cerebral ischemia. Thus, TCMs exert potent anti-inflammatory properties in ischemic stroke and warrant further investigation. PMID:27703487

  9. Effect of dl-3-n-butylphthalide on brain edema in rats subjected to focal cerebral ischemia.

    PubMed

    Deng, W; Feng, Y

    1997-06-01

    The present study evaluated the effect of dl-3-n-butylphthalide(NBP), a novel brain protective agent, on brain edema in rats following focal ischemia. Edema was induced by occluding the right middle cerebral artery (MCAO), producing permanent focal ischemia in the right cerebral hemisphere, which developed ipsilateral brain edema reproducibly. Edema was assessed 24 h after MCA occlusion by determining the brain water content from wet and dry weight measurements, and the sodium, potassium concentrations with ion-selective electrodes. In this model, NBP at the dose of 80, 160 and 240 mg/kg p.o. 15 min after MCAO prevented from brain edema in a dose-dependent manner. A significant reduction of sodium content and an increase in potassium level were observed in all drug-treated groups. It showed that NBP strongly attenuated brain water entry, sodium accumulation and potassium loss. Nimodipine treatment (5 mg/kg s.c.) also reduced brain edema (P < 0.05). The results suggest that a strong anti-edema activity of NBP may play an important role to contribute to the treatment of ischemic damage.

  10. Treatment with lutein provides neuroprotection in mice subjected to transient cerebral ischemia.

    PubMed

    Sun, Ya-Xuan; Liu, Ting; Dai, Xue-Ling; Zheng, Qiu-Sheng; Hui, Bo-Di; Jiang, Zhao-Feng

    2014-01-01

    Lutein is known to be a nonprovitamin A carotenoid found in broccoli and spinach. The aim of present study was to investigate whether lutein can protect brain against ischemic injury by reducing oxidative stress. Male ICR mice were randomly divided into five experimental groups: model group, sham group, lutein high, middle, and low-dose groups (30, 15, and 7.5 mg/kg). Mice were subjected to a 2-h middle cerebral artery occlusion followed by reperfusion for 22 h. The reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, antioxidant enzyme activities, malondialdehyde (MDA), and the carbonyl content in oxidatively modified proteins in brain tissue were determined with colorimetric method. The 8-hydroxy deoxyguanosine (8-OHdG) expression was measured by immunohistochemistry assay, and the neuron apoptosis was detected by TdT-mediated dUTP nick end labeling assay. Then, the neurological deficit scores were measured at last. Treatment of lutein significantly elevated the ratio of GSH/GSSG as well as activities of superoxide dismutase, glutathione peroxidase, and catalase and obviously decreased the contents of MDA, brain carbonyl, the expression of 8-OHdG, the number of apoptotic cells, and neurological deficit scores. Our results demonstrate that administration of lutein affords strong neuroprotective effect against transient cerebral ischemic injury and that the effect might be associated with its antioxidant property.

  11. Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion.

    PubMed

    Sosa, P M; Schimidt, H L; Altermann, C; Vieira, A S; Cibin, F W S; Carpes, F P; Mello-Carpes, P B

    2015-09-01

    Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise. PMID:26222650

  12. Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion

    PubMed Central

    Sosa, P.M.; Schimidt, H.L.; Altermann, C.; Vieira, A.S.; Cibin, F.W.S.; Carpes, F.P.; Mello-Carpes, P.B.

    2015-01-01

    Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise. PMID:26222650

  13. Induction of Nerve Injury-Induced Protein 1 (Ninjurin 1) in Myeloid Cells in Rat Brain after Transient Focal Cerebral Ischemia

    PubMed Central

    Lee, Hye-Kyung; Lee, Hahnbie; Luo, Lidan

    2016-01-01

    Nerve injury-induced protein-1 (Ninjurin-1, Ninj1) was initially identified as a novel adhesion molecule in rat sciatic nerve and to be up-regulated in neurons and Schwann cells of distal nerve segments after nerve transection or crush injury. Recently, Ninj1 was found to act as a modulator of cell migration, angiogenesis, and apoptosis. Accumulating evidence indicates that innate immune response plays beneficial and deleterious roles in brain ischemia, and the trans-endothelial migration of blood-derived immune cells is key initiator of this response. In the present study, we examined the expression profile and cellular distribution of Ninj1 in rat brain after transient focal cerebral ischemia. Ninj1 expression was found to be significantly induced in cortical penumbras 1 day after 60 min of middle cerebral artery occlusion (MCAO) and to increase gradually for 8 days and then declined. In infarction cores of cortices, patterns of Ninj1 expression were similar to those observed in cortical penumbras, except induction was maintained for 10 days. At 1 day post-MCAO, Ninj1 inductions were detected mainly in neutrophils and endothelial cells in both infarction cores and penumbras, but reactive macrophages were the major cellular expressers of Ninj1 at 4 days post-MCAO. Expressional induction in reactive macrophages was maintained in infarction cores after 12 days post-MCAO but not in penumbras. These dynamic expressions of Ninj1 in different immune cells at different times suggest that this protein performs various, critical roles in the modulation of acute and delayed immune responses in the postischemic brain. PMID:27122992

  14. Curcumin treatment recovery the decrease of protein phosphatase 2A subunit B induced by focal cerebral ischemia in Sprague-Dawley rats

    PubMed Central

    Shah, Fawad-Ali; Park, Dong-Ju; Gim, Sang-Ah

    2015-01-01

    Curcumin provides various biological effects through its anti-inflammatory and antioxidant properties. Moreover, curcumin exerts a neuroprotective effect against ischemic condition-induced brain damage. Protein phosphatase 2A (PP2A) is a ubiquitous serine and threonine phosphatase with various cell functions and broad substrate specificity. Especially PP2A subunit B plays an important role in nervous system. This study investigated whether curcumin regulates PP2A subunit B expression in focal cerebral ischemia. Cerebral ischemia was induced surgically by middle cerebral artery occlusion (MCAO). Adult male rats were injected with either vehicle or curcumin (50 mg/kg) 1 h after MCAO and cerebral cortex tissues were isolated 24 h after MCAO. A proteomics study, reverse transverse-PCR and Western blot analyses were performed to examine PP2A subunit B expression levels. We identified a reduction in PP2A subunit B expression in MCAO-operated animals using a proteomic approach. However, curcumin treatment prevented injury-induced reductions in PP2A subunit B levels. Reverse transverse-PCR and Western blot analyses confirmed that curcumin treatment attenuated the injury-induced reduction in PP2A subunit B levels. These findings can suggest that the possibility that curcumin maintains levels of PP2A subunit B in response to cerebral ischemia, which likely contributes to the neuroprotective function of curcumin in cerebral ischemic injury. PMID:26472966

  15. Enhancement in the Neuroprotective Power of Riluzole Against Cerebral Ischemia Using a Brain Targeted Drug Delivery Vehicle.

    PubMed

    Verma, Shashi K; Arora, Indu; Javed, Kalim; Akhtar, Mohd; Samim, Mohammed

    2016-08-01

    Riluzole is the only available drug for motor neuron diseases quite well-known for its neuroprotective activity. But its poor aqueous solubility, short half-life with some side-effects at higher concentration poses a limitation to its use as a therapeutic agent. The present study was performed to investigate the therapeutic potential of nanoriluzole (NR), i.e., riluzole encapsulated in nanoparticles against cerebral ischemia (stroke) at three different concentrations [10 (NRL), 20 (NRM), and 40 (NRH) μg/kg body weight intraperitoneally (i.p.)]. Chitosan conjugated NIPAAM (N-isopropylacrylamide) nanoparticles coated with tween80 were synthesized through free radical polymerization. The particles were characterized with Transmission Electron Microscopy, Dynamic Light Scattering, and Fourier Transform Infrared spectroscopy and were found to have size of ∼50 nm. Cerebral ischemia was induced by Middle Cerebral Artery Occlusion (MCAO) model for 1 h and NR was given intraperitoneally after 1 h of MCAO. Animals were dissected after a reperfusion period of 24 h for evaluation of various parameters. Triphenyl tetrazolium chloride staining shows substantial reduction in infarct size in all three treated groups. It was also supported by histopathological results, biochemical parameters, and behavioral studies. Immunological parameters like NOS-2, NF-kB, and COX-2 also show profound reduction in expression in NR treated groups. Thus, the present work clearly demonstrated that the nanoparticle was good enough to carry large amount of drug across the Blood Brain Barrier which results in significant neuroprotection even at a very low concentration. It also substantially lowered the required concentration by overcoming the poor aqueous solubility; hence hardly leaving any scope for side-effects. PMID:27378322

  16. A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death.

    PubMed

    Kim, Jin Hee; Choi, Bo Young; Kim, Hyun Jung; Kim, In Yeol; Lee, Bo Eun; Sohn, Min; Park, Hyoung Jin; Suh, Sang Won

    2015-01-01

    This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting.

  17. A Water-Ethanol Extract from the Willow Bracket Mushroom, Phellinus igniarius (Higher Basidiomycetes), Reduces Transient Cerebral Ischemia-Induced Neuronal Death.

    PubMed

    Kim, Jin Hee; Choi, Bo Young; Kim, Hyun Jung; Kim, In Yeol; Lee, Bo Eun; Sohn, Min; Park, Hyoung Jin; Suh, Sang Won

    2015-01-01

    This study investigated the potential neuroprotective effect of a mushroom extract from Phellinus igniarius (Piwep) after transient cerebral ischemia. Ph. Igniarius, which has a history of traditional medicinal use, contains immunomodulatory compounds that have been described to have effects on the human immune system. Using a model of transient cerebral ischemia induced by both common carotid artery occlusion and hypovolemia, a water-ethanol extract precipitate of Ph. Igniarius (Piwep) was delivered intraperitoneally immediately after the insult and was injected subsequently every other day for the experimental course. Neuronal death was examined by Fluoro-Jade B staining 1 week after the insult. Piwep injection lead to decreased hippocampal neuronal death, suppression of oxidative injury, activation of microglia, and disruption of the blood-brain barrier. We conclude that Piwep potently inhibits hippocampal neuronal death following ischemia and may have a high therapeutic potential for ameliorating stroke-induced neuron death in the clinical setting. PMID:26756300

  18. Myeloid-Specific Deletion of the Mineralocorticoid Receptor Reduces Infarct Volume and Alters Inflammation During Cerebral Ischemia

    PubMed Central

    Frieler, Ryan A.; Meng, He; Duan, Sheng Zhong; Berger, Stefan; Schütz, Günther; He, Yangdong; Xi, Guohua; Wang, Michael M.; Mortensen, Richard M.

    2011-01-01

    Background and Purpose Mineralocorticoid receptor (MR) antagonists have protective effects in rodent models of ischemic stroke, but the cell-type-specific actions of these drugs are unknown. In the present study, we examined the contribution of myeloid cell MR during focal cerebral ischemia using myeloid-specific MR knockout (MyMRKO) mice. Methods MyMRKO mice were subjected to transient (90 minutes) middle cerebral artery occlusion (MCAo) followed by 24 hours reperfusion (n = 5–7/group). Ischemic cerebral infarcts were identified by hematoxylin and eosin staining and quantified with image analysis software. Immunohistochemical localization of microglia and macrophages was performed using Iba1 staining, and the expression of inflammatory markers was measured after 24 hours of reperfusion by qRT-PCR. Results MyMRKO resulted in a 65 % reduction in infarct volume (P = 0.005) following MCAo. This was accompanied by a significant reduction in activated microglia and macrophages in the ischemic core. Furthermore, MyMRKO suppressed classically activated M1 macrophage markers TNFα, IL-1β, MCP1, MIP1α and IL-6 while partially preserving the induction of alternatively activated, M2, markers Arg1 and Ym1. Conclusions These data demonstrate that myeloid MR activation exacerbates stroke and identify myeloid MR as a critical target for MR antagonists. Further, these data indicate that MR activation has an important role in controlling immune cell function during the inflammatory response to stroke. PMID:21106954

  19. Receptor-interacting protein kinase 3-mediated programmed cell necrosis in rats subjected to focal cerebral ischemia-reperfusion injury

    PubMed Central

    DONG, YANRU; BAO, CUIFEN; YU, JINGWEI; LIU, XIA

    2016-01-01

    In the current study, the activation of tumor necrosis factor-α receptor 1 (TNFR1) and receptor-interacting protein kinase 3 (RIP3) were investigated following cerebral ischemia-reperfusion injury (CIRI). Healthy SD rats were randomly divided into 3 groups: Sham operation group, model group and inhibitor group. The model group and inhibitor group were further divided into 4 subgroups of 6, 12, 24 and 72 h following CIRI. Using right middle cerebral artery embolization, the CIRI model was generated. To confirm that the CIRI model was established, neurological scores, TTC staining and brain water content measurements were conducted. Immunohistochemistry and western blotting were conducted to investigate the expression of TNFR1 and RIP3 in the cerebral cortex. It was observed that nerve cell necrosis occurred following 6 h of CIRI. The appearance of necrotic cells was gradually increased with increasing CIRI duration. TNFR1 and RIP3 were positively expressed following 6 h of CIRI. With increasing durations of CIRI, the protein expression levels of TNFR1 and RIP3 were significantly increased. Pre-administration with Z-VAD-FMK (zVAD) significantly increased the protein level of RIP3, however, had no effect on the levels of TNFR1, and was accompanied by a reduction in necrosis. In conclusion, RIP3-mediated cell necrosis was enhanced by caspase blockade zVAD and the function of zVAD was independent of TNFR1 signaling following IR. PMID:27220678

  20. Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons

    PubMed Central

    Hao, Lingyun; Wei, Xuewen; Guo, Peng; Zhang, Guangyi; Qi, Suhua

    2016-01-01

    Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies. PMID:27420046

  1. Neuroprotective Effects of Inhibiting Fyn S-Nitrosylation on Cerebral Ischemia/Reperfusion-Induced Damage to CA1 Hippocampal Neurons.

    PubMed

    Hao, Lingyun; Wei, Xuewen; Guo, Peng; Zhang, Guangyi; Qi, Suhua

    2016-07-12

    Nitric oxide (NO) can regulate signaling pathways via S-nitrosylation. Fyn can be post-translationally modified in many biological processes. In the present study, using a rat four-vessel-occlusion ischemic model, we aimed to assess whether Fyn could be S-nitrosylated and to evaluate the effects of Fyn S-nitrosylation on brain damage. In vitro, Fyn could be S-nitrosylated by S-nitrosoglutathione (GSNO, an exogenous NO donor), and in vivo, endogenous NO synthesized by NO synthases (NOS) could enhance Fyn S-nitrosylation. Application of GSNO, 7-nitroindazole (7-NI, an inhibitor of neuronal NOS) and hydrogen maleate (MK-801, the N-methyl-d-aspartate receptor (NMDAR) antagonist) could decrease the S-nitrosylation and phosphorylation of Fyn induced by cerebral ischemia/reperfusion (I/R). Cresyl violet staining validated that these compounds exerted neuroprotective effects against the cerebral I/R-induced damage to hippocampal CA1 neurons. Taken together, in this study, we demonstrated that Fyn can be S-nitrosylated both in vitro and in vivo and that inhibiting S-nitrosylation can exert neuroprotective effects against cerebral I/R injury, potentially via NMDAR-mediated mechanisms. These findings may lead to a new field of inquiry to investigate the underlying pathogenesis of stroke and the development of novel treatment strategies.

  2. Dictionary-Driven Ischemia Detection From Cardiac Phase-Resolved Myocardial BOLD MRI at Rest.

    PubMed

    Bevilacqua, Marco; Dharmakumar, Rohan; Tsaftaris, Sotirios A

    2016-01-01

    Cardiac Phase-resolved Blood-Oxygen-Level Dependent (CP-BOLD) MRI provides a unique opportunity to image an ongoing ischemia at rest. However, it requires post-processing to evaluate the extent of ischemia. To address this, here we propose an unsupervised ischemia detection (UID) method which relies on the inherent spatio-temporal correlation between oxygenation and wall motion to formalize a joint learning and detection problem based on dictionary decomposition. Considering input data of a single subject, it treats ischemia as an anomaly and iteratively learns dictionaries to represent only normal observations (corresponding to myocardial territories remote to ischemia). Anomaly detection is based on a modified version of One-class Support Vector Machines (OCSVM) to regulate directly the margins by incorporating the dictionary-based representation errors. A measure of ischemic extent (IE) is estimated, reflecting the relative portion of the myocardium affected by ischemia. For visualization purposes an ischemia likelihood map is created by estimating posterior probabilities from the OCSVM outputs, thus obtaining how likely the classification is correct. UID is evaluated on synthetic data and in a 2D CP-BOLD data set from a canine experimental model emulating acute coronary syndromes. Comparing early ischemic territories identified with UID against infarct territories (after several hours of ischemia), we find that IE, as measured by UID, is highly correlated (Pearson's r=0.84) with respect to infarct size. When advances in automated registration and segmentation of CP-BOLD images and full coverage 3D acquisitions become available, we hope that this method can enable pixel-level assessment of ischemia with this truly non-invasive imaging technique.

  3. Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus.

    PubMed

    Kim, D H; Lee, H E; Kwon, K J; Park, S J; Heo, H; Lee, Y; Choi, J W; Shin, C Y; Ryu, J H

    2015-01-22

    Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3β/β-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice.

  4. Arylalkylamine N-acetyltransferase (AANAT) is expressed in astrocytes and melatonin treatment maintains AANAT in the gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Park, Ok Kyu; Yoo, Ki-Yeon; Lee, Choong Hyun; Choi, Jung Hoon; Hwang, In Koo; Park, Jun Hong; Kwon, Young-Guen; Kim, Young-Myeong; Won, Moo-Ho

    2010-07-15

    Melatonin is synthesized from serotonin by the action of arylalkylamine N-acetyltransferase (AANAT) and hydroxyindole-O-methyltransferase. In this study, we observed cellular changes of arylalkylamine N-acetyltransferase (EC 2.3.1.87; AANAT) in the hippocampal CA1 region at various time points after ischemia/reperfusion. In vehicle-treated sham group, AANAT immunoreaction was detected in pyramidal neurons of the CA1 region. AANAT immunoreactivity in the neurons was highest 2 days and disappeared from 4 days after ischemia/reperfusion. From 3 days after ischemia/reperfusion, AANAT immunoreaction was expressed in astrocytes in the strata oriens and radiatum of the CA1 region. AANAT protein and mRNA levels were significantly increased 2 days after ischemia/reperfusion, and markedly decreased from 5 days after ischemia/reperfusion. The repeated administration of melatonin (10 mg/kg, i.p.) 3 times (once a day) to gerbils before ischemia/reperfusion significantly reduced ischemia-induced hyperactivity as well as neuronal death compared to those in the vehicle-treated ischemia group. Melatonin treatment also maintained AANAT immunoreactivity and its protein levels in the CA1 region after ischemia/reperfusion. These results suggest that the reduction of AANAT in ischemic CA1 region is associated with delayed neuronal death following transient ischemia, and melatonin treatment shows neuroprotection with maintenance of AANAT levels in the ischemic CA1 region.

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

    PubMed Central

    2010-01-01

    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. PMID:20955558

  6. Protective mechanisms of CA074-me (other than cathepsin-B inhibition) against programmed necrosis induced by global cerebral ischemia/reperfusion injury in rats.

    PubMed

    Xu, Yang; Wang, Jingye; Song, Xinghui; Wei, Ruili; He, Fangping; Peng, Guoping; Luo, Benyan

    2016-01-01

    Many studies have demonstrated the key role of lysosomes in ischemic cell death in the brain and have led to the "lysosomocentric" hypothesis. In this hypothesis, the release of cathepsin-B due to a change of lysosomal membrane permeabilization (LMP) or rupture is critical, and this can be prevented by its inhibitors CA074 and CA074-me. However, the role of CA074-me in neuronal death and its effect on the change of lysosomal membrane integrity after global cerebral ischemia/reperfusion (I/R) injury is not clear, so we investigated this here. Rat hippocampal CA1 neuronal death was evaluated after 20-min global cerebral I/R injury. CA074-me (1 μg, 10 μg) were given intracerebroventricularly 1h before ischemia or 1h post reperfusion. The changes of heat shock protein 70 (Hsp70), cathepsin-B, lysosomal-associated membrane protein 1 (LAMP-1), receptor-interacting protein 3 (RIP3), and the change of lysosomal pH were evaluated respectively. Hippocampal CA1 neuronal programmed necrosis induced by global cerebral I/R injury was prevented by CA074-me both pre-treatment and post-treatment. Diffuse cytoplasmic cathepsin-B and LAMP-1 immunostaining synchronized with the pyknotic nuclear changes 2 days post reperfusion, and a rise of lysosomal pH with the leakage of DND-153, a dye of lysosomes, after oxygen-glucose deprivation (OGD) was detected. Both of these changes demonstrated the rupture of lysosomal membrane and the leakage of cathepsin-B, and this was strongly inhibited by CA074-me pre-treatment. The overexpression and nuclear translocation of RIP3 and the reduction of NAD(+) level after I/R injury were also inhibited, while the upregulation of Hsp70 was strengthened by CA074-me pre-treatment. Delayed fulminant leakage of cathepsin-B due to lysosomal rupture is a critical harmful factor in neuronal programmed necrosis induced by 20-min global I/R injury. In addition to being an inhibitor of cathepsin-B, CA074-me may have an indirect neuroprotective effect by

  7. Surgical treatment of cerebral ischemia by means of diode laser: first experimental results and comparison with theoretical model

    NASA Astrophysics Data System (ADS)

    Signorelli, C. D.; Giaquinta, A.; Iofrida, G.; Donato, G.; Signorelli, Fr.; Bellecci, C.; Lo Feudo, T.; Gaudio, P.; Gelfusa, M.

    2007-07-01

    In the present paper feasibility and potential advantages of using diode laser for surgical treatment of cerebral ischemia and intracranial aneurysms will be evaluated. At this purpose non linear mathematical model was developed and experimentally validated to investigate the effects of the changes in tissue physical properties, in terms of operating time, tensile strength and tissue damage during medical laser application. The numerical simulations have been carried on by a finite-elements based software package (FEMLAB). In vitro results of human saphenous veins of inferior limbs (n=55) after 799 nm diode laser soldering, combined with an indocyanine green-enhanced, will be presented. The simulations results and their comparison with experimental measurements will be reported.

  8. Application of Mathematical Modelling as a Tool to Analyze the EEG Signals in Rat Model of Focal Cerebral Ischemia

    NASA Astrophysics Data System (ADS)

    Paul, S.; Bhattacharya, P.; Pandey, A. K.; Patnaik, R.

    2014-01-01

    The present paper envisages the application of mathematical modelling with the autoregressive (AR) model method as a tool to analyze electroencephalogram data in rat subjects of transient focal cerebral ischemia. This modelling method was used to determine the frequencies and characteristic changes in brain waveforms which occur as a result of disorders or fluctuating physiological states. This method of analysis was utilized to ensure actual correlation of the different mathematical paradigms. The EEG data was obtained from different regions of the rat brain and was modelled by AR method in a MATLAB platform. AR modelling was utilized to study the long-term functional outcomes of a stroke and also is preferable for EEG signal analysis because the signals consist of discrete frequency intervals. Modern spectral analysis, namely AR spectrum analysis, was used to correlate the conditional and prevalent changes in brain function in response to a stroke.

  9. Microglia, apoptosis and interleukin-1beta expression in the effect of sophora japonica l. on cerebral infarct induced by ischemia-reperfusion in rats.

    PubMed

    Lao, Chih-Jui; Lin, Jaung-Geng; Kuo, Jon-Son; Chao, Pei-dawn Lee; Cheng, Chin-Yi; Tang, Nou-Ying; Hsieh, Ching-Liang

    2005-01-01

    Sophora Japonica L. (SJ) is a traditional Chinese herb used to cool blood, stop bleeding and to treat hemorrhoids with bleeding. Although several recent studies found that both SJ and Ginkgo biloba have the same components of quercetin and rutin, only Ginkgo biloba has been widely used to treat cerebrovascular disorders and dementia in humans. This study investigated the effect of SJ on cerebral infarct in rats. A total of 66 Sprague-Dawley (SD) rats were studied. Focal cerebral infarct was established by occluding the bilateral common carotid arteries and the right middle cerebral artery for 90 minutes. After 24 hours of reperfusion, the neurological status was evaluated. The rats were then killed, and brain tissue was stained with 2,3,5-triphenyl-tetrazolium chloride. The grading scale of neurological deficit and the ratio of cerebral infarction area were used as an index to evaluate the effect of SJ on cerebral infarct. In addition, the number of ED1 and interleukin-1beta immunostaining positive cells, and apoptotic cells were measured in the cerebral infarction zone. The results indicated that pre-treatment with 100 or 200 mg/kg SJ and post-treatment with 200 mg/kg SJ significantly reduced the grade of neurological deficit and the ratio of cerebral infarction area. In addition, pre-treatment with 200 mg/kg SJ also significantly reduced ED1 and interleukin-1beta immunostaining positive cells, and apoptotic cells in ischemia-reperfusion cerebral infarct rats. This study demonstrated that SJ could reduce the cerebral infarction area and neurological deficit induced by ischemia-reperfusion in rats, suggesting its potential as a treatment for cerebral infarct in humans. This effect of SJ involves its suppressive action of microglia, interleukin-1beta and apoptosis. PMID:16047560

  10. Electroacupuncture Attenuates Cerebral Ischemia and Reperfusion Injury in Middle Cerebral Artery Occlusion of Rat via Modulation of Apoptosis, Inflammation, Oxidative Stress, and Excitotoxicity

    PubMed Central

    Shen, Mei-hong; Zhang, Chun-bing; Zhang, Jia-hui; Li, Peng-fei

    2016-01-01

    Electroacupuncture (EA) has several properties such as antioxidant, antiapoptosis, and anti-inflammatory properties. The current study was to investigate the effects of EA on the prevention and treatment of cerebral ischemia-reperfusion (I/R) injury and to elucidate possible molecular mechanisms. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h followed by reperfusion for 24 h. EA stimulation was applied to both Baihui and Dazhui acupoints for 30 min in each rat per day for 5 successive days before MCAO (pretreatment) or when the reperfusion was initiated (treatment). Neurologic deficit scores, infarction volumes, brain water content, and neuronal apoptosis were evaluated. The expressions of related inflammatory cytokines, apoptotic molecules, antioxidant systems, and excitotoxic receptors in the brain were also investigated. Results showed that both EA pretreatment and treatment significantly reduced infarct volumes, decreased brain water content, and alleviated neuronal injury in MCAO rats. Notably, EA exerts neuroprotection against I/R injury through improving neurological function, attenuating the inflammation cytokines, upregulating antioxidant systems, and reducing the excitotoxicity. This study provides a better understanding of the molecular mechanism underlying the traditional use of EA. PMID:27123035

  11. Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia.

    PubMed

    Hermann, Dirk M; Zechariah, Anil; Kaltwasser, Britta; Bosche, Bert; Caglayan, Ahmet B; Kilic, Ertugrul; Doeppner, Thorsten R

    2015-11-01

    According to the French paradox, red wine consumption reduces the incidence of vascular diseases even in the presence of highly saturated fatty acid intake. This phenomenon is widely attributed to the phytoalexin resveratrol, a red wine ingredient. Experimental studies suggesting that resveratrol has neuroprotective properties mostly used prophylactic delivery strategies associated with short observation periods. These studies did not allow conclusions to be made about resveratrol's therapeutic efficacy post-stroke. Herein, we systematically analyzed effects of prophylactic, acute and post-acute delivery of resveratrol (50mg/kg) on neurological recovery, tissue survival, and angioneurogenesis after focal cerebral ischemia induced by intraluminal middle cerebral artery occlusion in mice. Over an observation period of four weeks, only prolonged post-acute resveratrol delivery induced sustained neurological recovery as assessed by rota rod, tight rope and corner turn tests. Although prophylactic and acute resveratrol delivery reduced infarct volume and enhanced blood-brain-barrier integrity at 2 days post-ischemia by elevating resveratrol's downstream signal sirtuin-1, increasing cell survival signals (phosphorylated Akt, heme oxygenase-1, Bcl-2) and decreasing cell death signals (Bax, activated caspase-3), a sustained reduction of infarct size on day 28 was not observed in any of the three experimental conditions. Instead, enhanced angiogenesis and neurogenesis were noted in animals receiving post-acute resveratrol delivery, which were associated with elevated concentrations of GDNF and VEGF in the brain. Thus, sustained neurological recovery induced by resveratrol depends on successful brain remodeling rather than structural neuroprotection. The recovery promoting effect of delayed resveratrol delivery opens promising perspectives for stroke therapy. PMID:26316359

  12. The effect of cationic albumin-conjugated PEGylated tanshinone IIA nanoparticles on neuronal signal pathways and neuroprotection in cerebral ischemia.

    PubMed

    Liu, Xin; Ye, Ming; An, Chiying; Pan, Liqiang; Ji, Litong

    2013-09-01

    Targeted treatment of ischemic stroke remains problem due to the complex pathogenesis of this disease and the difficulty in drug delivery across the blood-brain barrier (BBB). In the present study, the delivery efficiency of cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles (CBSA-PEG-TIIA-NPs) in rat brain was investigated. We further explored whether the protective mechanism of CBSA-PEG-TIIA-NPs in cerebral ischemia was associated with modulating neuronal signaling pathways. The experimental cerebral ischemia model was established to evaluate the treatment efficacy of CBSA-PEG-TIIA-NPs. The pharmacokinetics demonstrated that CBSA-PEG-TIIA-NPs could obviously prolong circulation time and increase plasma concentration compared with intravenously administrated TIIA solution. The biodistribution and brain uptake study confirmed that CBSA-PEG-TIIA-NPs possessed better brain delivery efficacy with a high drug accumulation and fluorescence quantitative level in brain. CBSA-PEG-TIIA-NPs effectively reduced infarction volume, neurological dysfunctions, neutrophils infiltration and neuronal apoptosis. Moreover, CBSA-PEG-TIIA-NPs significantly suppressed the expression of pro-inflammatory cytokines TNF-α and IL-8; upregulated the expression of anti-inflammatory cytokines IL-10 and increase TGF-β1 level in the ischemic brain. In addition, treatment with CBSA-PEG-TIIA-NPs markedly inhibited the mRNA expressions of GFAP, MMP-9, COX-2, p38MAPK, ERK1/2 and JNK, downregulated the protein levels of GFAP, MMP-9 and COX-2, as well as decreased the phosphorylation of ERK1/2, p38MAPK and JNK. These results demonstrated that CBSA-PEG-TIIA-NPs displayed remarkable neuroprotective effects on ischemic stroke through modulation of MAPK signal pathways involved in the cascades of neuroinflammation. PMID:23768781

  13. Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia.

    PubMed

    Pérez-Mato, M; Ramos-Cabrer, P; Sobrino, T; Blanco, M; Ruban, A; Mirelman, D; Menendez, P; Castillo, J; Campos, F

    2014-01-09

    Blood glutamate scavenging is a novel and attractive protecting strategy to reduce the excitotoxic effect of extracellular glutamate released during ischemic brain injury. Glutamate oxaloacetate transaminase 1 (GOT1) activation by means of oxaloacetate administration has been used to reduce the glutamate concentration in the blood. However, the protective effect of the administration of the recombinant GOT1 (rGOT1) enzyme has not been yet addressed in cerebral ischemia. The aim of this study was to analyze the protective effect of an effective dose of oxaloacetate and the human rGOT1 alone and in combination with a non-effective dose of oxaloacetate in an animal model of ischemic stroke. Sixty rats were subjected to a transient middle cerebral artery occlusion (MCAO). Infarct volumes were assessed by magnetic resonance imaging (MRI) before treatment administration, and 24 h and 7 days after MCAO. Brain glutamate levels were determined by in vivo MR spectroscopy (MRS) during artery occlusion (80 min) and reperfusion (180 min). GOT activity and serum glutamate concentration were analyzed during the occlusion and reperfusion period. Somatosensory test was performed at baseline and 7 days after MCAO. The three treatments tested induced a reduction in serum and brain glutamate levels, resulting in a reduction in infarct volume and sensorimotor deficit. Protective effect of rGOT1 supplemented with oxaloacetate at 7 days persists even when treatment was delayed until at least 2 h after onset of ischemia. In conclusion, our findings indicate that the combination of human rGOT1 with low doses of oxaloacetate seems to be a successful approach for stroke treatment.

  14. Baicalin's Therapeutic Time Window of Neuroprotection during Transient Focal Cerebral Ischemia and Its Antioxidative Effects In Vitro and In Vivo

    PubMed Central

    Cheng, Fafeng; Lu, Yi; Zhong, Xianggen; Song, Wenting; Wang, Xueqian; Sun, Xiaoguang; Guo, Shaoying; Wang, Qingguo

    2013-01-01

    We investigated the effects of baicalin on an ischemia-reperfusion-induced brain injury model in rats and its antioxidative activities in vitro and in vivo. An ischemia-reperfusion injury of the brain via a middle cerebral artery occlusion (MCAO) was induced in rats. Baicalin was injected at different time points (0, 2, 4, and 6 h) after the MCAO was induced. Baicalin can improve neurological function and significantly decrease brain infarction within a time window of 4 h. Moreover, baicalin was able to reduce cell apoptosis and had the strong antioxidative effect of reducing reactive oxygen species production and malondialdehyde generation. In contrast, baicalin interfered with superoxide dismutase and nicotinamide adenine dinucleotide 2′-phosphate oxidase activities. Moreover, baicalin also exhibited strong neuroprotective effects against H2O2-mediated injury and improved the SOD activity of neurons. Furthermore, baicalin demonstrated good scavenging of hydroxyl radicals, superoxide anions, and DPPH radicals and exerted an additional effect of inhibiting xanthine oxidase. Baicalin showed beneficial effects against MCAO-induced injury within a 4 h time window, and its antioxidative effects both in vitro and in vivo may partly elucidate its mechanism of action. PMID:23878589

  15. Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats

    PubMed Central

    Wang, Peng; Yao, Lan; Zhou, Li-li; Liu, Yuan-shan; Chen, Ming-di; Wu, Hai-dong; Chang, Rui-ming; Li, Yi; Zhou, Ming-gen; Fang, Xiang-shao; Yu, Tao; Jiang, Long-yuan; Huang, Zi-tong

    2016-01-01

    Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis. PMID:27489503

  16. A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia

    PubMed Central

    Castillo, Ximena; Rosafio, Katia; Wyss, Matthias T; Drandarov, Konstantin; Buck, Alfred; Pellerin, Luc; Weber, Bruno; Hirt, Lorenz

    2015-01-01

    Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate. PMID:26036941

  17. Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats.

    PubMed

    Wang, Peng; Yao, Lan; Zhou, Li-Li; Liu, Yuan-Shan; Chen, Ming-di; Wu, Hai-Dong; Chang, Rui-Ming; Li, Yi; Zhou, Ming-Gen; Fang, Xiang-Shao; Yu, Tao; Jiang, Long-Yuan; Huang, Zi-Tong

    2016-01-01

    Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis.

  18. Carbon Monoxide Improves Neurologic Outcomes by Mitochondrial Biogenesis after Global Cerebral Ischemia Induced by Cardiac Arrest in Rats.

    PubMed

    Wang, Peng; Yao, Lan; Zhou, Li-Li; Liu, Yuan-Shan; Chen, Ming-di; Wu, Hai-Dong; Chang, Rui-Ming; Li, Yi; Zhou, Ming-Gen; Fang, Xiang-Shao; Yu, Tao; Jiang, Long-Yuan; Huang, Zi-Tong

    2016-01-01

    Mitochondrial dysfunction contributes to brain injury following global cerebral ischemia after cardiac arrest. Carbon monoxide treatment has shown potent cytoprotective effects in ischemia/reperfusion injury. This study aimed to investigate the effects of carbon monoxide-releasing molecules on brain mitochondrial dysfunction and brain injury following resuscitation after cardiac arrest in rats. A rat model of cardiac arrest was established by asphyxia. The animals were randomly divided into the following 3 groups: cardiac arrest and resuscitation group, cardiac arrest and resuscitation plus carbon monoxide intervention group, and sham control group (no cardiac arrest). After the return of spontaneous circulation, neurologic deficit scores (NDS) and S-100B levels were significantly decreased at 24, 48, and 72 h, but carbon monoxide treatment improved the NDS and S-100B levels at 24 h and the 3-day survival rates of the rats. This treatment also decreased the number of damaged neurons in the hippocampus CA1 area and increased the brain mitochondrial activity. In addition, it increased mitochondrial biogenesis by increasing the expression of biogenesis factors including peroxisome proliferator-activated receptor-γ coactivator-1α, nuclear respiratory factor-1, nuclear respiratory factor-2 and mitochondrial transcription factor A. Thus, this study showed that carbon monoxide treatment alleviated brain injury after cardiac arrest in rats by increased brain mitochondrial biogenesis. PMID:27489503

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

    PubMed

    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.

  20. Radix Ilicis Pubescentis total flavonoids combined with mobilization of bone marrow stem cells to protect against cerebral ischemia/reperfusion injury

    PubMed Central

    Miao, Ming-san; Guo, Lin; Li, Rui-qi; Ma, Xiao

    2016-01-01

    Previous studies have shown that Radix Ilicis Pubescentis total flavonoids have a neuroprotective effect, but it remains unclear whether Radix Ilicis Pubescentis total flavonoids have a synergistic effect with the recombinant human granulocyte colony stimulating factor-mobilized bone marrow stem cell transplantation on cerebral ischemia/reperfusion injury. Rat ischemia models were administered 0.3, 0.15 and 0.075 g/kg Radix Ilicis Pubescentis total flavonoids from 3 days before modeling to 2 days after injury. Results showed that Radix Ilicis Pubescentis total flavonoids could reduce pathological injury in rats with cerebral ischemia/reperfusion injury. The number of Nissl bodies increased, Bax protein expression decreased, Bcl-2 protein expression increased and the number of CD34-positive cells increased. Therefore, Radix Ilicis Pubescentis total flavonoids can improve the bone marrow stem cell mobilization effect, enhance the anti-apoptotic ability of nerve cells, and have a neuroprotective effect on cerebral ischemia/reperfusion injury in rats. PMID:27073381

  1. A new approach to reduce the number of animals used in experimental focal cerebral ischemia models.

    PubMed

    Burggraf, Dorothe; Martens, Helge K; Liebetrau, Martin; Vosko, Milan R; Dichgans, Martin; Hamann, Gerhard F

    2005-09-30

    We describe a novel experimental set-up that allows biochemical, immunohistochemical and morphometric recording of multiple parameters from a single rat brain. The whole brain was cut (coronal sectioning) in a volumetric manner, and 100 cryo-sections (10 microm) were collected from the region of infarction. By use of a scalpel to dissect the cryosection, crude brain material was obtained from the cortical and basal ganglia areas of ischemic and non-ischemic hemispheres. Material from four 10 microm thick sections of the same animal was pooled. About 30 microg protein lysate was extracted per four sections with various lysis buffers; this sufficed for one biochemical or enzymatic test called "micro-Western-blots" or "micro-zymographies". Scraping brain material from cryosections allows the detection of up to 25 parameters from adjacent brain sections of one single rat brain. Different analysis are possible, we have chosen, e.g. to compare factors affecting the basal lamina of cerebral microvessels like the content of the metalloproteinases-2/-9, their tissue inhibitors, the plasminogen activators, collagen type IV, parameters to test the blood-brain barrier: hemoglobin and the protein of the perfusion solution BSA and the infarction volume. On the basis of these parameters it was possible to compare the interactions of the complex processes in the ischemic brain in the same animal in adjacent sections. Thus, this method increases the validity of data comparisons and reduces significantly the number of animals needed in various experimental settings.

  2. Effects of total saponins of Panax notoginseng on immature neuroblasts in the adult olfactory bulb following global cerebral ischemia/reperfusion.

    PubMed

    He, Xu; Deng, Feng-Jun; Ge, Jin-Wen; Yan, Xiao-Xin; Pan, Ai-Hua; Li, Zhi-Yuan

    2015-09-01

    The main active components extracted from Panax notoginseng are total saponins. They have been shown to inhibit platelet aggregation, increase cerebral blood flow, improve neurological behavior, decrease infarct volume and promote proliferation and differentiation of neural stem cells in the hippocampus and lateral ventricles. However, there is a lack of studies on whether total saponins of Panax notoginseng have potential benefits on immature neuroblasts in the olfactory bulb following ischemia and reperfusion. This study established a rat model of global cerebral ischemia and reperfusion using four-vessel occlusion. Rats were administered total saponins of Panax notoginseng at 75 mg/kg intraperitoneally 30 minutes after ischemia then once a day, for either 7 or 14 days. Total saponins of Panax notoginseng enhanced the number of doublecortin (DCX)(+) neural progenitor cells and increased co-localization of DCX with neuronal nuclei and phosphorylated cAMP response element-binding/DCX(+) neural progenitor cells in the olfactory bulb at 7 and 14 days post ischemia. These findings indicate that following global brain ischemia/reperfusion, total saponins of Panax notoginseng promote differentiation of DCX(+) cells expressing immature neuroblasts in the olfactory bulb and the underlying mechanism is related to the activation of the signaling pathway of cyclic adenosine monophosphate response element binding protein. PMID:26604906

  3. Polyethylene glygol conjugated superoxide dismutase (PEG-SOD) improves recovery of hypercapnia cerebral blood flow (CBF) reactivity following transient global ischemia in piglets

    SciTech Connect

    Traystman, R.J.; Kirsch, J.R.; Helfaer, M.A.; Haun, S.E. )

    1991-03-15

    This study tested the hypothesis that alteration in hypercapnic cerebral blood flow (CBF) reactivity is due to oxygen-derived free radical mediated vascular damage and therefore could be inhibited by treatment with PEG-SOD. Pentobarbital anesthetized piglets were mechanically ventilated and hemodynamically monitored. CBF was measured at PaCO{sub 2} of approximately 25, 40 and 55 mmHg. Reactivity was tested in all piglets prior to and 2 hours following reperfusion from global ischemia. Control piglets received PEG prior to ischemia and at reperfusion. Experimental piglets received either PEG-SOD prior to ischemia and PEG at reperfusion or PEG prior to ischemia and PEG-SOD at reperfusion. During reperfusion cerebral perfusion pressure was maintained constant between groups by intravenous infusion of epinephrine. Pre-ischemic hypercapnic reactivity was not different between groups. At 2 hr reperfusion hypercapnic CBF reactivity in control piglets was diminished to forebrain and brainstem but hypercapnic reactivity was not different than preischemic values in either group receiving PEG-SOD. The authors conclude that administration of PEG-SOD, either prior to or following transient global ischemia, improves recovery of post-ischemic hypercapnic reactivity in piglets. This implicates oxygen-derived free radicals as important mediators of reperfusion injury in brain.

  4. 3-Nitropropionic acid-induced ischemia tolerance in the rat brain is mediated by reduced metabolic activity and cerebral blood flow

    PubMed Central

    Bracko, Oliver; Di Pietro, Valentina; Lazzarino, Giacomo; Amorini, Angela M; Tavazzi, Barbara; Artmann, Judith; Wong, Eric C; Buxton, Richard B; Weller, Michael; Luft, Andreas R; Wegener, Susanne

    2014-01-01

    Tissue tolerance to ischemia can be achieved by noxious stimuli that are below a threshold to cause irreversible damage (‘preconditioning'). Understanding the mechanisms underlying preconditioning may lead to the identification of novel therapeutic targets for diseases such as stroke. We here used the oxidative chain inhibitor 3-nitropropionic acid (NPA) to induce ischemia tolerance in a rat middle cerebral artery occlusion (MCAO) stroke model. Cerebral blood flow (CBF) and structural integrity were characterized by longitudinal magnetic resonance imaging (MRI) in combination with behavioral, histologic, and biochemical assessment of NPA-preconditioned animals and controls. Using this approach we show that the ischemia-tolerant state is characterized by a lower energy charge potential and lower CBF, indicating a reduced baseline metabolic demand, and therefore a cellular mechanism of neural protection. Blood vessel density and structural integrity were not altered by NPA treatment. When subjected to MCAO, preconditioned animals had a characteristic MRI signature consisting of enhanced CBF maintenance within the ischemic territory and intraischemic reversal of the initial cytotoxic edema, resulting in reduced infarct volumes. Thus, our data show that tissue protection through preconditioning occurs early during ischemia and indicate that a reduced cellular metabolism is associated with tissue tolerance to ischemia. PMID:24938399

  5. Effects of total saponins of Panax notoginseng on immature neuroblasts in the adult olfactory bulb following global cerebral ischemia/reperfusion

    PubMed Central

    He, Xu; Deng, Feng-jun; Ge, Jin-wen; Yan, Xiao-xin; Pan, Ai-hua; Li, Zhi-yuan

    2015-01-01

    The main active components extracted from Panax notoginseng are total saponins. They have been shown to inhibit platelet aggregation, increase cerebral blood flow, improve neurological behavior, decrease infarct volume and promote proliferation and differentiation of neural stem cells in the hippocampus and lateral ventricles. However, there is a lack of studies on whether total saponins of Panax notoginseng have potential benefits on immature neuroblasts in the olfactory bulb following ischemia and reperfusion. This study established a rat model of global cerebral ischemia and reperfusion using four-vessel occlusion. Rats were administered total saponins of Panax notoginseng at 75 mg/kg intraperitoneally 30 minutes after ischemia then once a day, for either 7 or 14 days. Total saponins of Panax notoginseng enhanced the number of doublecortin (DCX)+ neural progenitor cells and increased co-localization of DCX with neuronal nuclei and phosphorylated cAMP response element-binding/DCX+ neural progenitor cells in the olfactory bulb at 7 and 14 days post ischemia. These findings indicate that following global brain ischemia/reperfusion, total saponins of Panax notoginseng promote differentiation of DCX+ cells expressing immature neuroblasts in the olfactory bulb and the underlying mechanism is related to the activation of the signaling pathway of cyclic adenosine monophosphate response element binding protein. PMID:26604906

  6. Effect of ageing and ischemia on enzymatic activities linked to Krebs' cycle, electron transfer chain, glutamate and aminoacids metabolism of free and intrasynaptic mitochondria of cerebral cortex.

    PubMed

    Villa, Roberto Federico; Gorini, Antonella; Hoyer, Siegfried

    2009-12-01

    The effect of ageing and the relationships between the catalytic properties of enzymes linked to Krebs' cycle, electron transfer chain, glutamate and aminoacid metabolism of cerebral cortex, a functional area very sensitive to both age and ischemia, were studied on mitochondria of adult and aged rats, after complete ischemia of 15 minutes duration. The maximum rate (Vmax) of the following enzyme activities: citrate synthase, malate dehydrogenase, succinate dehydrogenase for Krebs' cycle; NADH-cytochrome c reductase as total (integrated activity of Complex I-III), rotenone sensitive (Complex I) and cytochrome oxidase (Complex IV) for electron transfer chain; glutamate dehydrogenase, glutamate-oxaloacetate-and glutamate-pyruvate transaminases for glutamate metabolism were assayed in non-synaptic, perikaryal mitochondria and in two populations of intra-synaptic mitochondria, i.e., the light and heavy mitochondrial fraction. The results indicate that in normal, steady-state cerebral cortex, the value of the same enzyme activity markedly differs according (a) to the different populations of mitochondria, i.e., non-synaptic or intra-synaptic light and heavy, (b) and respect to ageing. After 15 min of complete ischemia, the enzyme activities of mitochondria located near the nucleus (perikaryal mitochondria) and in synaptic structures (intra-synaptic mitochondria) of the cerebral tissue were substantially modified by ischemia. Non-synaptic mitochondria seem to be more affected by ischemia in adult and particularly in aged animals than the intra-synaptic light and heavy mitochondria. The observed modifications in enzyme activities reflect the metabolic state of the tissue at each specific experimental condition, as shown by comparative evaluation with respect to the content of energy-linked metabolites and substrates. The derangements in enzyme activities due to ischemia is greater in aged than in adult animals and especially the non-synaptic and the intra-synaptic light

  7. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia-reperfusion injury in rats - A possible new hydrogen resource for clinical use.

    PubMed

    Cui, Jin; Chen, Xiao; Zhai, Xiao; Shi, Dongchen; Zhang, Rongjia; Zhi, Xin; Li, Xiaoqun; Gu, Zhengrong; Cao, Liehu; Weng, Weizong; Zhang, Jun; Wang, Liping; Sun, Xuejun; Ji, Fang; Hou, Jiong; Su, Jiacan

    2016-10-29

    Hydrogen is a kind of noble gas with the character to selectively neutralize reactive oxygen species. Former researches proved that low-concentration of hydrogen can be used to ameliorating cerebral ischemia/reperfusion injury. Hydrogen electrolyzed from water has a hydrogen concentration of 66.7%, which is much higher than that used in previous studies. And water electrolysis is a potential new hydrogen resource for regular clinical use. This study was designed and carried out for the determination of safety and neuroprotective effects of water electrolysis-derived hydrogen. Sprague-Dawley rats were used as experimental animals, and middle cerebral artery occlusion was used to make cerebral ischemia/reperfusion model. Pathologically, tissues from rats in hydrogen inhalation group showed no significant difference compared with the control group in HE staining pictures. The blood biochemical findings matched the HE staining result. TTC, Nissl, and TUNEL staining showed the significant improvement of infarction volume, neuron morphology, and neuron apoptosis in rat with hydrogen treatment. Biochemically, hydrogen inhalation decreased brain caspase-3, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine-positive cells and inflammation factors concentration. Water electrolysis-derived hydrogen inhalation had neuroprotective effects on cerebral ischemia/reperfusion injury in rats with the effect of suppressing oxidative stress and inflammation, and it is a possible new hydrogen resource to electrolyze water at the bedside clinically. PMID:27555551

  8. Inhalation of water electrolysis-derived hydrogen ameliorates cerebral ischemia-reperfusion injury in rats - A possible new hydrogen resource for clinical use.

    PubMed

    Cui, Jin; Chen, Xiao; Zhai, Xiao; Shi, Dongchen; Zhang, Rongjia; Zhi, Xin; Li, Xiaoqun; Gu, Zhengrong; Cao, Liehu; Weng, Weizong; Zhang, Jun; Wang, Liping; Sun, Xuejun; Ji, Fang; Hou, Jiong; Su, Jiacan

    2016-10-29

    Hydrogen is a kind of noble gas with the character to selectively neutralize reactive oxygen species. Former researches proved that low-concentration of hydrogen can be used to ameliorating cerebral ischemia/reperfusion injury. Hydrogen electrolyzed from water has a hydrogen concentration of 66.7%, which is much higher than that used in previous studies. And water electrolysis is a potential new hydrogen resource for regular clinical use. This study was designed and carried out for the determination of safety and neuroprotective effects of water electrolysis-derived hydrogen. Sprague-Dawley rats were used as experimental animals, and middle cerebral artery occlusion was used to make cerebral ischemia/reperfusion model. Pathologically, tissues from rats in hydrogen inhalation group showed no significant difference compared with the control group in HE staining pictures. The blood biochemical findings matched the HE staining result. TTC, Nissl, and TUNEL staining showed the significant improvement of infarction volume, neuron morphology, and neuron apoptosis in rat with hydrogen treatment. Biochemically, hydrogen inhalation decreased brain caspase-3, 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine-positive cells and inflammation factors concentration. Water electrolysis-derived hydrogen inhalation had neuroprotective effects on cerebral ischemia/reperfusion injury in rats with the effect of suppressing oxidative stress and inflammation, and it is a possible new hydrogen resource to electrolyze water at the bedside clinically.

  9. Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia.

    PubMed

    Tan, S; Zhi, P K; Luo, Z K; Shi, J

    2015-09-10

    Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling.

  10. Neuroprotection of total steroid saponins from Dioscorea zingiberensis against transient focal cerebral ischemia-reperfusion injury in rats via anti-inflammatory and antiapoptotic effects.

    PubMed

    Zhang, Xin-xin; Chen, Lin; Liu, Jian-li; Ito, Yoichiro; He, Jiao; Sun, Wen-ji

    2014-11-01

    Total steroid saponins isolated from Dioscorea zingiberensis have shown a variety of beneficial bioactivities. However, there are no reports about their neuroprotective effects, until now. Therefore, in the present study, we explored the neuroprotective effects of the total steroid saponins from D. zingiberensis on rats against transient focal cerebral ischemia-reperfusion and their underlying mechanisms. Healthy adult Sprague-Dawley rats were randomly assigned to six groups. After pretreatment with D. zingiberensis total steroid saponins intragastrically for six days, the rats were subjected to an ischemia injury by surgery on the middle cerebral artery occlusion for 90 min. Compared to the ischemia-reperfusion group, the D. zingiberensis total steroid saponin group of rats, especially those given a 30-mg/kg dose, showed not only a marked reduction in neurological deficit scores, cerebral infarct volume, and brain edema, but also an increase in neuron survival (Nissl bodies) in the hippocampal cornuammons 1 and cortex hemisphere of the ipsilateral ischemia. At the same time, the inflammatory cytokines in serum induced by the middle cerebral artery occlusion were significantly decreased by the preadministration of D. zingiberensis total steroid saponins. Furthermore, the increase of caspase-3 was evidently reduced in the hippocampal cornuammons 1 and cortex of the hemisphere injured brain. Finally, the downregulating antiapoptotic Bcl-2 and upregulating proapoptotic Bax proteins were obviously suppressed. Taken together, the current findings suggest that D. zingiberensis total steroid saponins played a potential neuroprotective role against a severe injury induced by transient focal cerebral ischemic reperfusion in a rat experimental model, and this role may be mediated by its anti-inflammatory and antiapoptotic actions.

  11. Electroacupuncture alleviates cerebral ischemia and reperfusion injury via modulation of the ERK1/2 signaling pathway

    PubMed Central

    Jin, Xiao-lu; Li, Peng-fei; Zhang, Chun-bing; Wu, Jin-ping; Feng, Xi-lian; Zhang, Ying; Shen, Mei-hong

    2016-01-01

    Electroacupuncture (EA) has anti-oxidative and anti-inflammatory actions, but whether the neuroprotective effect of EA against cerebral ischemia-reperfusion (I/R) injury involves modulation of the extracellular regulated kinase 1/2 (ERK1/2) signaling pathway is unclear. Middle cerebral artery occlusion (MCAO) was performed in Sprague-Dawley rats for 2 hours followed by reperfusion for 24 hours. A 30-minute period of EA stimulation was applied to both Baihui (DU20) and Dazhui (DU14) acupoints in each rat (10 mm EA penetration depth, continuous wave with a frequency of 3 Hz, and a current intensity of 1–3 mA) when reperfusion was initiated. EA significantly reduced infarct volume, alleviated neuronal injury, and improved neurological function in rats with MCAO. Furthermore, high mRNA expression of Bax and low mRNA expression of Bcl-2 induced by MCAO was prevented by EA. EA substantially restored total glutathione reductase (GR), glutathione (GSH) and glutathione peroxidase (GSH-Px) levels. Additionally, Nrf2 and glutamylcysteine synthetase (GCS) expression levels were markedly increased by EA. Interestingly, the neuroprotective effects of EA were attenuated when ERK1/2 activity was blocked by PD98059 (a specific MEK inhibitor). Collectively, our findings indicate that activation of the ERK1/2 signaling pathway contributes to the neuroprotective effects of EA. Our study provides a better understanding of the regulatory mechanisms underlying the therapeutic effectiveness of EA. PMID:27630691

  12. Electroacupuncture alleviates cerebral ischemia and reperfusion injury via modulation of the ERK1/2 signaling pathway.

    PubMed

    Jin, Xiao-Lu; Li, Peng-Fei; Zhang, Chun-Bing; Wu, Jin-Ping; Feng, Xi-Lian; Zhang, Ying; Shen, Mei-Hong

    2016-07-01

    Electroacupuncture (EA) has anti-oxidative and anti-inflammatory actions, but whether the neuroprotective effect of EA against cerebral ischemia-reperfusion (I/R) injury involves modulation of the extracellular regulated kinase 1/2 (ERK1/2) signaling pathway is unclear. Middle cerebral artery occlusion (MCAO) was performed in Sprague-Dawley rats for 2 hours followed by reperfusion for 24 hours. A 30-minute period of EA stimulation was applied to both Baihui (DU20) and Dazhui (DU14) acupoints in each rat (10 mm EA penetration depth, continuous wave with a frequency of 3 Hz, and a current intensity of 1-3 mA) when reperfusion was initiated. EA significantly reduced infarct volume, alleviated neuronal injury, and improved neurological function in rats with MCAO. Furthermore, high mRNA expression of Bax and low mRNA expression of Bcl-2 induced by MCAO was prevented by EA. EA substantially restored total glutathione reductase (GR), glutathione (GSH) and glutathione peroxidase (GSH-Px) levels. Additionally, Nrf2 and glutamylcysteine synthetase (GCS) expression levels were markedly increased by EA. Interestingly, the neuroprotective effects of EA were attenuated when ERK1/2 activity was blocked by PD98059 (a specific MEK inhibitor). Collectively, our findings indicate that activation of the ERK1/2 signaling pathway contributes to the neuroprotective effects of EA. Our study provides a better understanding of the regulatory mechanisms underlying the therapeutic effectiveness of EA. PMID:27630691

  13. The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats

    PubMed Central

    Krupka, Jennifer; May, Frauke; Weimer, Thomas; Pragst, Ingo; Kleinschnitz, Christoph; Stoll, Guido; Panousis, Con; Dickneite, Gerhard; Nolte, Marc W.

    2016-01-01

    Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury. PMID:26815580

  14. Electroacupuncture alleviates cerebral ischemia and reperfusion injury via modulation of the ERK1/2 signaling pathway

    PubMed Central

    Jin, Xiao-lu; Li, Peng-fei; Zhang, Chun-bing; Wu, Jin-ping; Feng, Xi-lian; Zhang, Ying; Shen, Mei-hong

    2016-01-01

    Electroacupuncture (EA) has anti-oxidative and anti-inflammatory actions, but whether the neuroprotective effect of EA against cerebral ischemia-reperfusion (I/R) injury involves modulation of the extracellular regulated kinase 1/2 (ERK1/2) signaling pathway is unclear. Middle cerebral artery occlusion (MCAO) was performed in Sprague-Dawley rats for 2 hours followed by reperfusion for 24 hours. A 30-minute period of EA stimulation was applied to both Baihui (DU20) and Dazhui (DU14) acupoints in each rat (10 mm EA penetration depth, continuous wave with a frequency of 3 Hz, and a current intensity of 1–3 mA) when reperfusion was initiated. EA significantly reduced infarct volume, alleviated neuronal injury, and improved neurological function in rats with MCAO. Furthermore, high mRNA expression of Bax and low mRNA expression of Bcl-2 induced by MCAO was prevented by EA. EA substantially restored total glutathione reductase (GR), glutathione (GSH) and glutathione peroxidase (GSH-Px) levels. Additionally, Nrf2 and glutamylcysteine synthetase (GCS) expression levels were markedly increased by EA. Interestingly, the neuroprotective effects of EA were attenuated when ERK1/2 activity was blocked by PD98059 (a specific MEK inhibitor). Collectively, our findings indicate that activation of the ERK1/2 signaling pathway contributes to the neuroprotective effects of EA. Our study provides a better understanding of the regulatory mechanisms underlying the therapeutic effectiveness of EA.

  15. A selective cysteine protease inhibitor is non-toxic and cerebroprotective in rats undergoing transient middle cerebral artery ischemia.

    PubMed

    Seyfried, D M; Veyna, R; Han, Y; Li, K; Tang, N; Betts, R L; Weinsheimer, S; Chopp, M; Anagli, J

    2001-05-18

    Ischemic neuronal injury mediated by cysteine proteases such as calpains and caspases has been demonstrated in various experimental models. Cathepsins B and L are also cysteine proteases which may contribute to neuronal death after ischemia. The authors measured in vitro and in vivo toxicity and post-ischemic cytoprotective effects of a cysteine protease inhibitor which does not block calpain or caspase but, rather, is relatively selective for cathepsins B and L. The compound belongs to the peptidyl-diazomethane family (cysteine protease inhibitor 1, termed CP-1). In vitro toxicity was measured using an assay of cell viability, and in vivo toxicity was measured by histological tissue analysis after infusion of CP-1 in rats. Two hours of middle cerebral artery (MCA) occlusion in rats was performed by the intravascular suture method. Immediately following reperfusion, intravenous infusion of CP-1 or vehicle was performed for 4 h at 0.9 ml/h. After a 7-day survival, the infarct volumes were measured. CP-1 was non-toxic to cultured glial cells to a local concentration of 200 microM, and relatively non-toxic to cultured endothelial cells at concentrations of 100-200 microM. No animal exhibited toxic effects at any of the doses used. Histologic comparisons revealed no signs of tissue toxicity. CP-1 significantly reduced hemispheric infarct volume compared to control (37+/-8.2%) at concentrations of 10, 50, and 250 microM [22+/-15%, P=0.008; 20+/-13%, P=0.002; 23+/-15%, P=0.022, respectively (mean+/-standard deviation; N=7-10 per group)]. CP-1, at the concentration of 50 microM, improved the functional score of the animals, but did not significantly alter cerebral blood flow. This study supports the hypothesis that the lysosomal cathepsins B and/or L contribute to cerebral injury after focal ischemia with reperfusion. Cysteine protease inhibitors which are relatively selective for cathepsins B and L, but not the calpains or caspases, are effective at reducing infarct

  16. Sodium-23 magnetic resonance imaging during and after transient cerebral ischemia: multinuclear stroke protocols for double-tuned 23Na/1H resonator systems

    NASA Astrophysics Data System (ADS)

    Wetterling, Friedrich; Ansar, Saema; Handwerker, Eva

    2012-11-01

    A double-tuned 23Na/1H resonator system was developed to record multinuclear MR image data during and after transient cerebral ischemia. 1H-diffusion-, 1H perfusion, 1H T2-, 1H arterial blood flow- and 23Na spin density-weighted images were then acquired at three time points in a rodent stroke model: (I) during 90 min artery occlusion, (II) directly after arterial reperfusion and (III) one day after arterial reperfusion. Normal 23Na was detected in hypoperfused stroke tissue which exhibited a low 1H apparent diffusion coefficient (ADC) and no changes in 1H T2 relaxation time during transient ischemia, while 23Na increased and ADC values recovered to normal values directly after arterial reperfusion. For the first time, a similar imaging protocol was set-up on a clinical 3T MRI site in conjunction with a commercial double-tuned 1H/23Na birdcage resonator avoiding a time-consuming exchange of resonators or MRI systems. Multinuclear 23Na/1H MRI data sets were obtained from one stroke patient during both the acute and non-acute stroke phases with an aquisition time of 22 min. The lesion exhibiting low ADC was found to be larger compared to the lesion with high 23Na at 9 h after symptom onset. It is hoped that the presented pilot data demonstrate that fast multinuclear 23Na/1H MRI preclinical and clinical protocols can enable a better understanding of how temporal and regional MRI parameter changes link to pathophysiological variations in ischemic stroke tissue.

  17. Complications following transfemoral cerebral angiography for cerebral ischemia. Report of 159 angiograms and correlation with surgical risk.

    PubMed

    Theodotou, B C; Whaley, R; Mahaley, M S

    1987-08-01

    One hundred fifty-nine transfemoral cerebral angiograms for patients with carotid stenosis who subsequently underwent carotid endarterectomy were reviewed. No patient with an asymptomatic carotid bruit developed cerebrovascular complications during angiography. Patients with transient ischemic attacks (TIAs) had a 4.5% incidence of complications. Patients with stroke in evolution had a complication rate of 7.7%. Patients with completed strokes had no angiographic complications. No complication lasted more than 1 hour; all occurred during angiography or immediately afterwards. Stroke in progress has too high a surgical and angiographic risk to warrant study. Transient ischemic attacks have an acceptable morbidity both surgically and angiographically. PMID:3603359

  18. Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats.

    PubMed

    Fisher, M; Meadows, M E; Do, T; Weise, J; Trubetskoy, V; Charette, M; Finklestein, S P

    1995-11-01

    Basic fibroblast growth factor (bFGF) is a polypeptide that supports the survival of brain cells (including neurons, glia, and endothelia) and protects neurons against a number of toxins and insults in vitro. This factor is also a potent dilator of cerebral pial arterioles in vivo. In previous studies, we found that intraventricularly administered bFGF reduced infarct volume in a model of focal cerebral ischemia in rats. In the current study, bFGF (45 micrograms/kg/h) in vehicle, or vehicle alone, was infused intravenously for 3 h, beginning at 30 min after permanent middle cerebral artery occlusion by intraluminal suture in mature Sprague-Dawley rats. After 24 h, neurological deficit (as assessed by a 0- to 5-point scale, with 5 = most severe) was 2.6 +/- 1.0 in vehicle-treated and 1.5 +/- 1.3 in bFGF-treated rats (mean +/- SD; N = 12 vs. 11; p = 0.009). Infarct volume was 297 +/- 65 mm3 in vehicle- and 143 +/- 135 mm3 in bFGF-treated animals (p = 0.002). During infusion, there was a modest decrease in mean arterial blood pressure but no changes in arterial blood gases or core or brain temperature in bFGF-treated rats. Autoradiography following intravenous administration of 111In-labeled bFGF showed that labeled bFGF crossed the damaged blood-brain barrier to enter the ischemic (but not the nonischemic) hemisphere. Whether the infarct-reducing effects of bFGF depend on intraparenchymal or intravascular mechanisms requires further study.

  19. Breakthrough: new guidance for silent cerebral ischemia and infarction in sickle cell disease.

    PubMed

    Quinn, Charles T

    2014-12-01

    Silent cerebral infarction (SCI) is a highly prevalent and morbid condition in sickle cell disease (SCD). SCI can occur beginning in the first year of life and becomes more common with increasing age. Potentially modifiable risk factors for SCI include anemia and blood pressure. Headache does not appear to be associated with SCI, so neurologically normal children with headache do not necessarily warrant screening MRI for SCI. SCI does affect cognition, but biological determinants of cognition are not more important than socioeconomic factors. The recent identification of acute silent cerebral ischemic events indicates that the total burden of ischemic injury to the brain in SCD is far greater than previously realized. Acute anemic events appear to increase the risk of acute silent cerebral ischemic events and SCI dramatically. The medical management of SCI is not yet defined, but documentation of the presence of SCI may qualify affected individuals for special resources because comprehensive interventions are needed to optimize patients' academic and vocational outcomes.

  20. Amelioration of cognitive impairment and changes in microtubule-associated protein 2 after transient global cerebral ischemia are influenced by complex environment experience.

    PubMed

    Briones, Teresita L; Woods, Julie; Wadowska, Magdalena; Rogozinska, Magdalena

    2006-04-01

    In this study we examined whether expression of microtubule-associated protein 2 (MAP2) after transient global cerebral ischemia can be influenced by behavioral experience and if the changes are associated with functional improvement. Rats received either ischemia or sham surgery then assigned to: complex environment housing (EC) or social housing (SC) as controls for 14 days followed by water maze testing. Upregulation of MAP2 was seen in all ischemic animals with a significant overall increase evident in the EC housed rats. Behaviorally, all animals learned to perform the water maze task over time but the ischemia SC rats had the worst performance overall while all the EC housed animals demonstrated the best performance in general. Regression analysis showed that increase MAP2 expression was able to explain some of the variance in the behavioral parameters in the water maze suggesting that this cytoskeletal protein probably played a role in mediating enhanced functional outcomes.

  1. [The relation between gene of lipoprotein-lipase and carrier protein of cholesterol ethers and life duration in patients with chronic cerebral ischemia].

    PubMed

    Kostomarov, I V; Vodolagina, N N; Malygina, N A; Mitina, Z S

    2008-01-01

    Comparative analysis of frequency distribution of genotypes and alleles of HindIII-polymorphism of gene LPL and TaqIB-polymorphism of gene CETP in 267 patients of various ages with chronic cerebral ischemia (CCI) was performed. Relation between age and polymorphous variants of genes LPL and CETP was noticed. It was shown that genotype of H+H+ HindIII-polymorphism of and genotype B1B1 TaqIB-polymorphism of gene CETP were found more frequently in more young patients with chronic cerebral ischemia (CCI). Since there is an association of these genotypes with atherogenic dislipidemias, they apparently can be considered as risk factors of CCI development. On the contrary, genotype of gene LPL and B2 allele of gene CETP in patients elder 90 years (long-livers) are found significantly more frequently than in younger patients, that makes possible to consider they as markers of favorable course of disease and patients' long life.

  2. Extremely low frequency magnetic field (50 Hz, 0.5 mT) reduces oxidative stress in the brain of gerbils submitted to global cerebral ischemia.

    PubMed

    Rauš Balind, Snežana; Selaković, Vesna; Radenović, Lidija; Prolić, Zlatko; Janać, Branka

    2014-01-01

    Magnetic field as ecological factor has influence on all living beings. The aim of this study was to determine if extremely low frequency magnetic field (ELF-MF, 50 Hz, 0.5 mT) affects oxidative stress in the brain of gerbils submitted to 10-min global cerebral ischemia. After occlusion of both carotid arteries, 3-month-old gerbils were continuously exposed to ELF-MF for 7 days. Nitric oxide and superoxide anion production, superoxide dismutase activity and index of lipid peroxidation were examined in the forebrain cortex, striatum and hippocampus on the 7(th) (immediate effect of ELF-MF) and 14(th) day after reperfusion (delayed effect of ELF-MF). Ischemia per se increased oxidative stress in the brain on the 7(th) and 14(th) day after reperfusion. ELF-MF also increased oxidative stress, but to a greater extent than ischemia, only immediately after cessation of exposure. Ischemic gerbils exposed to ELF-MF had increased oxidative stress parameters on the 7(th) day after reperfusion, but to a lesser extent than ischemic or ELF-MF-exposed animals. On the 14(th) day after reperfusion, oxidative stress parameters in the brain of these gerbils were mostly at the control levels. Applied ELF-MF decreases oxidative stress induced by global cerebral ischemia and thereby reduces possible negative consequences which free radical species could have in the brain. The results presented here indicate a beneficial effect of ELF-MF (50 Hz, 0.5 mT) in the model of global cerebral ischemia.

  3. Extremely Low Frequency Magnetic Field (50 Hz, 0.5 mT) Reduces Oxidative Stress in the Brain of Gerbils Submitted to Global Cerebral Ischemia

    PubMed Central

    Rauš Balind, Snežana; Selaković, Vesna; Radenović, Lidija; Prolić, Zlatko; Janać, Branka

    2014-01-01

    Magnetic field as ecological factor has influence on all living beings. The aim of this study was to determine if extremely low frequency magnetic field (ELF-MF, 50 Hz, 0.5 mT) affects oxidative stress in the brain of gerbils submitted to 10-min global cerebral ischemia. After occlusion of both carotid arteries, 3-month-old gerbils were continuously exposed to ELF-MF for 7 days. Nitric oxide and superoxide anion production, superoxide dismutase activity and index of lipid peroxidation were examined in the forebrain cortex, striatum and hippocampus on the 7th (immediate effect of ELF-MF) and 14th day after reperfusion (delayed effect of ELF-MF). Ischemia per se increased oxidative stress in the brain on the 7th and 14th day after reperfusion. ELF-MF also increased oxidative stress, but to a greater extent than ischemia, only immediately after cessation of exposure. Ischemic gerbils exposed to ELF-MF had increased oxidative stress parameters on the 7th day after reperfusion, but to a lesser extent than ischemic or ELF-MF-exposed animals. On the 14th day after reperfusion, oxidative stress parameters in the brain of these gerbils were mostly at the control levels. Applied ELF-MF decreases oxidative stress induced by global cerebral ischemia and thereby reduces possible negative consequences which free radical species could have in the brain. The results presented here indicate a beneficial effect of ELF-MF (50 Hz, 0.5 mT) in the model of global cerebral ischemia. PMID:24586442

  4. Cerebral CT angiography and CT perfusion in acute stroke detection: a systematic review of diagnostic value

    PubMed Central

    Subramaniam, Cantiriga; Sun, Zhonghua

    2014-01-01

    The purpose of this study was to analyse the diagnostic value of cerebral CT angiography (CTA) and CT perfusion (CTP) examinations in the detection of acute stroke based on a systematic review of the current literature. The review was conducted based on searching of seven databases for articles published between 1993 and 2013. Diagnostic value in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy was analysed from 21 articles which were found to meet selection criteria. The mean sensitivity, specificity, PPV, NPV and accuracy for CTA were significantly higher than those for CTP with 83.2% (95% CI: 57.9-100.0%), 95.0% (95% CI: 74.4-100%), 84.1% (95% CI: 50.0-100%), 97.1 (95% CI: 94.0-100%) and 94.0% (95% CI: 83.0-99.0) versus 69.9% (95% CI: 20.0-97.0%), 87.4 (95% CI: 61.0-100.0%), 76.4% (95% CI: 48.0-95.4%), 78.2% (95% CI: 55.8-93.9%) and 89.8% (95% CI: 75.7-97.1%), respectively. This analysis shows that CTA has high diagnostic value in detecting high degree of cerebral arterial stenosis (>70%) whereas CTP provides high specificity in the detection of ischemia and infarct tissue of brain. PMID:25202664

  5. Cerebral Microbleeds: Detection, Associations and Clinical Implications.

    PubMed

    Yakushiji, Yusuke

    2015-01-01

    Vigorous investigations for cerebral microbleeds (CMBs) have been made since the late 1990s. CMBs on paramagnetic-sensitive magnetic resonance sequences correspond pathologically to clusters of hemosiderin-laden macrophages and have emerged as an important new imaging marker of cerebral small vessel disease, including intracerebral hemorrhage (ICH). The prevalence of CMBs varies according to the specific disease settings (stroke subtypes and dementing disorders) and is highest (60%) in ICH patients. The associations of CMBs with aging, hypertension and apolipoprotein E genotype are consistent with the two major underlying pathogeneses of CMBs: hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). The distributional patterns of CMBs might help us to understand the predominant small vessel disease pathogenesis in the brain; the strictly lobar type of CMBs often reflects the presence of advanced CAA, while the other types of CMBs, such as 'deep or infratentorial CMBs', including the mixed type, are strongly associated with hypertension. CMBs might be associated with cognitive function (especially executive function), gait performance, and cerebrovascular events (spontaneous, antithrombotic drug-related or post-thrombolysis ICH). In the field of CAA, an understanding of CAA-related CMBs might help to guide decision making with regard to new therapeutic approaches, including the use of monoclonal antibodies against vascular amyloid. These concepts of CMBs might allow us to advance research on ICH as well as for dementia. PMID:26587900

  6. No Additional Prognostic Value of Genetic Information in the Prediction of Vascular Events after Cerebral Ischemia of Arterial Origin: The PROMISe Study

    PubMed Central

    Achterberg, Sefanja; Kappelle, L. Jaap; de Bakker, Paul I. W.; Traylor, Matthew; Algra, Ale

    2015-01-01

    Background Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events. PMID:25906364

  7. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    PubMed

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury.

  8. Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation.

    PubMed

    Fan, Tao; Jiang, Wei Long; Zhu, Jian; Feng Zhang, Yu

    2012-01-01

    Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

  9. Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation.

    PubMed

    Fan, Tao; Jiang, Wei Long; Zhu, Jian; Feng Zhang, Yu

    2012-01-01

    Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism. PMID:22972486

  10. Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia.

    PubMed

    Longhurst, Hilary

    2008-03-01

    Pharming NV and Esteve are developing Rhucin, a recombinant human C1 esterase inhibitor. Rhucin is currently undergoing phase III clinical trials in North America and is awaiting regulatory approval in Western Europe for the treatment of prophylactic and acute hereditary angioedema. Pharming is also investigating Rhucin for the potential treatment of cerebral ischemic injury. PMID:18311668

  11. Yifei Xuanfei Jiangzhuo formula, a Chinese herbal decoction, improves memory impairment through inhibiting apoptosis and enhancing PKA/CREB signal transduction in rats with cerebral ischemia/reperfusion

    PubMed Central

    WU, LIN; ZHAO, QING-SHAN; LI, TIAN-WEI; LI, HAI-YUAN; WANG, QING-BI; BI, XIN-YA; CAI, XIN-KUN; TANG, NONG

    2015-01-01

    Apoptosis and the dysfunction of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-responsive element binding protein (CREB) signaling pathway have a key role in memory impairment in vascular dementia (VaD), a challenging clinical problem. Yifei Xuanfei Jiangzhuo formula (YXJF), a Chinese herbal decoction, has been used to treat VaD in clinical practice and has produced positive outcomes; however, convincing evidence is currently lacking. The present study aimed to investigate the effects of YXJF on memory impairment in rats with cerebral ischemia/reperfusion and to explore the underlying mechanism. YXJF ameliorated memory impairment in rats with cerebral ischemia/reperfusion, inhibited hippocampal apoptosis in a dose-dependent manner and attenuated increases in the protein expression of B-cell lymphoma 2 (Bcl-2)-associated X protein as well as c-Jun and a reduction in Bcl-2 protein expression in the hippocampal tissue of the rats. Furthermore, administration of YXJF significantly increased the protein expression of PKA C-α and CREB, and promoted CREB phosphorylation. The results indicated that YXJF improves memory impairment through inhibiting apoptosis and enhancing PKA/CREB signal transduction in rats with cerebral ischemia/reperfusion. PMID:26094797

  12. Paeonia lactiflora Extract Attenuating Cerebral Ischemia and Arterial Intimal Hyperplasia Is Mediated by Paeoniflorin via Modulation of VSMC Migration and Ras/MEK/ERK Signaling Pathway

    PubMed Central

    Chen, Yuh-Fung; Wu, Kuo-Jen; Wood, W. Gibson

    2013-01-01

    Paeonia lactiflora is a well-known traditional Chinese medicine. Paeoniflorin is an active component found in Paeonia lactiflora, which is used to treat smooth muscle spasms and pain and to protect the cardiovascular system. The objective of this study was to determine if Paeonia lactiflora would be protective in rodent models of cerebral ischemia and arterial intimal hyperplasia. Paeonia lactiflora extract (PLex) and paeoniflorin (PF) significantly attenuated cerebral infarction in ischemia/reperfusion injury rats and the severity of intimal hyperplasia in mice where the carotid artery was ligated. PLex and PF reduced PDGF-stimulated VSMC proliferation and migration in a dose-dependent manner by MTT, wound healing, and transwell assays. PF significantly reduced protein levels of Ras, MEK, p-MEK and p-ERK, but not MMP-2 and MMP-9. In summary, Paeonia lactiflora reduced cerebral ischemia and arterial intimal hyperplasia which were mainly made via the intermediary of PF. The protective effect of PF was related to the modulation of the Ras/MEK/ERK signaling pathway. PMID:23818926

  13. Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia.

    PubMed

    Belisário, André Rolim; Sales, Rahyssa Rodrigues; Toledo, Nayara Evelin; Muniz, Maristela Braga de Sousa Rodrigues; Velloso-Rodrigues, Cibele; Silva, Célia Maria; Viana, Marcos Borato

    2016-10-01

    Stroke is a severe clinical manifestation of sickle cell anemia (SCA). Despite the prognostic relevance of transcranial Doppler (TCD), more accurate tools to assess stroke risk in children with SCA are required. Here, we describe the effect of clinical, laboratory, and molecular features on the risk of stroke and high-risk TCD in children from the newborn cohort of Minas Gerais, Brazil. Outcomes studied were acute cerebral ischemia and high-risk TCD. Clinical and hematological data were retrieved from children's records. Genetic markers, which were known for their association with stroke risk, were genotyped by polymerase chain reaction/restriction fragment length polymorphism and sequencing. The cumulative incidence of acute cerebral ischemia by the age of 8 years was 7.4 % and that of high-risk TCD by the age of 11.5 years was 14.2 %. The final multivariate model for acute cerebral ischemia risk included high white blood cell count and reticulocyte count, acute chest syndrome rate, and the single nucleotide polymorphisms (SNPs) TEK rs489347 and TNF-α rs1800629. The model for high-risk TCD included high reticulocyte count and the SNPs TEK rs489347 and TGFBR3 rs284875. Children with risk factors should be considered for intensive risk monitoring and for intervention therapy. PMID:27520094

  14. Ilexonin A Promotes Neuronal Proliferation and Regeneration via Activation of the Canonical Wnt Signaling Pathway after Cerebral Ischemia Reperfusion in Rats

    PubMed Central

    Zhang, Bi-Qin; Zheng, Guan-Yi; Han, Yu; Chen, Xiao-Dong; Jiang, Qiong

    2016-01-01

    Aims. Ilexonin A (IA), a component of the Chinese medicine Ilex pubescens, has been shown to be neuroprotective during ischemic injury. However, the specific mechanism underlying this neuroprotective effect remains unclear. Methods. In this study, we employed a combination of immunofluorescence staining, western blotting, RT-PCR, and behavioral tests, to investigate the molecular mechanisms involved in IA regulation of neuronal proliferation and regeneration after cerebral ischemia and reperfusion in rodents. Results. Increases in β-catenin protein and LEF1 mRNA and decreases in GSK3β protein and Axin mRNA observed in IA-treated compared to control rodents implicated the canonical Wnt pathway as a key signaling mechanism activated by IA treatment. Furthermore, rodents in the IA treatment group showed less neurologic impairment and a corresponding increase in the number of Brdu/nestin and Brdu/NeuN double positive neurons in the parenchymal ischemia tissue following middle cerebral artery occlusion compared to matched controls. Conclusion. Altogether, our data indicate that IA can significantly diminish neurological deficits associated with cerebral ischemia reperfusion in rats as a result of increased neuronal survival via modulation of the canonical Wnt pathway. PMID:27057202

  15. Reticulocyte count is the most important predictor of acute cerebral ischemia and high-risk transcranial Doppler in a newborn cohort of 395 children with sickle cell anemia.

    PubMed

    Belisário, André Rolim; Sales, Rahyssa Rodrigues; Toledo, Nayara Evelin; Muniz, Maristela Braga de Sousa Rodrigues; Velloso-Rodrigues, Cibele; Silva, Célia Maria; Viana, Marcos Borato

    2016-10-01

    Stroke is a severe clinical manifestation of sickle cell anemia (SCA). Despite the prognostic relevance of transcranial Doppler (TCD), more accurate tools to assess stroke risk in children with SCA are required. Here, we describe the effect of clinical, laboratory, and molecular features on the risk of stroke and high-risk TCD in children from the newborn cohort of Minas Gerais, Brazil. Outcomes studied were acute cerebral ischemia and high-risk TCD. Clinical and hematological data were retrieved from children's records. Genetic markers, which were known for their association with stroke risk, were genotyped by polymerase chain reaction/restriction fragment length polymorphism and sequencing. The cumulative incidence of acute cerebral ischemia by the age of 8 years was 7.4 % and that of high-risk TCD by the age of 11.5 years was 14.2 %. The final multivariate model for acute cerebral ischemia risk included high white blood cell count and reticulocyte count, acute chest syndrome rate, and the single nucleotide polymorphisms (SNPs) TEK rs489347 and TNF-α rs1800629. The model for high-risk TCD included high reticulocyte count and the SNPs TEK rs489347 and TGFBR3 rs284875. Children with risk factors should be considered for intensive risk monitoring and for intervention therapy.

  16. A novel inhibitor of advanced glycation and endoplasmic reticulum stress reduces infarct volume in rat focal cerebral ischemia.

    PubMed

    Takizawa, Shunya; Izuhara, Yuko; Kitao, Yasuko; Hori, Osamu; Ogawa, Satoshi; Morita, Yuko; Takagi, Shigeharu; van Ypersele de Strihou, Charles; Miyata, Toshio

    2007-12-01

    We have developed a novel, non-toxic inhibitor of advanced glycation and oxidative stress, TM2002, devoid of effect on blood pressure. In transient focal ischemia, TM2002 significantly decreased infarct volume compared with vehicle (79.5+/-18.7 vs. 183.3+/-22.9 mm3, p<0.01). In permanent focal ischemia, TM2002 (2.79, 5.58, and 11.16 mg/kg twice a day) dose-dependently reduced infarct volume (242.1+/-32.3, 201.3+/-15.1, and 171.3+/-15.2 mm3, respectively), and improved neurological deficits. Reduction of infarct volume is demonstrable, provided that TM2002 was administered within 1.5 h after the occlusion. To unravel TM2002's mechanism of action, we examined its in vitro effect on endoplasmic reticulum (ER) stress, using aortic smooth muscle cells isolated from ORP 150(+/-) mice and F9 Herp null mutated cells. Cell death induced by ER stress (tunicamycin or hypoxia) was dose-dependently prevented by TM2002. In vivo immunohistochemical study demonstrated a significant reduction of ORP- and TUNEL-positive apoptotic cells, especially in the penumbra. Inhibition of advanced glycation and oxidative stress was confirmed by a significantly reduced number of cells positive for advanced glycation end products and heme oxygenase-1. TM2002 reduced the levels of protein carbonyl formation in ischemic caudate. The efficacy of TM2002 is equivalent to that of a known neuroprotective agent, NXY-059. In conclusion, TM2002 significantly ameliorates ischemic cerebral damage through reduction of ER stress, advanced glycation, and oxidative stress, independently of blood pressure lowering.

  17. The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response.

    PubMed

    Xian, Wenjing; Wu, Yan; Xiong, Wei; Li, Longyan; Li, Tong; Pan, Shangwen; Song, Limin; Hu, Lisha; Pei, Lei; Yao, Shanglong; Shang, You

    2016-03-25

    Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brain tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. PMID:26915798

  18. Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase

    NASA Astrophysics Data System (ADS)

    Huang, Zhihong; Huang, Paul L.; Panahian, Nariman; Dalkara, Turgay; Fishman, Mark C.; Moskowitz, Michael A.

    1994-09-01

    The proposal that nitric oxide (NO) or its reactant products mediate toxicity in brain remains controversial in part because of the use of nonselective agents that block NO formation in neuronal, glial, and vascular compartments. In mutant mice deficient in neuronal NO synthase (NOS) activity, infarct volumes decreased significantly 24 and 72 hours after middle cerebral artery occlusion, and the neurological deficits were less than those in normal mice. This result could not be accounted for by differences in blood flow or vascular anatomy. However, infarct size in the mutant became larger after endothelial NOS inhibition by nitro-L-arginine administration. Hence, neuronal NO production appears to exacerbate acute ischemic injury, whereas vascular NO protects after middle cerebral artery occlusion. The data emphasize the importance of developing selective inhibitors of the neuronal isoform.

  19. Down-regulation of Bcl-2 in rat substantia nigra after focal cerebral ischemia.

    PubMed

    Arango-Dávila, Cesar A; Cardona-Gomez, Gloria P; Gallego-Gomez, Juan C; Garcia-Segura, Luis M; Pimienta, Hernán J

    2004-06-28

    After occlusion of the middle cerebral artery in rats, a robust neuronal loss occurs in the ipsilateral substantia nigra reticulata. In this study we have assessed whether degeneration of the substantia nigra is accompanied by changes in the expression of the anti-apoptotic protein Bcl-2. Neuronal loss was assessed by neuronal nuclei (NeuN) immunoreactivity. A significant decrease of Bcl-2 expression was observed in the substantia nigra 12, 24 and 72 h after middle cerebral artery occlusion. These results suggest that the secondary neuronal loss in the substantia nigra could be related with the modification of proteins regulating programmed cell death. Exo-focal cell death may explain the appearance of neuropsychiatric symptoms that are not correlated with the primary site of lesion.

  20. An effective solution to discover synergistic drugs for anti-cerebral ischemia from traditional Chinese medicinal formulae.

    PubMed

    Li, Shaojing; Wu, Chuanhong; Chen, Jianxin; Lu, Peng; Chen, Chang; Fu, Meihong; Fang, Jing; Gao, Jian; Zhu, Li; Liang, Rixin; Shen, Xin; Yang, Hongjun

    2013-01-01

    Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interestingly, combination therapies have been used for more than 2500 years in traditional Chinese medicine (TCM). Understanding optimal proportions and synergistic mechanisms of multi-component drugs are critical for developing novel strategies to combat complex diseases. A new multi-objective optimization algorithm based on least angle regression-partial least squares was proposed to construct the predictive model to evaluate the synergistic effect of the three components of a novel combination drug Yi-qi-jie-du formula (YJ), which came from clinical TCM prescription for the treatment of encephalopathy. Optimal proportion of the three components, ginsenosides (G), berberine (B) and jasminoidin (J) was determined via particle swarm optimum. Furthermore, the combination mechanisms were interpreted using PLS VIP and principal components analysis. The results showed that YJ had optimal proportion 3(G): 2(B): 0.5(J), and it yielded synergy in the treatment of rats impaired by middle cerebral artery occlusion induced focal cerebral ischemia. YJ with optimal proportion had good pharmacological effects on acute ischemic stroke. The mechanisms study demonstrated that the combination of G, B and J could exhibit the strongest synergistic effect. J might play an indispensable role in the formula, especially when combined with B for the acute stage of stroke. All these data in this study suggested that in the treatment of acute ischemic stroke, besides restoring blood supply and protecting easily damaged cells in the area of the ischemic penumbra as early as possible, we should pay more attention to the removal of the toxic metabolites at the same time. Mathematical system modeling may be an essential tool for the analysis of the complex pharmacological effects of multi-component drug. The powerful mathematical analysis method could greatly

  1. An Effective Solution to Discover Synergistic Drugs for Anti-Cerebral Ischemia from Traditional Chinese Medicinal Formulae

    PubMed Central

    Lu, Peng; Chen, Chang; Fu, Meihong; Fang, Jing; Gao, Jian; Zhu, Li; Liang, Rixin; Shen, Xin; Yang, Hongjun

    2013-01-01

    Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interest