Science.gov

Sample records for cerebral ischemia detected

  1. [Cerebral ischemia and histamine].

    PubMed

    Adachi, Naoto

    2002-10-01

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

  2. Automation of Classical QEEG Trending Methods for Early Detection of Delayed Cerebral Ischemia: More Work to Do.

    PubMed

    Wickering, Ellis; Gaspard, Nicolas; Zafar, Sahar; Moura, Valdery J; Biswal, Siddharth; Bechek, Sophia; OʼConnor, Kathryn; Rosenthal, Eric S; Westover, M Brandon

    2016-06-01

    The purpose of this study is to evaluate automated implementations of continuous EEG monitoring-based detection of delayed cerebral ischemia based on methods used in classical retrospective studies. We studied 95 patients with either Fisher 3 or Hunt Hess 4 to 5 aneurysmal subarachnoid hemorrhage who were admitted to the Neurosciences ICU and underwent continuous EEG monitoring. We implemented several variations of two classical algorithms for automated detection of delayed cerebral ischemia based on decreases in alpha-delta ratio and relative alpha variability. Of 95 patients, 43 (45%) developed delayed cerebral ischemia. Our automated implementation of the classical alpha-delta ratio-based trending method resulted in a sensitivity and specificity (Se,Sp) of (80,27)%, compared with the values of (100,76)% reported in the classic study using similar methods in a nonautomated fashion. Our automated implementation of the classical relative alpha variability-based trending method yielded (Se,Sp) values of (65,43)%, compared with (100,46)% reported in the classic study using nonautomated analysis. Our findings suggest that improved methods to detect decreases in alpha-delta ratio and relative alpha variability are needed before an automated EEG-based early delayed cerebral ischemia detection system is ready for clinical use.

  3. Oligodendrogenesis after cerebral ischemia

    PubMed Central

    Zhang, Ruilan; Chopp, Michael; Zhang, Zheng Gang

    2013-01-01

    Neural stem cells in the subventricular zone (SVZ) of the lateral ventricle of adult rodent brain generate oligodendrocyte progenitor cells (OPCs) that disperse throughout the corpus callosum and striatum where some of OPCs differentiate into mature oligodendrocytes. Studies in animal models of stroke demonstrate that cerebral ischemia induces oligodendrogenesis during brain repair processes. This article will review evidence of stroke-induced proliferation and differentiation of OPCs that are either resident in white matter or are derived from SVZ neural progenitor cells and of therapies that amplify endogenous oligodendrogenesis in ischemic brain. PMID:24194700

  4. Different CT perfusion algorithms in the detection of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

    PubMed

    Cremers, Charlotte H P; Dankbaar, Jan Willem; Vergouwen, Mervyn D I; Vos, Pieter C; Bennink, Edwin; Rinkel, Gabriel J E; Velthuis, Birgitta K; van der Schaaf, Irene C

    2015-05-01

    Tracer delay-sensitive perfusion algorithms in CT perfusion (CTP) result in an overestimation of the extent of ischemia in thromboembolic stroke. In diagnosing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH), delayed arrival of contrast due to vasospasm may also overestimate the extent of ischemia. We investigated the diagnostic accuracy of tracer delay-sensitive and tracer delay-insensitive algorithms for detecting DCI. From a prospectively collected series of aSAH patients admitted between 2007-2011, we included patients with any clinical deterioration other than rebleeding within 21 days after SAH who underwent NCCT/CTP/CTA imaging. Causes of clinical deterioration were categorized into DCI and no DCI. CTP maps were calculated with tracer delay-sensitive and tracer delay-insensitive algorithms and were visually assessed for the presence of perfusion deficits by two independent observers with different levels of experience. The diagnostic value of both algorithms was calculated for both observers. Seventy-one patients were included. For the experienced observer, the positive predictive values (PPVs) were 0.67 for the delay-sensitive and 0.66 for the delay-insensitive algorithm, and the negative predictive values (NPVs) were 0.73 and 0.74. For the less experienced observer, PPVs were 0.60 for both algorithms, and NPVs were 0.66 for the delay-sensitive and 0.63 for the delay-insensitive algorithm. Test characteristics are comparable for tracer delay-sensitive and tracer delay-insensitive algorithms for the visual assessment of CTP in diagnosing DCI. This indicates that both algorithms can be used for this purpose.

  5. [Prothrombotic states and cerebral ischemia].

    PubMed

    Barinagarrementeria, F; González-Duarte, A; Cantú-Brito, C

    1998-01-01

    Hematological disorders per se represent unusual causes of cerebral ischemia, explaining in young people 4% of strokes. Hematological disorders that induce a thrombotic tendency contribute to overall ischemic stroke risk and may directly cause cerebral ischemia in patients without other risk factors. The frequency of cerebral infarctions caused by prothrombotic states is not known. This review will focus on disorders such as prothrombotic coagulopaties, including resistance to activated protein C and antiphospholipid syndrome as cause of cerebral infarction. Cerebral venous thrombosis and cerebral infarction from arterial origin are the most common form of neurological involvement. Pathophysiological mechanism of stroke in these patients are multiple and can include as in antiphospholipid syndrome embolism from valves abnormalities related to hematological disturbance, as well as thrombosis of extracranial or intracranial vessels. Is clear, however, that prothrombotic states could explains a high percentage of cases of those so called cryptogenic cerebral infarction in young people.

  6. CT perfusion for detection of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

    PubMed

    Mir, D I A; Gupta, A; Dunning, A; Puchi, L; Robinson, C L; Epstein, H-A B; Sanelli, P C

    2014-05-01

    Delayed cerebral ischemia is a significant cause of morbidity and mortality after aneurysmal SAH, leading to poor outcomes. The purpose of this study was to evaluate the usefulness of CTP in determining delayed cerebral ischemia in patients with aneurysmal SAH. We conducted a systematic review evaluating studies that assessed CTP in patients with aneurysmal SAH for determining delayed cerebral ischemia. Studies using any of the following definitions of delayed cerebral ischemia were included in the systematic review: 1) new onset of clinical deterioration, 2) cerebral infarction identified on follow-up CT or MR imaging, and 3) functional disability. A random-effects meta-analysis was performed assessing the strength of association between a positive CTP result and delayed cerebral ischemia. The systematic review identified 218 studies that met our screening criteria, of which 6 cohort studies met the inclusion criteria. These studies encompassed a total of 345 patients, with 155 (45%) of 345 patients classified as having delayed cerebral ischemia and 190 (55%) of 345 patients as not having delayed cerebral ischemia. Admission disease severity was comparable across all groups. Four cohort studies reported CTP test characteristics amenable to the meta-analysis. The weighted averages and ranges of the pooled sensitivity and specificity of CTP in the determination of delayed cerebral ischemia were 0.84 (0.7-0.95) and 0.77 (0.66-0.82), respectively. The pooled odds ratio of 23.14 (95% CI, 5.87-91.19) indicates that patients with aneurysmal SAH with positive CTP test results were approximately 23 times more likely to experience delayed cerebral ischemia compared with patients with negative CTP test results. Perfusion deficits on CTP are a significant finding in determining delayed cerebral ischemia in aneurysmal SAH. This may be helpful in identifying patients with delayed cerebral ischemia before development of infarction and neurologic deficits. © 2014 by American

  7. Sirt1 in cerebral ischemia

    PubMed Central

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

    2015-01-01

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

  8. 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.

  9. Rodent models of cerebral ischemia

    SciTech Connect

    Ginsberg, M.D.; Busto, R. )

    1989-12-01

    The use of physiologically regulated, reproducible animal models is crucial to the study of ischemic brain injury--both the mechanisms governing its occurrence and potential therapeutic strategies. Several laboratory rodent species (notably rats and gerbils), which are readily available at relatively low cost, are highly suitable for the investigation of cerebral ischemia and have been widely employed for this purpose. We critically examine and summarize several rodent models of transient global ischemia, resulting in selective neuronal injury within vulnerable brain regions, and focal ischemia, typically giving rise to localized brain infarction. We explore the utility of individual models and emphasize the necessity for meticulous experimental control of those variables that modulate the severity of ischemic brain injury.169 references.

  10. Ultra-early Detection of Microcirculatory Injury as Predictor of Developing Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage.

    PubMed

    Gölitz, Philipp; Hoelter, Philip; Rösch, Julie; Roessler, Karl; Knossalla, Frauke; Doerfler, Arnd

    2017-08-15

    Delayed cerebral ischemia (DCI) still remains a major complication after subarachnoid hemorrhage (SAH). The aim of our study was to evaluate whether flow analysis of admission digital subtraction angiography (DSA) using parametric color coding (PCC), a postprocessing algorithm, allows ultra-early identification of SAH patients at risk for developing subsequent symptomatic vasospasm. In this study 52 patients who suffered SAH from aneurysm rupture, were retrospectively enrolled. Of the patients 26 developed DCI and angiographically proven cerebral vasospasm and 26 age, gender-and clinical status-matched SAH patients without DCI served as controls. Using PCC, the following flow parameters were calculated: cerebral circulation time (CirT), cortical relative time to peak (rTTP) and microvascular transit time (TT). Mean cerebral CirT and cortical rTTP were longer in the DCI group (6.42 s ± 1.54 and 3.16 s ± 0.86, respectively) than in the non-DCI group (5.77 s ± 1.86 and 3.11 s ± 1.41, respectively), but without statistical significance. The mean microvascular TT was statistically significantly (p = 0.04) longer in the DCI group (3.19 s ± 0.78) than in the non-DCI group (2.67 s ± 0.73). Angiographic flow analysis might be suitable for ultra-early detection and quantitative assessment of microcirculatory injury in SAH patients, predictive of developing subsequent DCI. Prolonged microvascular TT seems to be a significant independent factor positively associated with DCI development. Identifying SAH patients at risk for DCI ultra-early after ictus might contribute to initiate prophylactic therapies before clinical deterioration.

  11. 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.

  12. Mitochondrial Targeted Antioxidant in Cerebral Ischemia.

    PubMed

    Ahmed, Ejaz; Donovan, Tucker; Yujiao, Lu; Zhang, Quanguang

    There has been much evidence suggesting that reactive oxygen species (ROS) generated in mitochondria during cerebral ischemia play a major role in programming the senescence of organism. Antioxidants dealing with mitochondria slow down the appearance and progression of symptoms in cerebral ischemia and increase the life span of organisms. The mechanisms of mitochondrial targeted antioxidants, such as SKQ1, Coenzyme Q10, MitoQ, and Methylene blue, include increasing adenosine triphosphate (ATP) production, decreasing production of ROS and increasing antioxidant defenses, providing benefits in neuroprotection following cerebral ischemia. A number of studies have shown the neuroprotective role of these mitochondrial targeted antioxidants in cerebral ischemia. Here in this short review we have compiled the literature supporting consequences of mitochondrial dysfunction, and the protective role of mitochondrial targeted antioxidants.

  13. 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.

  14. 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.

  15. Cumulative Effect of Repeated Brief Cerebral Ischemia

    DTIC Science & Technology

    1993-05-31

    KL, Pohost GM and Conger KA, Correlating EEG and Lactate Kinetics During Repeated Brief Cerebral Ischemia, Proceedings of the American Heart Association 1993...Cornelating EEG and Lactate Kinetics During Repeated Brief Cerebral Ischemia, Proceedings of the American Heart Association 1993. 4) HP Hetherington...thes Bernhard Foundation. ass- 134 󈧑&.1 n5. 9# American Heart Association 026085 66th Scientific Sessions Abstract Form Medical Research Nursing

  16. Enhanced detection of paroxysmal atrial fibrillation by early and prolonged continuous holter monitoring in patients with cerebral ischemia presenting in sinus rhythm.

    PubMed

    Stahrenberg, Raoul; Weber-Krüger, Mark; Seegers, Joachim; Edelmann, Frank; Lahno, Rosine; Haase, Beatrice; Mende, Meinhard; Wohlfahrt, Janin; Kermer, Pawel; Vollmann, Dirk; Hasenfuss, Gerd; Gröschel, Klaus; Wachter, Rolf

    2010-12-01

    Diagnosis of paroxysmal atrial fibrillation is difficult but highly relevant in patients presenting with cerebral ischemia yet free from atrial fibrillation on admission. Early initiation and prolongation of continuous Holter monitoring may improve diagnostic yield compared with the standard of care including a 24-hour Holter recording. In the observational Find-AF trial (ISRCTN 46104198), consecutive patients presenting with symptoms of cerebral ischemia were included. Patients free from atrial fibrillation at presentation received 7-day Holter monitoring. Two hundred eighty-one patients were prospectively included. Forty-four (15.7%) had atrial fibrillation documented by routine electrocardiogram on admission. All remaining patients received Holter monitors at a median of 5.5 hours after presentation. In those 224 patients who received Holter monitors but had no previously known paroxysmal atrial fibrillation, the detection rate with early and prolonged (7 days) Holter monitoring (12.5%) was significantly higher than for any 24-hour (mean of 7 intervals: 4.8%, P = 0.015) or any 48-hour monitoring interval (mean of 6 intervals: 6.4%, P = 0.023). Of those 28 patients with new atrial fibrillation on Holter monitoring, 15 (6.7%) had been discharged without therapeutic anticoagulation after routine clinical care (ie, with data from 24-hour Holter monitoring only). Detection rates were 43.8% or 6.3% for short supraventricular runs of ≥ 10 beats or prolonged episodes (> 5 hours) of atrial fibrillation, respectively. Diagnostic yield appeared to be only slightly and not significantly increased during the first 3 days after the index event. Prolongation of Holter monitoring in patients with symptoms of cerebral ischemic events increases the rate of detection of paroxysmal atrial fibrillation up to Day 7, leading to a relevant change in therapy in a substantial number of patients. Early initiation of monitoring does not appear to be crucial. Hence, prolonged Holter

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

    PubMed

    Putilina, M V

    2015-01-01

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

  18. 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

  19. Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: A systematic review and diagnostic test accuracy meta-analysis.

    PubMed

    Katsanos, Aristeidis H; Psaltopoulou, Theodora; Sergentanis, Theodoros N; Frogoudaki, Alexandra; Vrettou, Agathi-Rosa; Ikonomidis, Ignatios; Paraskevaidis, Ioannis; Parissis, John; Bogiatzi, Chrysa; Zompola, Christina; Ellul, John; Triantafyllou, Nikolaos; Voumvourakis, Konstantinos; Kyritsis, Athanassios P; Giannopoulos, Sotirios; Alexandrov, Anne W; Alexandrov, Andrei V; Tsivgoulis, Georgios

    2016-04-01

    Patent foramen ovale (PFO) can be detected in up to 43% of patients with cryptogenic cerebral ischemia undergoing investigation with transesophageal echocardiography (TEE). The diagnostic value of transthoracic echocardiography (TTE) in the detection of PFO in patients with cryptogenic ischemic stroke or transient ischemic attack has not been compared with that of transcranial Doppler (TCD) using a comprehensive meta-analytical approach. We performed a systematic literature review to identify all prospective observational studies of patients with cryptogenic cerebral ischemia that provided both sensitivity and specificity measures of TTE, TCD, or both compared to the gold standard of TEE. Our literature search identified 35 eligible studies including 3,067 patients. The pooled sensitivity and specificity for TCD was 96.1% (95% confidence interval [CI] = 93.0-97.8%) and 92.4% (95% CI = 85.5-96.1%), whereas the respective measures for TTE were 45.1% (95% CI = 30.8-60.3%) and 99.6% (95% CI = 96.5-99.9%). TTE was superior in terms of higher positive likelihood ratio values (LR+ = 106.61, 95% CI = 15.09-753.30 for TTE vs LR+ = 12.62, 95% CI = 6.52-24.43 for TCD; p = 0.043), whereas TCD demonstrated lower negative likelihood values (LR- = 0.04, 95% CI = 0.02-0.08) compared to TTE (LR- = 0.55, 95% CI = 0.42-0.72; p < 0.001). Finally, the area under the summary receiver operating curve (AUC) was significantly greater (p < 0.001) in TCD (AUC = 0.98, 95% CI = 0.97-0.99) compared to TTE studies (AUC = 0.86, 95% CI = 0.82-0.89). TCD is more sensitive but less specific compared to TTE for the detection of PFO in patients with cryptogenic cerebral ischemia. The overall diagnostic yield of TCD appears to outweigh that of TTE. © 2016 American Neurological Association.

  20. Encephaloduroarteriosynangiosis for cerebral proliferative angiopathy with cerebral ischemia.

    PubMed

    Kono, Kenichi; Terada, Tomoaki

    2014-12-01

    Cerebral proliferative angiopathy (CPA) is a rare clinical entity. This disorder is characterized by diffuse vascular abnormalities with intermingled normal brain parenchyma, and is differentiated from classic arteriovenous malformations. The management of CPA in patients presenting with nonhemorrhagic neurological deficits due to cerebral ischemia is challenging and controversial. The authors report a case of adult CPA with cerebral ischemia in which neurological deficits were improved after encephaloduroarteriosynangiosis (EDAS). A 28-year-old man presented with epilepsy. Magnetic resonance imaging and angiography showed a diffuse vascular network (CPA) in the right hemisphere. Antiepileptic medications were administered. Four years after the initial onset of epilepsy, the patient's left-hand grip strength gradually decreased over the course of 1 year. The MRI studies showed no infarcts, but technetium-99m-labeled ethyl cysteinate dimer ((99m)Tc-ECD) SPECT studies obtained with acetazolamide challenge demonstrated hypoperfusion and severely impaired cerebrovascular reactivity over the affected hemisphere. This suggested that the patient's neurological deficits were associated with cerebral ischemia. The authors performed EDAS for cerebral ischemia, and the patient's hand grip strength gradually improved after the operation. Follow-up angiography studies obtained 7 months after the operation showed profound neovascularization through the superficial temporal artery and the middle meningeal artery. A SPECT study showed slight improvement of hypoperfusion at the focal region around the right motor area, indicating clinical improvement from the operation. The authors conclude that EDAS may be a treatment option for CPA-related hypoperfusion.

  1. Magnetic resonance imaging detection of multiple ischemic injury produced in an adult rat model of minor stroke followed by mild transient cerebral ischemia.

    PubMed

    Tuor, Ursula I; Qiao, Min

    2017-04-01

    To determine whether cumulative brain damage produced adjacent to a minor stroke that is followed by a mild transient ischemia is detectable with MRI and histology, and whether acute or chronic recovery between insults influences this damage. A minor photothrombotic (PT) stroke was followed acutely (1-2 days) or chronically (7 days) by a mild transient middle cerebral artery occlusion (tMCAO). MRI was performed after each insult, followed by final histology. The initial PT produced small hyperintense T2 and DW infarct lesions and peri-lesion regions of scattered necrosis and modestly increased T2. Following tMCAO, in a slice and a region adjacent to the PT, a region of T2 augmentation was observed when recovery between insults was acute but not chronic. Within the PT slice, a modest region of exacerbated T2 change proximate to the PT was also observed in the chronic group. Corresponding histological changes within regions of augmented T2 included increased vacuolation and cell death. Within regions adjacent to an experimental minor stroke, a recurrence of a mild transient cerebral ischemia augmented T2 above increases produced by tMCAO alone, reflecting increased damage in this region. Exacerbation appeared broader with acute versus chronic recovery between insults.

  2. 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.

  3. Glibenclamide in cerebral ischemia and stroke.

    PubMed

    Simard, J Marc; Sheth, Kevin N; Kimberly, W Taylor; Stern, Barney J; del Zoppo, Gregory J; Jacobson, Sven; Gerzanich, Volodymyr

    2014-04-01

    The sulfonylurea receptor 1 (Sur1)-transient receptor potential 4 (Trpm4) channel is an important molecular element in focal cerebral ischemia. The channel is upregulated in all cells of the neurovascular unit following ischemia, and is linked to microvascular dysfunction that manifests as edema formation and secondary hemorrhage, which cause brain swelling. Activation of the channel is a major molecular mechanism of cytotoxic edema and "accidental necrotic cell death." Blockade of Sur1 using glibenclamide has been studied in different types of rat models of stroke: (i) in conventional non-lethal models (thromboembolic, 1-2 h temporary, or permanent middle cerebral artery occlusion), glibenclamide reduces brain swelling and infarct volume and improves neurological function; (ii) in lethal models of malignant cerebral edema, glibenclamide reduces edema, brain swelling, and mortality; (iii) in models with rtPA, glibenclamide reduces swelling, hemorrhagic transformation, and death. Retrospective studies of diabetic patients who present with stroke have shown that those whose diabetes is managed with a sulfonylurea drug and who are maintained on the sulfonylurea drug during hospitalization for stroke have better outcomes at discharge and are less likely to suffer hemorrhagic transformation. Here, we provide a comprehensive review of the basic science, preclinical experiments, and retrospective clinical studies on glibenclamide in focal cerebral ischemia and stroke. We also compare the preclinical work in stroke models to the updated recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR). The findings reviewed here provide a strong foundation for a translational research program to study glibenclamide in patients with ischemic stroke.

  4. Epigenetic mechanisms in cerebral ischemia

    PubMed Central

    Schweizer, Sophie; Meisel, Andreas; Märschenz, Stefanie

    2013-01-01

    Treatment efficacy for ischemic stroke represents a major challenge. Despite fundamental advances in the understanding of stroke etiology, therapeutic options to improve functional recovery remain limited. However, growing knowledge in the field of epigenetics has dramatically changed our understanding of gene regulation in the last few decades. According to the knowledge gained from animal models, the manipulation of epigenetic players emerges as a highly promising possibility to target diverse neurologic pathologies, including ischemia. By altering transcriptional regulation, epigenetic modifiers can exert influence on all known pathways involved in the complex course of ischemic disease development. Beneficial transcriptional effects range from attenuation of cell death, suppression of inflammatory processes, and enhanced blood flow, to the stimulation of repair mechanisms and increased plasticity. Most striking are the results obtained from pharmacological inhibition of histone deacetylation in animal models of stroke. Multiple studies suggest high remedial qualities even upon late administration of histone deacetylase inhibitors (HDACi). In this review, the role of epigenetic mechanisms, including histone modifications as well as DNA methylation, is discussed in the context of known ischemic pathways of damage, protection, and regeneration. PMID:23756691

  5. 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

  6. 13-Methyltetradecanoic acid mitigates cerebral ischemia/reperfusion injury

    PubMed Central

    Yu, Juan; Yang, Li-nan; Wu, Yan-yun; Li, Bao-hua; Weng, Sheng-mei; Hu, Chun-lan; Han, Yong-ling

    2016-01-01

    13-Methyltetradecanoic acid can stabilize cell membrane and have anti-inflammatory, antioxidant and anti-apoptotic effects. Previous studies mainly focused on peripheral nerve injury, but seldom on the central nervous system. We investigated whether these properties of 13-methyltetradecanoic acid have a neuroprotective effect on focal cerebral ischemia/reperfusion injury, and detected the expression of basic fibroblast growth factor and vascular endothelial growth factor. This study established rat models of middle cerebral artery occlusion/reperfusion injury by ischemia for 2 hours and reperfusion for 24 hours. At the beginning of reperfusion, 13-methyltetradecanoic acid 10, 40 or 80 mg/kg was injected into the tail vein. Results found that various doses of 13-methyltetradecanoic acid effectively reduced infarct volume, mitigate cerebral edema, and increased the mRNA and protein expression of basic fibroblast growth factor and vascular endothelial growth factor at 24 hours of reperfusion. The effect was most significant in the 13-methyltetradecanoic acid 40 and 80 mg/kg groups. The findings suggest that 13-methyltetradecanoic acid can relieve focal ischemia/reperfusion injury immediately after reperfusion, stimulate the upregulation of basic fibroblast growth factor and vascular endothelial growth factor to exert neuroprotective effects. PMID:27857745

  7. Transient cerebral ischemia. Association of apoptosis induction with hypoperfusion.

    PubMed Central

    Vexler, Z S; Roberts, T P; Bollen, A W; Derugin, N; Arieff, A I

    1997-01-01

    Apoptosis is thought to be important in the pathogenesis of cerebral ischemia. The mechanism of apoptosis induction remains unclear but several studies suggest that it is preferentially triggered by mild/moderate microcirculatory disturbances. We examined in cats whether induction of apoptosis after 2.5 h of unilateral middle cerebral artery occlusion plus 10 h of reperfusion is influenced by the degree of cerebral microcirculatory disturbance. Quantitative monitoring over time of the disturbances of cerebral microcirculation in ischemic brain areas and evaluation of cytotoxic edema associated with perfusion deficits was achieved by using two noninvasive magnetic resonance imaging techniques: (a) high-speed echo planar imaging combined with a bolus of magnetic susceptibility contrast agent; and (b) diffusion-weighted imaging. Apoptosis-positive cells were counted in anatomic areas with different severity of ischemic injury characterized by magnetic resonance imaging, triphenyltetrazolium chloride, and hemotoxylin and eosin staining. The number of apoptosis-positive cells was significantly higher in anatomic areas with severe perfusion deficits during occlusion and detectable histologic changes 10 h after reperfusion. In contrast, in areas where perfusion was reduced but maintained during occlusion there were no detectable histological changes and significantly fewer apoptosis-positive cells. A similar number of cells that undergo apoptosis were shown in regions with transient or prolonged subtotal perfusion deficits. These results suggest that the apoptotic process is induced in the ischemic core and contributes significantly in the degeneration of neurons associated with transient ischemia. PMID:9077555

  8. Nonhuman primate models of focal cerebral ischemia

    PubMed Central

    Fan, Jingjing; Li, Yi; Fu, Xinyu; Li, Lijuan; Hao, Xiaoting; Li, Shasha

    2017-01-01

    Rodents have been widely used in the production of cerebral ischemia models. However, successful therapies have been proven on experimental rodent stroke model, and they have often failed to be effective when tested clinically. Therefore, nonhuman primates were recommended as the ideal alternatives, owing to their similarities with the human cerebrovascular system, brain metabolism, grey to white matter ratio and even their rich behavioral repertoire. The present review is a thorough summary of ten methods that establish nonhuman primate models of focal cerebral ischemia; electrocoagulation, endothelin-1-induced occlusion, microvascular clip occlusion, autologous blood clot embolization, balloon inflation, microcatheter embolization, coil embolization, surgical suture embolization, suture, and photochemical induction methods. This review addresses the advantages and disadvantages of each method, as well as precautions for each model, compared nonhuman primates with rodents, different species of nonhuman primates and different modeling methods. Finally it discusses various factors that need to be considered when modelling and the method of evaluation after modelling. These are critical for understanding their respective strengths and weaknesses and underlie the selection of the optimum model. PMID:28400817

  9. 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

  10. 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.

  11. Temperature modulation of cerebral depolarization during focal cerebral ischemia in rats: correlation with ischemic injury.

    PubMed

    Chen, Q; Chopp, M; Bodzin, G; Chen, H

    1993-05-01

    The role of cerebral depolarizations in focal cerebral ischemia is unknown. We therefore measured the direct current (DC) electrical activity in the cortex of Wistar rats subjected to transient occlusion of the middle cerebral artery (MCA). Focal ischemia was induced for 90 min by insertion of an intraluminal filament to occlude the MCA. To modulate cell damage, we subjected the rats to hypothermic (30 degrees C, n = 4), normothermic (37 degrees C, n = 4), and hyperthermic (40 degrees C, n = 6) ischemia. Controlled temperatures were also maintained during 1 h of reperfusion. Continuous cortical DC potential changes were measured using two active Ag-AgCl electrodes placed in the cortical lesion. Animals were killed 1 week after ischemia. The brains were sectioned and stained with hematoxylin and eosin, for evaluation of neuronal damage, and calculation of infarct volume. All animals exhibited an initial depolarization within 30 min of ischemia, followed by a single depolarization event in hypothermic animals, and multiple periodic depolarization events in both normothermic and hyperthermic animals. Hyperthermic animals exhibited significantly more (p < 0.05) DC potential deflections (n = 6.17 +/- 0.67) than normothermic animals (n = 2.75 +/- 0.96). The ischemic infarct volume (% of hemisphere) was significantly different for the various groups; hypothermic animals exhibited no measurable infarct volume, while the ischemic infarct volume was 10.2 +/- 12.3% in normothermic animals and 36.5 +/- 3.4% in hyperthermic animals (p < 0.05). A significant correlation was detected between the volume of infarct and number of depolarization events (r = 0.90, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Effect of retinoic acid on expression of LINGO-1 and neural regeneration after cerebral ischemia.

    PubMed

    Xing, Hong-yi; Meng, Er-yan; Xia, Yuan-peng; Peng, Hai

    2015-02-01

    The purpose of this study was to observe the expression of LINGO-1 after cerebral ischemia, investigate the effects of retinoic acid (RA) on the expression of LINGO-1 and GAP-43, and the number of synapses, and to emplore the repressive effect of LINGO-1 on neural regeneration after cerebral ischemia. The model of permanent focal cerebral ischemia was established by the modified suture method of middle cerebral artery occlusion (MCAO) in Sprague-Dawley (SD) rats. The expression of LINGO-1 was detected by Western blotting and that of GAP-43 by immunohistochemistry. The number of synapses was observed by transmission electron microscopy. The SD rats were divided into three groups: sham operation (sham) group, cerebral ischemia (CI) group and RA treatment (RA) group. The results showed that the expression level of LINGO-1 at 7th day after MCAO in sham, CI and RA groups was 0.266 ± 0.019, 1.215 ± 0.063 and 0.702 ± 0.081, respectively (P<0.01). The number of Gap-43-positive nerve cells at 7th day after MCAO in sham, CI and RA group was 0, 59.08 ± 1.76 and 76.20 ± 3.12 per high power field, respectively (P<0.05). The number of synapses at 7th day after MCAO was 8.42 ± 0.13, 1.74 ± 0.37 and 5.39 ± 0.26 per μm², respectively (P<0.05). It is concluded that LINGO-1 expression is up-regulated after cerebral ischemia, and RA inhibits the expression of LINGO-1, promotes the expression of GAP-43 and increases the number of synapses. It suggests that LINGO-1 may be involved in the pathogenesis of cerebral ischemia, which may provide an experimenal basis for LINGO-1 antogonist, RA, for the treatment of cerebral ischemia.

  13. Rat model of focal cerebral ischemia in the dominant hemisphere

    PubMed Central

    Zhang, Hua; Shen, Yan; Wang, Wei; Gao, Huanmin

    2015-01-01

    In the human brain, the dominant hemisphere is more complex than the non-dominant hemisphere. Hence, cerebral ischemia of the dominant hemisphere often leads to serious consequences. This study aims to establish a rodent model of focal cerebral ischemia in the dominant hemisphere. The quadruped feeding test was used to screen 70 male Sprague Dawley rats. From this test, 48 rats with right paw preference were selected and randomly assigned numbers. Half were assigned to the dominant hemisphere ischemia (DHI) group, and the other half were assigned to the non-dominant hemisphere ischemia (NDHI) group. The middle cerebral artery was occluded 2 h before reperfusion. Neurological functions were tested. TTC and HE staining were performed. The volume of cerebral infarction was calculated. Rats in the DHI group had significantly worse neurological scores than rats in the NDHI group (P < 0.05). TTC staining indicated ischemia had more severe consequences in the dominant hemisphere than in the non-dominant hemisphere. The dominant hippocampus indicated severe neuronal loss and disorderly cellular arrangement. The volume of cerebral infarction was also greater in the DHI group compared to the NDHI group (P < 0.05). Compared to MCA occlusion in the non-dominant hemisphere, MCA occlusion in the dominant hemisphere caused greater impairment in neurological functions. The proposed rodent model is reliable and has high levels of reproducibility. Therefore, his model can be reliably for investigating the mechanism of focal cerebral ischemia in the dominant hemisphere of human brains. PMID:25785023

  14. Neuroprotective effects of rutaecarpine on cerebral ischemia reperfusion injury

    PubMed Central

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

    2013-01-01

    Rutaecarpine, an active component of the traditional Chinese medicine Tetradium ruticarpum, has been shown to improve myocardial ischemia reperfusion injury. Because both cardiovascular and cerebrovascular diseases are forms of ischemic vascular disease, they are closely related. We hypothesized that rutaecarpine also has neuroprotective effects on cerebral ischemia reperfusion injury. A cerebral ischemia reperfusion model was established after 84, 252 and 504 μg/kg carpine were given to mice via intraperitoneal injection, daily for 7 days. Results of the step through test, 2,3,5-triphenyl tetrazolium chloride dyeing and oxidative stress indicators showed that rutaecarpine could improve learning and memory ability, neurological symptoms and reduce infarction volume and cerebral water content in mice with cerebral ischemia reperfusion injury. Rutaecarpine could significantly decrease the malondialdehyde content and increase the activities of superoxide dismutase and glutathione peroxidase in mouse brain. Therefore, rutaecarpine could improve neurological function following injury induced by cerebral ischemia reperfusion, and the mechanism of this improvement may be associated with oxidative stress. These results verify that rutaecarpine has neuroprotective effects on cerebral ischemia reperfusion in mice. PMID:25206511

  15. 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

  16. 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).

  17. Alterations of interneurons of the gerbil hippocampus after transient cerebral ischemia: effect of pitavastatin.

    PubMed

    Himeda, Toshiki; Hayakawa, Natsumi; Tounai, Hiroko; Sakuma, Mio; Kato, Hiroyuki; Araki, Tsutomu

    2005-11-01

    We investigated the immunohistochemical alterations of parvalbumin (PV)-expressing interneurons in the hippocampus after transient cerebral ischemia in gerbils in comparison with neuronal nitric oxide synthase (nNOS)-expressing interneurons. We also examined the effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin against the damage of neurons and interneurons in the hippocampus after cerebral ischemia. Severe neuronal damage was observed in the hippocampal CA1 pyramidal neurons 5 and 14 days after ischemia. The PV immunoreactivity was unchanged up to 2 days after ischemia. At 5 and 14 days after ischemia, in contrast, a conspicuous reduction of PV immunoreactivity was observed in interneurons of the hippocampal CA1 sector. Furthermore, a significant decrease of PV immunoreactivity was found in interneurons of the hippocampal CA3 sector. No damage of nNOS-immunopositive interneurons was detected in the gerbil hippocampus up to 1 day after ischemia. Thereafter, a decrease of nNOS immunoreactive interneurons was found in the hippocampal CA1 sector up to 14 days after ischemia. Pitavastatin significantly prevented the neuronal cell loss in the hippocampal CA1 sector 5 days after ischemia. Our immunohistochemical study also showed that pitavastatin prevented significant decrease of PV- and nNOS-positive interneurons in the hippocampus after ischemia. Double-labeled immunostainings showed that PV immunoreactivity was not found in nNOS-immunopositive interneurons of the brain. The present study demonstrates that cerebral ischemia can cause a loss of both PV- and nNOS-immunoreactive interneurons in the hippocampal CA1 sector. Our findings also show that the damage to nNOS-immunopositive interneurons may precede the neuronal cell loss in the hippocampal CA1 sector after ischemia and nNOS-positive interneurons may play some role in the pathogenesis of cerebral ischemic diseases. Furthermore, our present study indicates that pitavastatin can

  18. Neuroprotection by Alpha 2-Adrenergic Agonists in Cerebral Ischemia

    PubMed Central

    Zhang, Yonghua; Kimelberg, Harold K.

    2005-01-01

    Ischemic brain injury is implicated in the pathophysiology of stroke and brain trauma, which are among the top killers worldwide, and intensive studies have been performed to reduce neural cell death after cerebral ischemia. Alpha 2-adrenergic agonists have been shown to improve the histomorphological and neurological outcome after cerebral ischemic injury when administered during ischemia, and recent studies have provided considerable evidence that alpha 2-adrenergic agonists can protect the brain from ischemia/reperfusion injury. Thus, alpha 2-adrenergic agonists are promising potential drugs in preventing cerebral ischemic injury, but the mechanisms by which alpha 2-adrenergic agonists exert their neuroprotective effect are unclear. Activation of both the alpha 2-adrenergic receptor and imidazoline receptor may be involved. This mini review examines the recent progress in alpha 2-adrenergic agonists - induced neuroprotection and its proposed mechanisms in cerebral ischemic injury. PMID:18369397

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

    PubMed

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

    2005-01-01

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

  20. 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.

  1. Neuroprotective effect of penehyclidine hydrochloride on focal cerebral ischemia-reperfusion injury★

    PubMed Central

    Yu, Cuicui; Wang, Junke

    2013-01-01

    Penehyclidine hydrochloride can promote microcirculation and reduce vascular permeability. However, the role of penehyclidine hydrochloride in cerebral ischemia-reperfusion injury remains unclear. In this study, in vivo middle cerebral artery occlusion models were established in experimental rats, and penehyclidine hydrochloride pretreatment was given via intravenous injection prior to model establishment. Tetrazolium chloride, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and immunohistochemical staining showed that, penehyclidine hydrochloride pretreatment markedly attenuated neuronal histopathological changes in the cortex, hippocampus and striatum, reduced infarction size, increased the expression level of Bcl-2, decreased the expression level of caspase-3, and inhibited neuronal apoptosis in rats with cerebral ischemia-reperfusion injury. Xanthine oxidase and thiobarbituric acid chromogenic results showed that penehyclidine hydrochloride upregulated the activity of superoxide dismutase and downregulated the concentration of malondialdehyde in the ischemic cerebral cortex and hippocampus, as well as reduced the concentration of extracellular excitatory amino acids in rats with cerebral ischemia-reperfusion injury. In addition, penehyclidine hydrochloride inhibited the expression level of the NR1 subunit in hippocampal nerve cells in vitro following oxygen-glucose deprivation, as detected by PCR. Experimental findings indicate that penehyclidine hydrochloride attenuates neuronal apoptosis and oxidative stress injury after focal cerebral ischemia-reperfusion, thus exerting a neuroprotective effect. PMID:25206707

  2. Multislice diffusion mapping for 3-D evolution of cerebral ischemia in a rat stroke model.

    PubMed

    Reith, W; Hasegawa, Y; Latour, L L; Dardzinski, B J; Sotak, C H; Fisher, M

    1995-01-01

    Diffusion-weighted magnetic resonance imaging (DWI) can quantitatively demonstrate cerebral ischemia within minutes after the onset of ischemia. The use of a DWI echo-planar multislice technique in this study and the mapping of the apparent diffusion coefficient (ADC) of water, a reliable indicator of ischemic regions, allow for the detection of the three-dimensional (3-D) evolution of ischemia in a rat stroke model. We evaluated 13 time points from 5 to 180 minutes after occlusion of the middle cerebral artery (MCA) and monitored the 3-D spread of ischemia. Within 5 minutes after the onset of ischemia, regions with reduced ADC values occurred. The core of the lesion, with the lowest absolute ADC values, first appeared in the lateral caudoputamen and frontoparietal cortex, then spread to adjacent areas. The volume of ischemic tissue was 224 +/- 48.5 mm3 (mean +/- SEM) after 180 minutes, ranging from 92 to 320 mm3, and this correlated well with the corrected infarct volume at postmortem (194 +/- 23.1 mm3, r = 0.72, p < 0.05). This experiment demonstrated that 3-D multislice diffusion mapping can detect ischemic regions noninvasively 5 minutes after MCA occlusion and follow the development of ischemia. The distribution of changes in absolute ADC values within the ischemic region can be followed over time, giving important information about the evolution of focal ischemia.

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

    PubMed

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

    1992-05-01

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

  4. The protective role of heme oxygenase-1 in cerebral ischemia.

    PubMed

    Aztatzi-Santillán, Emmanuel; Nares-López, Felipe Eduardo; Márquez-Valadez, Berenice; Aguilera, Penélope; Chánez-Cárdenas, María Elena

    2010-12-01

    Cerebral ischemia is one of the leading causes of death and disability in industrialized countries, with no curative treatments to date. Identification of potential targets and elucidation of their physiological role under stress conditions may give support to the development of drugs and strategies to contend with this pathology. In the last years, Heme oxygenase-1 (HO-1) has been considered by many groups as a potential target in ischemic damage. HO-1 is the enzyme responsible for the conversion of the heme group to billiverdin, carbon monoxide and iron; a highly regulated cytoprotective enzyme able to respond to numerous chemical or physical stressors, many of which decrease oxygen availability and generate oxidative stress. The disruption of HO-1 activity has been widely associated with a bad outcome in many disorders, and a protective role through its heme catabolism products has been observed in transplantation, cardiac ischemia, limb ischemia/reperfusion and different alterations that involve ischemia and reperfusion events. Here, we review recent reports supporting the protective role of HO-1 in cerebral ischemia. Results on the endogenous HO-1 response, overexpression of HO-1 and compounds that reduce ischemic damage through the induction of HO-1 in cerebral ischemia in in vivo and in vitro models are analyzed.

  5. Management of delayed cerebral ischemia after subarachnoid hemorrhage.

    PubMed

    Francoeur, Charles L; Mayer, Stephan A

    2016-10-14

    For patients who survive the initial bleeding event of a ruptured brain aneurysm, delayed cerebral ischemia (DCI) is one of the most important causes of mortality and poor neurological outcome. New insights in the last decade have led to an important paradigm shift in the understanding of DCI pathogenesis. Large-vessel cerebral vasospasm has been challenged as the sole causal mechanism; new hypotheses now focus on the early brain injury, microcirculatory dysfunction, impaired autoregulation, and spreading depolarization. Prevention of DCI primarily relies on nimodipine administration and optimization of blood volume and cardiac performance. Neurological monitoring is essential for early DCI detection and intervention. Serial clinical examination combined with intermittent transcranial Doppler ultrasonography and CT angiography (with or without perfusion) is the most commonly used monitoring paradigm, and usually suffices in good grade patients. By contrast, poor grade patients (WFNS grades 4 and 5) require more advanced monitoring because stupor and coma reduce sensitivity to the effects of ischemia. Greater reliance on CT perfusion imaging, continuous electroencephalography, and invasive brain multimodality monitoring are potential strategies to improve situational awareness as it relates to detecting DCI. Pharmacologically-induced hypertension combined with volume is the established first-line therapy for DCI; a good clinical response with reversal of the presenting deficit occurs in 70 % of patients. Medically refractory DCI, defined as failure to respond adequately to these measures, should trigger step-wise escalation of rescue therapy. Level 1 rescue therapy consists of cardiac output optimization, hemoglobin optimization, and endovascular intervention, including angioplasty and intra-arterial vasodilator infusion. In highly refractory cases, level 2 rescue therapies are also considered, none of which have been validated. This review provides an overview of

  6. Changes of c-fos, malondialdehyde and lactate in brain tissue after global cerebral ischemia under different brain temperatures.

    PubMed

    Zhang, Hong; Li, Li; Xu, Guo-ying; Mei, Yuan-wu; Zhang, Jun-jian; Murong, Shen-xing; Sun, Sheng-gang; Tong, E-tang

    2014-06-01

    Under global cerebral ischemia, the effect of different brain temperature on cerebral ischemic injury was studied. Male Sprague-Dawley rats were divided into normothermic (37-38°C) ischemia, mild hypothermic (31-32°C) ischemia, hyperthermic (41-42°C) ischemia and sham-operated groups. Global cerebral ischemia was established using the Pulsinelli four-vessel occlusion model and brain temperature was maintained at defined level for 60 min after 20-min ischemia. The expression of c-fos protein and the levels of malondialdehyde (MDA) and lactate in brain regions were detected by immunochemistry and spectrophotometrical methods, respectively. C-fos positive neurons were found in the hippocampus and cerebral cortex after cerebral ischemia reperfusion. Mild hypothermia increased the expression of c-fos protein in both areas, whereas hyperthermia decreased the expression of c-fos protein in the hippocampus at 24 h reperfusion, and the cerebral cortex at 48 h reperfusion when compared to normothermic conditions. In normothermic, mild hypothermic and hyperthermic ischemia groups, the levels of MDA and lactate in brain tissue were increased at 24, 48 and 72 h reperfusion following 20-min ischemia as compared with the sham-operated group (P<0.01). The levels of MDA and lactate in mild hypothermic group were significantly lower than those in normothermic group (P<0.01). It is suggested that brain temperature influences the translation of the immunoreactive protein product of c-fos after global cerebral ischemia, and MDA and lactate are also affected by hypothermia and hyperthermia.

  7. Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats.

    PubMed

    Chang, Cheng-Yi; Kao, Tsung-Kuei; Chen, Wen-Ying; Ou, Yen-Chuan; Li, Jian-Ri; Liao, Su-Lan; Raung, Shue-Ling; Chen, Chun-Jung

    2015-07-31

    Experimental studies have demonstrated the beneficial effects of tetramethylpyrazine (TMP) against ischemic stroke and highlighted its crucial role in anti-inflammatory activity. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its anti-inflammatory action against ischemic brain injury. We report a global inhibitory effect of TMP on inflammatory cell intracerebral activation and infiltration in a rat model of permanent cerebral ischemia. The results of immunohistochemistry, enzymatic assay, flow cytometric analysis, and cytological analysis revealed that intraperitoneal TMP administration reduced neuronal loss, macrophage/microglia activation, brain parenchyma infiltrative neutrophils, and circulating neutrophils after cerebral ischemia. Biochemical studies of cultured neutrophils further demonstrated that TMP attenuated neutrophil migration, endothelium adhesion, spontaneous nitric oxide (NO) production, and stimuli-activated NO production after cerebral ischemia. In parallel with these anti-neutrophil phenomena, TMP also attenuated the activities of ischemia-induced inflammation-associated signaling molecules, including plasma high-mobility group box-1 protein (HMGB1) and neutrophil toll-like receptor-4 (TLR4), Akt, extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase. Another finding in this study was that the anti-neutrophil effect of TMP was accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in neutrophils after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous anti-inflammatory defense capacity and the attenuation of pro-inflammatory responses via targeting of circulating neutrophils by elevating Nrf2/HO-1 expression and inhibiting HMGB1/TLR4, Akt, and ERK signaling might actively contribute to TMP-mediated neuroprotection against cerebral ischemia.

  8. Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis.

    PubMed

    Jeong, Ji Heun; Yu, Kwang Sik; Bak, Dong Ho; Lee, Je Hun; Lee, Nam Seob; Jeong, Young Gil; Kim, Dong Kwan; Kim, Jwa-Jin; Han, Seung-Yun

    2016-11-01

    Previous studies have demonstrated that autophagy induced by caloric restriction (CR) is neuroprotective against cerebral ischemia. However, it has not been determined whether intermittent fasting (IF), a variation of CR, can exert autophagy-related neuroprotection against cerebral ischemia. Therefore, the neuroprotective effect of IF was evaluated over the course of two weeks in a rat model of focal cerebral ischemia, which was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). Specifically, the role of autophagy modulation as a potential underlying mechanism for this phenomenon was investigated. It was demonstrated that IF reduced infarct volume and brain edema, improved neurobehavioral deficits, and rescued neuronal loss after MCAO/R. Furthermore, neuronal apoptosis was decreased by IF in the rat cortex. An increase in the number of autophagosomes (APs) was demonstrated in the cortices of IF-treated rats, using immunofluorescence staining and transmission electron microscopy. Using immunoblots, an IF-induced increase was detected in microtubule-associated protein 1 light chain 3 (LC3)-II, Rab7, and cathepsin D protein levels, which corroborated previous morphological studies. Notably, IF reduced the accumulation of APs and p62, demonstrating that IF attenuated the MCAO/R-induced disturbance of autophagic flux in neurons. The findings of the present study suggest that IF-induced neuroprotection in focal cerebral ischemia is due, at least in part, to the minimization of autophagic flux disturbance and inhibition of apoptosis.

  9. Intermittent fasting is neuroprotective in focal cerebral ischemia by minimizing autophagic flux disturbance and inhibiting apoptosis

    PubMed Central

    Jeong, Ji Heun; Yu, Kwang Sik; Bak, Dong Ho; Lee, Je Hun; Lee, Nam Seob; Jeong, Young Gil; Kim, Dong Kwan; Kim, Jwa-Jin; Han, Seung-Yun

    2016-01-01

    Previous studies have demonstrated that autophagy induced by caloric restriction (CR) is neuroprotective against cerebral ischemia. However, it has not been determined whether intermittent fasting (IF), a variation of CR, can exert autophagy-related neuroprotection against cerebral ischemia. Therefore, the neuroprotective effect of IF was evaluated over the course of two weeks in a rat model of focal cerebral ischemia, which was induced by middle cerebral artery occlusion and reperfusion (MCAO/R). Specifically, the role of autophagy modulation as a potential underlying mechanism for this phenomenon was investigated. It was demonstrated that IF reduced infarct volume and brain edema, improved neurobehavioral deficits, and rescued neuronal loss after MCAO/R. Furthermore, neuronal apoptosis was decreased by IF in the rat cortex. An increase in the number of autophagosomes (APs) was demonstrated in the cortices of IF-treated rats, using immunofluorescence staining and transmission electron microscopy. Using immunoblots, an IF-induced increase was detected in microtubule-associated protein 1 light chain 3 (LC3)-II, Rab7, and cathepsin D protein levels, which corroborated previous morphological studies. Notably, IF reduced the accumulation of APs and p62, demonstrating that IF attenuated the MCAO/R-induced disturbance of autophagic flux in neurons. The findings of the present study suggest that IF-induced neuroprotection in focal cerebral ischemia is due, at least in part, to the minimization of autophagic flux disturbance and inhibition of apoptosis. PMID:27882110

  10. Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

    PubMed Central

    Gulati, Anil

    2016-01-01

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

  11. Monocarboxylate transporter 4 plays a significant role in the neuroprotective mechanism of ischemic preconditioning in transient cerebral ischemia

    PubMed Central

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

    2015-01-01

    Monocarboxylate transporters (MCTs), which carry monocarboxylates such as lactate across biological membranes, have been associated with cerebral ischemia/reperfusion process. In this study, we studied the effect of ischemic preconditioning (IPC) on MCT4 immunoreactivity after 5 minutes of transient cerebral ischemia in the gerbil. Animals were randomly designated to four groups (sham-operated group, ischemia only group, IPC + sham-operated group and IPC + ischemia group). A serious loss of neuron was found in the stratum pyramidale of the hippocampal CA1 region (CA1), not CA2/3, of the ischemia-only group at 5 days post-ischemia; however, in the IPC + ischemia groups, neurons in the stratum pyramidale of the CA1 were well protected. Weak MCT4 immunoreactivity was found in the stratum pyramidale of the CA1 in the sham-operated group. MCT4 immunoreactivity in the stratum pyramidale began to decrease at 2 days post-ischemia and was hardly detected at 5 days post-ischemia; at this time point, MCT4 immunoreactivity was newly expressed in astrocytes. In the IPC + sham-operated group, MCT4 immunoreactivity in the stratum pyramidale of the CA1 was increased compared with the sham-operated group, and, in the IPC + ischemia group, MCT4 immunoreactivity was also increased in the stratum pyramidale compared with the ischemia only group. Briefly, present findings show that IPC apparently protected CA1 pyramidal neurons and increased or maintained MCT4 expression in the stratum pyramidale of the CA1 after transient cerebral ischemia. Our findings suggest that MCT4 appears to play a significant role in the neuroprotective mechanism of IPC in the gerbil with transient cerebral ischemia. PMID:26692857

  12. Mechanisms of Acupuncture Therapy for Cerebral Ischemia: an Evidence-Based Review of Clinical and Animal Studies on Cerebral Ischemia.

    PubMed

    Zhu, Wen; Ye, Yang; Liu, Yi; Wang, Xue-Rui; Shi, Guang-Xia; Zhang, Shuai; Liu, Cun-Zhi

    2017-05-19

    Ischemic stroke is a major cause of mortality and disability worldwide. As a part of Traditional Chinese Medicine (TCM), acupuncture has been shown to be effective in promoting recovery after stroke. In this article, we review the clinical and experimental studies that demonstrated the mechanisms of acupuncture treatment for cerebral ischemia. Clinical studies indicated that acupuncture activated relevant brain regions, modulated cerebral blood flow and related molecules in stroke patients. Evidence from laboratory indicated that acupuncture regulates cerebral blood flow and metabolism after the interrupt of blood supply. Acupuncture regulates multiple molecules and signaling pathways that lead to excitoxicity, oxidative stress, inflammation, neurons death and survival. Acupuncture also promotes neurogenesis, angiogenesis as well as neuroplasticity after ischemic damage. The evidence provided from clinical and laboratory suggests that acupuncture induces multi-level regulation via complex mechanisms and a single factor may not be enough to explain the beneficial effects against cerebral ischemia.

  13. [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.

  14. Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia.

    PubMed

    Pinto, M C X; Simão, F; da Costa, F L P; Rosa, D V; de Paiva, M J N; Resende, R R; Romano-Silva, M A; Gomez, M V; Gomez, R S

    2014-06-20

    Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by sarcosine, a GlyT-1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7 days (300 or 500 mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by sarcosine preconditioning. However, sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Neuroprotective Effects of Pregabalin on Cerebral Ischemia and Reperfusion.

    PubMed

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

    2016-03-01

    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. 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. Animal experimentation. 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. 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). Pregabalin may protect the damage of oxidative stress after ischemia + reperfusion. This result would illuminate clinical studies in the future.

  16. 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

  17. Control of cerebral ischemia with magnetic nanoparticles.

    PubMed

    Jia, Jie-Min; Chowdary, Praveen D; Gao, Xiaofei; Ci, Bo; Li, Wenjun; Mulgaonkar, Aditi; Plautz, Erik J; Hassan, Gedaa; Kumar, Amit; Stowe, Ann M; Yang, Shao-Hua; Zhou, Wei; Sun, Xiankai; Cui, Bianxiao; Ge, Woo-Ping

    2017-02-01

    The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

  18. Mitochondrial Dynamics Following Global Cerebral Ischemia

    PubMed Central

    Kumar, Rita; Bukowski, Melissa J.; Wider, Joseph M.; Reynolds, Christian A.; Calo, Lesley; Lepore, Bradley; Tousignant, Renee; Jones, Michelle; Przyklenk, Karin; Sanderson, Thomas H.

    2016-01-01

    Global brain ischemia/reperfusion induces neuronal damage in vulnerable brain regions, leading to mitochondrial dysfunction and subsequent neuronal death. Induction of neuronal death is mediated by release of cytochrome c (cyt c) from the mitochondria though a well-characterized increase in outer mitochondrial membrane permeability. However, for cyt c to be released it is first necessary for cyt c to be liberated from the cristae junctions which are gated by Opa1 oligomers. Opa1 has two known functions: maintenance of the cristae junction and mitochondrial fusion. These roles suggest that Opa1 could play a central role in both controlling cyt c release and mitochondrial fusion/fission processes during ischemia/reperfusion. To investigate this concept, we first utilized in vitro real-time imaging to visualize dynamic changes in mitochondria. Oxygen-glucose deprivation (OGD) of neurons grown in culture induced a dual-phase mitochondrial fragmentation profile: (i) fragmentation during OGD with no apoptosis activation, followed by fusion of mitochondrial networks after reoxygenation and a (ii) subsequent extensive fragmentation and apoptosis activation that preceded cell death. We next evaluated changes in mitochondrial dynamic state during reperfusion in a rat model of global brain ischemia. Evaluation of mitochondrial morphology with confocal and electron microscopy revealed a similar induction of fragmentation following global brain ischemia. Mitochondrial fragmentation aligned temporally with specific apoptotic events, including cyt c release, caspase 3/7 activation, and interestingly, release of the fusion protein Opa1. Moreover, we uncovered evidence of loss of Opa1 complexes during the progression of reperfusion, and electron microscopy micrographs revealed a loss of cristae architecture following global brain ischemia. These data provide novel evidence implicating a temporal connection between Opa1 alterations and dysfunctional mitochondrial dynamics following

  19. Effectiveness of sugammadex for cerebral ischemia/reperfusion injury.

    PubMed

    Ozbilgin, Sule; Yılmaz, Osman; Ergur, Bekir Ugur; Hancı, Volkan; Ozbal, Seda; Yurtlu, Serhan; Gunenc, Sakize Ferim; Kuvaki, Bahar; Kucuk, Burcu Ataseven; Sisman, Ali Rıza

    2016-06-01

    Cerebral ischemia may cause permanent brain damage and behavioral dysfunction. The efficacy and mechanisms of pharmacological treatments administered immediately after cerebral damage are not fully known. Sugammadex is a licensed medication. As other cyclodextrins have not passed the necessary phase tests, trade preparations are not available, whereas sugammadex is frequently used in clinical anesthetic practice. Previous studies have not clearly described the effects of the cyclodextrin family on cerebral ischemia/reperfusion (I/R) damage. The aim of this study was to determine whether sugammadex had a neuroprotective effect against transient global cerebral ischemia. Animals were assigned to control, sham-operated, S 16 and S 100 groups. Transient global cerebral ischemia was induced by 10-minute occlusion of the bilateral common carotid artery, followed by 24-hour reperfusion. At the end of the experiment, neurological behavior scoring was performed on the rats, followed by evaluation of histomorphological and biochemical measurements. Sugammadex 16 mg/kg and 100 mg/kg improved neurological outcome, which was associated with reductions in both histological and neurological scores. The hippocampus TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) and caspase results in the S 16 and S 100 treatment groups were significantly lower than those of the I/R group. Neurological scores in the treated groups were significantly higher than those of the I/R group. The study showed that treatment with 16 mg/kg and 100 mg/kg sugammadex had a neuroprotective effect in a transient global cerebral I/R rat model. However, 100 mg/kg sugammadex was more neuroprotective in rats. Copyright © 2016. Published by Elsevier Taiwan.

  20. Effect of minocycline on cerebral ischemia-reperfusion injury★

    PubMed Central

    Zheng, Yuanyin; Xu, Lijuan; Yin, Jinbao; Zhong, Zhichao; Fan, Hongling; Li, Xi; Chang, Quanzhong

    2013-01-01

    Minocylcine, a tetracycline derivate, has been shown to cross the blood-brain barrier and enter the central nervous system. In this study, cerebral ischemia-reperfusion injury models were established using the suture method, and minocycline was immediately injected intraperitoneally after cerebral ischemia-reperfusion (22.5 mg/kg, initially 45 mg/kg) at a 12-hour interval. Results showed that after minocycline treatment, the volume of cerebral infarction was significantly reduced, the number of surviving cell in the hippocampal CA1 region increased, the number of apoptotic cells decreased, the expression of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein was down-regulated, and the escape latency in the water maze test was significantly shortened compared with the ischemia-reperfusion group. Our experimental findings indicate that minocycline can protect against neuronal injury induced by focal ischemia-reperfusion, which may be mediated by the inhibition of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 protein expression. PMID:25206381

  1. Effect of the reperfusion after cerebral ischemia in neonatal rats using MRI monitoring.

    PubMed

    Fau, Sebastien; Po, Chrystelle; Gillet, Brigitte; Sizonenko, Stephane; Mariani, Jean; Meric, Philippe; Charriaut-Marlangue, Christiane

    2007-12-01

    Cerebral hypoxia-ischemia is an important cause of brain injury in the newborn infant. Our purpose was to study magnetic resonance (MR) imaging changes in P7 rat brains submitted to permanent or reversible ischemia. Ischemia was induced by permanent electro-cauterization of the middle cerebral artery combined with a permanent or a transient (50 min) common carotid artery occlusion. The early events during ischemia and reperfusion were investigated by T2-weighted images (T2WI) at 1 and 3 h and by serial diffusion-weighted images (DWI) during 3 h in a 7 T magnet with a standard weighted diffusion sequence (b=1282.04 s mm(-2)) and a SEMS sequence. Within the first hour after MCA occlusion, the T2WI areas of contrast enhancement increased to a mean volume of 12.9+/-6.4%, a steady state still detected at 3 h after the ischemic onset (10.5+/-2.5%). Contrast enhancement in DWI increased as soon as 15 min of ischemia in all animals up to 50 min after CCA occlusion. In permanent ischemia, DWI abnormalities volume then increased more slowly from 50 min to 3 h after CCA occlusion (+25%, n=5). In reversible ischemia, the DWI abnormalities volume either moderately decreased and reached a plateau (-8.4%, n=4) or dramatically decreased (-53.0%, n=3). Both T2WI and DWI evidenced a "patchy" pattern of recovery as also shown on cresyl violet-stained sections. In contrast to the adult, early ischemic injury in P7 rat brains is detected as an increase in hyper-intensities both in T2WI and DWI. Our data indicate that reperfusion is able to block edema evolution after neonatal stroke and that early T2WI and more accurately DWI allow to distinguish between different patterns of injury in reversible ischemia.

  2. In situ detection of neuronal DNA strand breaks using the Klenow fragment of DNA polymerase I reveals different mechanisms of neuron death after global cerebral ischemia.

    PubMed

    Jin, K; Chen, J; Nagayama, T; Chen, M; Sinclair, J; Graham, S H; Simon, R P

    1999-03-01

    Ischemic cell injury in the brain may involve a cascade of programmed cell death. DNA damage may be either a catalyst or a consequence of this cascade. Therefore, the induction of DNA strand breaks in the rat brain following transient global ischemia was examined using (a) the Klenow labeling assay, identifying DNA single-strand breaks (SSBs) or double-strand breaks (DSBs) with protruding 5' termini, and (b) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), detecting DNA DSBs with protruding 3' termini or blunt ends. Klenow-positive staining occurred within 2 h of reperfusion and increased with increasing durations of reperfusion. DNA damage detected with the Klenow labeling assay preceded that of TUNEL expression in the caudate putamen, reticular thalamus, thalamus, and cortex. However, in CA1, DNA SSBs were not detected until 72 h of reperfusion and occurred simultaneously with DSBs. Thus, the time course and fragmentation characteristics of DNA damage differ between the hippocampal CA1 and other selectively vulnerable brain regions. This distinct pattern suggests that the delayed neuronal death in CA1 following transient global ischemia may occur via an apoptotic mechanism different from that of other brain regions.

  3. 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.

  4. Maturation Phenomenon in Cerebral Ischemia IV

    DTIC Science & Technology

    2001-01-01

    of gonads and/or neurons. This study evaluated the existence of age-related changes in transcriptional expression of HSC70, HSP72 , and c-fos mRNA...young animals compared with that in adult animals showed: (1) more rapid and /or prolonged expression of HSC70, HSP72 , and c-fos mRNAs; (2) a marked...induction of HSP72 protein; and (3) enhanced pyramidal cell survival. The observed endogenous ’tolerance’ of CA1 neurons in young gerbils to ischemia/reperfusion injury may be related to the expression of HSC70, HSP72 and c-fos.

  5. Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia.

    PubMed

    Chi, O Z; Barsoum, S; Vega-Cotto, N M; Jacinto, E; Liu, X; Mellender, S J; Weiss, H R

    2016-03-01

    Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia-reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1h and reperfusion for 2h with and without rapamycin (20mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C(14)-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5±0.8% control vs. 21.5±0.9% rapamycin). We also found that ischemia-reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia-reperfusion.

  6. White Matter Hyperintensity Burden and Susceptibility to Cerebral Ischemia

    PubMed Central

    Rost, Natalia S; Fitzpatrick, Kaitlin; Biffi, Alessandro; Kanakis, Allison; Devan, William; Anderson, Christopher D.; Cortellini, Lynelle; Furie, Karen L; Rosand, Jonathan

    2010-01-01

    Background and Purpose White matter hyperintensity (WMH) burden increases risk of ischemic stroke; furthermore, it predicts infarct growth in acute cerebral ischemia. We hypothesized that WMH would be less severe in patients with transient ischemic attack (TIA), as compared to those with acute ischemic stroke (AIS) and completed infarct. Methods Cases (TIA, n=30) and controls (AIS, n=120) were selected from an ongoing longitudinal cohort study of patients with stroke and matched for age, gender, and race/ethnicity. All subjects had brain MRI within 48 hours of presentation to evaluate for acute cerebral ischemia. WMH burden on MRI was quantified using a validated computer-assisted program with high inter-rater reliability. Results Median WMH in individuals with TIA was 3.7 cm3 (IQR 1.5 - 8.33cm3) compared to 6.9 cm3 (IQR 3.1 - 11.9 cm3) in AIS (p<0.04). In multivariable analysis, the odds of completed infarct were higher (OR 2.19, 95% CI 1.27 - 3.77, p<0.005) in subjects with larger volumes of WMH. Conclusions WMH burden was significantly less in subjects with TIA as opposed to ischemic stroke. These data provide further evidence to support a detrimental role of WMH burden on the capacity of cerebral tissue to survive acute ischemia. PMID:20947843

  7. Heme oxygenase-2 is neuroprotective in cerebral ischemia.

    PubMed Central

    Doré, S.; Sampei, K.; Goto, S.; Alkayed, N. J.; Guastella, D.; Blackshaw, S.; Gallagher, M.; Traystman, R. J.; Hurn, P. D.; Koehler, R. C.; Snyder, S. H.

    1999-01-01

    Heme oxygenase (HO) is believed to be a potent antioxidant enzyme in the nervous system; it degrades heme from heme-containing proteins, giving rise to carbon monoxide, iron, and biliverdin, which is rapidly reduced to bilirubin. The first identified isoform of the enzyme, HO1, is an inducible heat-shock protein expressed in high levels in peripheral organs and barely detectable under normal conditions in the brain, whereas HO2 is constitutive and most highly concentrated in the brain. Interestingly, although HO2 is constitutively expressed, its activity can be modulated by phosphorylation. We demonstrated that bilirubin, formed from HO2, is neuroprotectant, as neurotoxicity is augmented in neuronal cultures from mice with targeted deletion of HO2 (HO2(-/-)) and reversed by low concentrations of bilirubin. We now show that neural damage following middle cerebral artery occlusion (MCAO) and reperfusion, a model of focal ischemia of vascular stroke, is substantially worsened in HO2(-/-) animals. By contrast, stroke damage is not significantly altered in HO1(-/-) mice, despite their greater debility. Neural damage following intracranial injections of N-methyl-d-aspartate (NMDA) is also accentuated in HO2(-/-) animals. These findings establish HO2 as an endogenous neuroprotective system in the brain whose pharmacologic manipulation may have therapeutic relevance. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:10602774

  8. Cerebral ischemia induces transcription of inflammatory and extracellular-matrix-related genes in rat cerebral arteries.

    PubMed

    Vikman, Petter; Ansar, Saema; Henriksson, Marie; Stenman, Emelie; Edvinsson, Lars

    2007-12-01

    Cerebral ischemia results in a local inflammatory response that contributes to the size of the lesion, however, the involvement of the cerebral vasculature is unknown. We hypothesise that the expression of inflammatory genes (Il6, iNOS, cxcl2, TNF-alpha and Il-1beta) and extracellular-matrix-related genes (MMP9, MMP13) is induced in cerebral arteries following cerebral ischemia via activation of mitogen activated kinases (MAPKs). This hypothesis was tested in vivo by experimental subarachnoid haemorrhage (SAH) and temporal middle cerebral artery occlusion (MCAO), and by organ culture of isolated cerebral arteries with quantitative real time PCR (mRNA expression) and immunohistochemistry (localization of protein expression). The gene promoters were investigated in silica with computer analysis. The mRNA analysis revealed that the ischemic models, SAH and MCAO, as well as organ culture of isolated cerebral arteries resulted in transcriptional upregulation of the abovementioned genes. The protein expression involved phosphorylation of three different MAPKs signalling pathways (p38, ERK 1/2 and SAPK/JNK) and the downstream transcription factors (ATF-2, Elk-1, c-Jun) shown by immunohistochemistry and quantified by image analysis. All three models revealed the same pattern of activation in the cerebrovascular smooth muscle cells. The in silica analysis demonstrated binding sites for said transcription factors. The results suggest that cerebral ischemia and organ culture induce activation of p38, ERK 1/2 and SAPK/JNK in cerebral arteries which in turn activate the transcription factors ATF-2, Elk-1 and c-Jun and the expression of inflammatory and extracellular-matrix-related genes in the wall of cerebral arteries.

  9. 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.

  10. [Histopathologic comparison of dexmedetomidine's and thiopental's cerebral protective effects on focal cerebral ischemia in rats].

    PubMed

    Çanakçı, Ebru; Özmen, Sevilay Akalp; Çolak, Mustafa Ferhat; Kürşad, Hüsnü

    This study was designed to investigate whether dexmedetomidine and thiopental have cerebral protective effects after focal cerebral ischemia in rats. Thirty male Sprague Dawley rats were randomly assigned to three groups: control group (Group C, n=10), dexmedetomidine group (Group D, n=10), thiopental group (Group T, n=10). After all rats were anesthetized, they were intubated, then mechanically ventilated. A catheter was inserted into the right femoral artery for continuous mean arterial pressure, physiological parameters and blood sampling at baseline, 5min after occlusion and 20min after reperfusion. A catheter was inserted into the left femoral vein for intravenous (IV) medication administration. Right common carotid artery of each rat was isolated and clamped for 45min. At the end of the duration common carotid artery were unclamped and the brain reperfusion was achieved for 90min. Dexmedetomidine was administered for Group D IV infusion, and Group T received thiopental IV. According to histopathologic scores cerebral ischemia was documented in all rats in Group C, but no ischemia was found in three rats in Group T and in four rats in Group D. Grade 3 cerebral ischemia was documented in three rats in Group C, and in only one rat in both groups T and D. For histopathologic grades the difference between Group T and Group D was not significant (p>0.05). But the differences between Group C and Group T (p<0.05) and Group C and Group D (p<0.01) were statically significant. In conclusion, we demonstrated that dexmedetomidine and thiopental have experimental histopathologic cerebral protective effects on experimental focal cerebral ischemia in rats. Copyright © 2015 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  11. X-Chromosome Dosage and the Response to Cerebral Ischemia

    PubMed Central

    Turtzo, L. Christine; Siegel, Chad; McCullough, Louise D.

    2011-01-01

    Gonadal hormones contribute to ischemic neuroprotection, but cannot fully explain the observed sexual dimorphism in stroke outcomes seen during life stages with low sex steroid hormones. Sex chromosomal complement (XX in females; XY in males) may also contribute to ischemic sexual dimorphism. A transient middle cerebral artery occlusion model was used to investigate the role of X chromosome dosage in female XX and XO littermates of two mouse strains (Paf and EdaTa). Cohorts of XX and XO gonadally intact, ovariectomized, and ovariectomized females supplemented with estrogen were examined. Infarct sizes were equivalent between ovariectomized XX and XO mice, between intact XX and XO mice, and between estrogen-supplemented ovariectomized XX and XO mice. This is the first study to investigate the role of sex chromosome dosage in the response to cerebral ischemia. Neither the number of X chromosomes, nor the parent of origin of the remaining X chromosome, had a significant effect on the degree of cerebral infarction after experimental stroke in adult female mice. Estrogen was protective against cerebral ischemia in both XX and XO mice. PMID:21917808

  12. Cumulative Effects of Repeated Brief Cerebral Ischemia

    DTIC Science & Technology

    1994-01-01

    Lactate in the Isolated , Perfused Dog Brain during Anoxia and Postanoxic Recovery, J. Biol. Chem., 248:2489-2496 1975. 8) Nilsson B, Norberg K...Flexible System of Enzy-1 8.6 15.4 matic Analysis, New York, Academic Press, pp 174-177 2 10.9 10.8 Lowry OH, Passonneau JV, Hasselberger FX, Schulz DW 3...Nilsson B, Norberg K, Nordstrom CH, Siesjo BK (1975) Rate of 7 7.9 9.1 energy utilization in the cerebral cortex of rats. Acta Physiol14.5 8.5 Scand 93:569

  13. Blood free Radicals Concentration Determined by Electron Paramagnetic Resonance Spectroscopy and Delayed Cerebral Ischemia Occurrence in Patients with Aneurysmal Subarachnoid Hemorrhage.

    PubMed

    Ewelina, Grzywna; Krzysztof, Stachura; Marek, Moskala; Krzysztof, Kruczala

    2017-09-25

    Pathophysiology of delayed cerebral ischemia and cerebral vasospasm following aneurysmal subarachnoid hemorrhage is still poorly recognized, however free radicals are postulated as one of the crucial players. This study was designed to scrutinize whether the concentration of free radicals in the peripheral venous blood is related to the occurrence of delayed cerebral ischemia associated with cerebral vasospasm. Twenty-four aneurysmal subarachnoid hemorrhage patients and seven patients with unruptured intracranial aneurysm (control group) have been studied. Free radicals in patients' blood have been detected by the electron paramagnetic resonance (CMH.HCl spin probe, 150 K, ELEXSYS E500 spectrometer) on admission and at least 72 h from disease onset. Delayed cerebral ischemia monitoring was performed by daily neurological follow-up and transcranial color coded Doppler. Delayed cerebral ischemia observed in six aneurysmal subarachnoid hemorrhage patients was accompanied by cerebral vasospasm in all six cases. No statistically significant difference in average free radicals concentration between controls and study subgroups was noticed on admission (p = .3; Kruskal-Wallis test). After 72 h free radicals concentration in delayed cerebral ischemia patients (3.19 ± 1.52 mmol/l) differed significantly from the concentration in aneurysmal subarachnoid hemorrhage patients without delayed cerebral ischemia (0.65 ± 0.37 mmol/l) (p = .012; Mann-Whitney test). These findings are consistent with our assumptions and seem to confirm the role of free radicals in delayed cerebral ischemia development. Preliminary results presented above are promising and we need perform further investigation to establish whether blood free radicals concentration may serve as the biomarker of delayed cerebral ischemia associated with cerebral vasospasm.

  14. [Intermittent focal cerebral ischemia in hypotension due to pacemaker syndrome].

    PubMed

    Hagendorff, A; Pizzulli, L; Dettmers, C; Block, A; Omran, H; Hartmann, A; Manz, M; Lüderitz, B

    1994-12-01

    A pacemaker syndrome manifested as transient sensoric aphasia in a 68-year-old woman with a VVI-pace-maker implanted after SA-block. The attack occurred during long-term blood pressure recording and Holter monitoring. Borderline hypotension was documented during ventricular pacing which induced a retrograde excitation of the atrium. Clinical investigations excluded any intracranial abnormality, any source of embolism or stenosis of extra- and intracranial cerebral arteries. Cerebral blood flow measurements revealed a significant increase during pacing at elevated heart rate. Therefore, a device for AV-sequential pacing was implanted and basic pacing rate was elevated. The present case report indicates that focal and not only global cerebral ischemia can be produced by an impairment of systemic hemodynamics due to hypotension and a pacemaker syndrome. Improvement of cerebral blood flow during pacing is an unexpected finding contrasting with the concept of autoregulation. In addition, pacemaker implantation should be discussed in patients with transient cerebral perfusion deficits if an improvement of cerebral blood flow is documented along with rising heart rate.

  15. [Mesoglycan in acute focal cerebral ischemia].

    PubMed

    Cazzato, G; Zorzon, M; Masé, G; Antonutti, L; Iona, L G

    1989-01-01

    An open, randomized, controlled study including 57 patients with acute cerebral infarct was performed. All the patients, followed and controlled by the same examiner, received, in the first ten days, 24 mg/die i.v. of dexamethasone. 28 patients were also treated with mesoglycan (150 mg/die i.m. for five days and 144 mg/die per os for a further twenty-five days). The differences between the basal and final scores in the mesoglycan group and in the controls were not statistically significant as analysed by the Mann-Whitney U test. The mesoglycan influenced only slightly the laboratory values (PT, PTT, alkaline phosphatase, GOT, GPT, cholesterol and triglycerides, fibrinogen, blood glucose, azotemia and creatinine) performed before the beginning of the treatment, as their changes after thirty days of therapy were in the normal range. The mesoglycan was very well tolerated and no side-effects were observed during the treatment.

  16. 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.

  17. Anti-inflammatory and neuroprotective effects of sanguinarine following cerebral ischemia in rats

    PubMed Central

    Wang, Qin; Dai, Peng; Bao, Han; Liang, Ping; Wang, Wei; Xing, An; Sun, Jianbin

    2017-01-01

    Stroke is one of the leading causes of mortality worldwide. Protective agents that can diminish injuries caused by cerebral ischemia-reperfusion (I/R) are important in alleviating the harmful outcomes of stroke. The aim of the present study was to investigate the protective role of sanguinarine in cerebral I/R injury. A rat middle cerebral artery occlusion model was used to assess the clinical effect of sanguinarine, and inflammatory cytokines in the serum were detected by ELISA. Western blotting was performed to examine the change in levels of apoptosis-associated proteins in the injured brains. The results suggested that sanguinarine, an anti-inflammatory agent derived from the roots of Sanguinaria canadensis, improved the state of cerebral ischemia in a rat model. The data demonstrated that when rats were treated with sanguinarine prior to middle cerebral artery occlusion, the infarct volume was reduced significantly. The inflammatory factors tumor necrosis factor-α, interleukin (IL)-6 and IL-1β were measured in sanguinarine and vehicle-treated groups using an enzyme-linked immunosorbent assay, and the expression levels of the three factors were significantly reduced following treatment with sanguinarine (P<0.05). In addition, western blot analysis demonstrated that the ratio of B-cell lymphoma 2/Bcl-2-associated X protein was significantly increased following treatment with sanguinarine (P<0.05). The study demonstrated that sanguinarine exerts a protective effect in cerebral ischemia, and that this effect is associated with the anti-inflammatory and anti-apoptotic properties of sanguinarine. PMID:28123499

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

    PubMed

    Cremers, Charlotte H P; Vos, Pieter C; van der Schaaf, Irene C; Velthuis, Birgitta K; Vergouwen, Mervyn D I; Rinkel, Gabriel J E; Dankbaar, Jan Willem

    2015-09-01

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

  19. Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

    PubMed Central

    Tamaki, Ryo; Orie, Samuel Ige; Alessandri, Beat; Kempski, Oliver; Heimann, Axel

    2017-01-01

    Endogenous neurogenesis can arise from a variety of physiological stimuli including exercise, learning, or “enriched environment” as well as pathological conditions such as ischemia, epilepsy or cortical spreading depression. Whether all these conditions use a common trigger to set off endogenous neurogenesis is yet unclear. We hypothesized that cortical spreading depression (CSD) induces neurogenesis in the cerebral cortex and dentate gyrus after cerebral venous ischemia. Forty-two Wistar rats alternatively underwent sham operation (Sham), induction of ten CSDs or venous ischemia provoked via occlusion of two adjacent superficial cortical vein followed by ten induced CSDs (CSD + 2-VO). As an additional control, 15 naïve rats received no intervention except 5-bromo-2′-deoxyuridine (BrdU) treatment for 7 days. Sagittal brain slices (40 μm thick) were co-stained for BrdU and doublecortin (DCX; new immature neuronal cells) on day 9 or NeuN (new mature neuronal cells) on day 28. On day 9 after sham operation, cell proliferation and neurogenesis occurred in the cortex in rats. The sole induction of CSD had no effect. But on days 9 and 28, more proliferating cells and newly formed neurons in the ipsilateral cortex were observed in rats subjected to CSD + 2VO than in rats subjected to sham operation. On days 9 and 28, cell proliferation and neurogenesis in the ipsilateral dentate gyrus was increased in sham-operated rats than in naïve rats. Our data supports the hypothesis that induced cortical neurogenesis after CSD + 2-VO is a direct effect of ischemia, rather than of CSD alone. PMID:28966642

  20. Spreading depolarizations: A therapeutic target against delayed cerebral ischemia after subarachnoid hemorrhage

    PubMed Central

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

    2016-01-01

    Delayed cerebral ischemia (DCI) is the most feared mechanism of secondary injury progression after subarachnoid hemorrhage. Initially thought to be a direct consequence of large artery spasm and territorial ischemia, recent data suggest a more complex picture with multiple concurrent and synergistic mechanisms underlying DCI, including microcirculatory dysfunction, inflammation, and microthrombosis. Among these mechanisms, spreading depolarizations (SD) are arguably the most elusive and underappreciated in the clinical setting. Although SDs have been experimentally detected and examined since the late 1970’s, their widespread occurrence in human brain was not unequivocally demonstrated until relatively recently. Today we 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. Here, we review 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. PMID:27258442

  1. Propofol inhibits inflammation and lipid peroxidation following cerebral ischemia/reperfusion in rabbits☆

    PubMed Central

    Wei, Xiaodong; Wan, Xing; Zhao, Bo; Hou, Jiabao; Liu, Min; Cheng, Bangchang

    2012-01-01

    The present study established a rabbit model of global cerebral ischemia using the ‘six-vessel’ method, which was reperfused after 30 minutes of ischemia. Rabbits received intravenous injection of propofol at 5 mg/kg prior to ischemia and 20 mg/kg per hour after ischemia until samples were prepared. Results revealed that propofol inhibited serum interleukin-8, endothelin-1 and malondialdehyde increases and promoted plasma superoxide dismutase activity after cerebral ischemia/reperfusion. In addition, cerebral cortex edema was attenuated with little neuronal nuclear degeneration and pyknosis with propofol treatment. The cross-sectional area of neuronal nuclei was, however, increased following propofol treatment. These findings suggested that propofol could improve anti-oxidant activity and inhibit synthesis of inflammatory factors to exert a protective effect on cerebral ischemia/reperfusion injury. PMID:25737711

  2. Pyruvate dehydrogenase activity in the rat cerebral cortex following cerebral ischemia.

    PubMed

    Cardell, M; Koide, T; Wieloch, T

    1989-06-01

    The effect of cerebral ischemia on the activity of pyruvate dehydrogenase (PDH) enzyme complex (PDHC) was investigated in homogenates of frozen rat cerebral cortex following 15 min of bilateral common carotid occlusion ischemia and following 15 min, 60 min, and 6 h of recirculation after 15 min of ischemia. In frozen cortical tissue from the same animals, the levels of labile phosphate compounds, glucose, glycogen, lactate, and pyruvate was determined. In cortex from control animals, the rate of [1(-14)C]pyruvate decarboxylation was 9.6 +/- 0.5 nmol CO2/(min-mg protein) or 40% of the total PDHC activity. This fraction increased to 89% at the end of 15 min of ischemia. At 15 min of recirculation following 15 min of ischemia, the PDHC activity decreased to 50% of control levels and was depressed for up to 6 h post ischemia. This decrease in activity was not due to a decrease in total PDHC activity. Apart from a reduction in ATP levels, the acute changes in the levels of energy metabolites were essentially normalized at 6 h of recovery. Dichloroacetate (DCA), an inhibitor of PDH kinase, given to rats at 250 mg/kg i.p. four times over 2 h, significantly decreased blood glucose levels from 7.4 +/- 0.6 to 5.1 +/- 0.3 mmol/L and fully activated PDHC. In animals in which the plasma glucose level was maintained at control levels of 8.3 +/- 0.5 mumol/g by intravenous infusion of glucose, the active portion of PDHC increased to 95 +/- 4%. In contrast, the depressed PDHC activity at 15 min following ischemia was not affected by the DCA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. Seinpin knockout exacerbates cerebral ischemia/reperfusion damage in mice.

    PubMed

    Chen, Yong; Wei, Lili; Tian, Jing; Wang, Yu-Hui; Liu, George; Wang, Chun

    2016-05-27

    Seipin, which regulates adipocyte differentiation and lipolysis, inducing severe lipodystrophy and metabolic syndromes, is also highly expressed in the nervous system and affects some neurological diseases. However, the impacts of seipin in stroke remain unclear. In this study, we subjected seipin knockout mice to cerebral ischemia/reperfusion injury and found that seipin knockout mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by blood-brain barrier (BBB) damages. Furthermore, we showed that seipin knockout aggravated endoplasmic reticulum (ER) stress and significantly increased glucose levels, decreased leptin and adiponectin levels in mouse plasma. Our findings reveal that seipin knockout exacerbates cerebral I/R-induced damages by increasing BBB permeability, amplifying ER stress and increasing glucose levels, as well as decreasing leptin and adiponectin levels, indicating that seipin may be a potential therapeutic target for stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

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

    PubMed

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

    1999-05-01

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

  5. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury.

    PubMed

    Yan, Xiao-Ge; Cheng, Bao-Hua; Wang, Xin; Ding, Liang-Cai; Liu, Hai-Qing; Chen, Jing; Bai, Bo

    2015-05-01

    Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 μg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis.

  6. 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.

  7. 3-N-butylphthalide improves neuronal morphology after chronic cerebral ischemia

    PubMed Central

    Zhao, Wanhong; Luo, Chao; Wang, Jue; Gong, Jian; Li, Bin; Gong, Yingxia; Wang, Jun; Wang, Hanqin

    2014-01-01

    3-N-butylphthalide is an effective drug for acute ischemic stroke. However, its effects on chronic cerebral ischemia-induced neuronal injury remain poorly understood. Therefore, this study ligated bilateral carotid arteries in 15-month-old rats to simulate chronic cerebral ischemia in aged humans. Aged rats were then intragastrically administered 3-n-butylphthalide. 3-N-butylphthalide administration improved the neuronal morphology in the cerebral cortex and hippocampus of rats with chronic cerebral ischemia, increased choline acetyltransferase activity, and decreased malondialdehyde and amyloid beta levels, and greatly improved cognitive function. These findings suggest that 3-n-butylphthalide alleviates oxidative stress caused by chronic cerebral ischemia, improves cholinergic function, and inhibits amyloid beta accumulation, thereby improving cerebral neuronal injury and cognitive deficits. PMID:25206879

  8. 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.

  9. 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.

  10. 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.

  11. Sleep Disruption Aggravates Focal Cerebral Ischemia in the Rat

    PubMed Central

    Gao, Bo; Cam, Ertugrul; Jaeger, H.; Zunzunegui, C.; Sarnthein, Johannes; Bassetti, Claudio L.

    2010-01-01

    Study Objectives: Sleep changes are frequent in stroke patients and predict a poor outcome. It remains unclear how sleep influences stroke evolution and recovery. We assessed effects of sleep disruption on brain damage and on the expression of axon sprouting genes after focal cerebral ischemia in rats. Design: 12 h after ischemia induced by occlusion of the middle cerebral artery, rats were subjected to sleep disruption including sleep deprivation for 12h (SDpv12h) and sleep disturbances (SDis) by SDpv12h for consecutive 3 days. Control groups included ischemia without SDpv12h or SDis, sham surgery plus SDis and sham surgery without SDis. Sleep changes were evaluated based on EEG and EMG recordings. Measurements and Results: SDpv12h increased the infarct volume by 40% (SDpv12h 82.8 ± 10.9 vs. control 59.2 ± 13.9 mm3, P = 0.008) and SDis by 76% (SDis 58.8 ± 20.4 vs. control 33.8 ± 6.3 mm3, P = 0.017). SDpv12h also increased the number of damaged cells, visualized by TUNEL staining, by 137% (SDpv12h 46.8 ± 15 vs. control 19.7 ± 7.7/mm2, P < 0.001) and SDis by 219% (SDis 32.9 ± 13.2 vs. control 10.3 ± 2.5/mm2, P = 0.002). In addition, SDis significantly elevated the expression of the axonal extension inhibitory molecule neurocan (SDis 14.3 ± 0.4 vs. control 6.2 ± 0.1-fold of change, P < 0.001) in the injured hemisphere. Conclusions: These results provide the first direct evidence for a detrimental impact of sleep disruption on stroke evolution and suggest a potential role of sleep modulating treatments on stroke outcomes. Citation: Gao B; Cam E; Jaeger H; Zunzunegui C; Sarnthein J; Bassetti CL. Sleep disruption aggravates focal cerebral ischemia in the rat. SLEEP 2010;33(7):879-887. PMID:20614848

  12. Exogenous hydrogen sulfide attenuates cerebral ischemia-reperfusion injury by inhibiting autophagy in mice.

    PubMed

    Shui, Mengyang; Liu, Xiaoyan; Zhu, Yuanjun; Wang, Yinye

    2016-06-22

    Hydrogen sulfide (H2S), the third gas transmitter, has been proven to be neuroprotective in cerebral ischemic injury, but whether its effect is mediated by regulating autophagy is not yet clear. The present study was undertaken to explore the underlying mechanisms of exogenous H2S on autophagy regulation in cerebral ischemia. The effects and its connection with autophagy of NaHS, a H2S donor, were observed through neurological deficits and cerebral infarct volume in middle cerebral artery occlusion (MCAO) mice; autophagy-related proteins and autophagy complex levels in the ischemic hemisphere were detected with Western blot assay. Compared with the model group, NaHS significantly decreased infarct volume and improved neurological deficits; rapamycin, an autophagy activator, abolished the effect of NaHS; NaHS decreased the expression of LC3-II and up-regulated p62 expression in the ischemic cortex 24 h after ischemia. However, NaHS did not significantly influence Beclin-1 expression. H2S has a neuroprotective effect on ischemic injury in MCAO mice; this effect is associated with its influence in down-regulating autophagosome accumulation.

  13. 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

  14. 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.

  15. Cerebral Ischemia/Reperfusion Injury in the Hyperthyroid Rat

    PubMed Central

    Keshavarz, Somaye; Dehghani, Gholam Abbas

    2017-01-01

    Background: Hyperthyroidism as a risk factor for stroke is not conclusive. There are no definite data on the relationship between ischemic cerebrovascular injury and hyperthyroidism. This study was designed to define whether the outcomes of post-ischemic stroke injury are influenced by chronic hyperthyroidism. Methods: Two groups of hyperthyroid (HT) and control euthyroid rats of equal numbers (n=22) were included in the study. Hyperthyroidism was induced for 4 weeks by adding L-thyroxine (300 μg/kg) to drinking water. The middle cerebral artery occlusion technique was used to induce focal cerebral ischemia. Neurological disability (neurological deficit score [NDS]) was evaluated after 24 hours, and the rats were sacrificed to obtain their brain. Triphenyl Tetrazolium Chloride (TTC) staining and Evans Blue (EB) extravasation were used to quantify cerebral infarct volume and cerebrovascular integrity disruption. Data analysis was done using SPSS, version 21. Results: Thyroid hormones levels, T3 (314±7 vs. 198±3 ng/dL;P=0.001) and T4 (9.8±0.3 vs. 3.08±0.07 μg/dL;P=0.001), were significantly higher in the HT group than in the controls. Furthermore, most clinical signs seen in hyperthyroid patients were also present in the HT group. Comparison of the data on cerebral ischemia between the HT and control groups showed significant increases in the NDS (2.76±0.16 vs. 2.23±0.09;P=0.03), cerebral infarct volume (479±12 vs. 266±17 mm3;P=0.001), and EB extravasation (50.08±2.4 vs. 32.6±1.2 μg/g;P=0.001) in the former group. Conclusion: The intensified cerebral infarct size and cerebrovascular integrity disruption suggested that chronic hyperthyroidism aggravated post-stroke injury in the rats. More investigation is required to analyze the pathological mechanisms underlying the association between cerebrovascular disease and hyperthyroidism. PMID:28293050

  16. 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.

  17. Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.

    PubMed

    Milner, Eric; Zhou, Meng-Liang; Johnson, Andrew W; Vellimana, Ananth K; Greenberg, Jacob K; Holtzman, David M; Han, Byung Hee; Zipfel, Gregory J

    2014-10-01

    We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury. © 2014 American Heart Association, Inc.

  18. Effect of cilostazol pretreatment on the PARP/AIF-mediated apoptotic pathway in rat cerebral ischemia-reperfusion models

    PubMed Central

    BA, XIAO-HONG; CAI, LI-PING; HAN, WEI

    2014-01-01

    The aim of this study was to observe the expression of poly ADP-ribose polymerase (PARP) and apoptosis-inducing factor (AIF) in the CA1 region of the hippocampus and to explore whether cilostazol pretreatment exerts a protective effect on the brain through the PARP/AIF-mediated pathway in a rat model of cerebral ischemia-reperfusion. Rats were randomly divided into three groups: Sham-surgery, ischemia-reperfusion and cilostazol (n=45 rats/group). Rat models of middle cerebral artery occlusion were prepared using a thread occlusion method. Rats in the cilostazol group were administered 30 mg/kg intragastric cilostazol 6 and 2 h before brain ischemia, respectively. Following reperfusion, samples were collected at different time-points (6, 24 and 72 h) and each group was further subdivided into three subgroups (n=15 rats/subgroup). Apoptosis was measured using the terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling method. The protein expression levels of AIF and PARP were detected using western blot analysis and the expression levels of AIF mRNA were determined using the reverse transcription-polymerase chain reaction. AIF nuclear translocation occurred following local cerebral ischemia-reperfusion injury. Apoptosis, levels of AIF and PARP protein expression and levels of AIF mRNA expression were significantly increased in the ischemia-reperfusion group compared with the sham-surgery group (P<0.05). However, apoptosis and the expression levels of AIF protein, PARP protein and AIF mRNA at different time-points were significantly decreased in the cilostazol group compared with the ischemia-reperfusion group (P<0.05). In conclusion, cilostazol has a protective effect on rat cerebral ischemia-reperfusion injury, and acts by inhibiting nerve cell apoptosis by preventing the excessive activation of PARP and AIF nuclear translocation. PMID:24940413

  19. Imaging mass spectrometry detection of gangliosides species in the mouse brain following transient focal cerebral ischemia and long-term recovery.

    PubMed

    Whitehead, Shawn N; Chan, Kenneth H N; Gangaraju, Sandhya; Slinn, Jacqueline; Li, Jianjun; Hou, Sheng T

    2011-01-01

    Gangliosides, a member of the glycosphingolipid family, are heterogeneously expressed in biological membranes and are particularly enriched within the central nervous system. Gangliosides consist of mono- or poly-sialylated oligosaccharide chains of variable lengths attached to a ceramide unit and are found to be intimately involved in brain disease development. The purpose of this study is to examine the spatial profile of ganglioside species using matrix-assisted laser desorption/ionization (MALDI) imaging (IMS) following middle cerebral artery occlusion (MCAO) reperfusion injury in the mouse. IMS is a powerful method to not only discriminate gangliosides by their oligosaccharide components, but also by their carbon length within their sphingosine base. Mice were subjected to a 30 min unilateral MCAO followed by long-term survival (up to 28 days of reperfusion). Brain sections were sprayed with the matrix 5-Chloro-2-mercaptobenzothiazole, scanned and analyzed for a series of ganglioside molecules using an Applied Biosystems 4800 MALDI TOF/TOF. Traditional histological and immunofluorescence techniques were performed to assess brain tissue damage and verification of the expression of gangliosides of interest. Results revealed a unique anatomical profile of GM1, GD1 and GT1b (d18:1, d20:1 as well as other members of the glycosphingolipid family). There was marked variability in the ratio of expression between ipsilateral and contralateral cortices for the various detected ganglioside species following MCAO-reperfusion injury. Most interestingly, MCAO resulted in the transient induction of both GM2 and GM3 signals within the ipsilateral hemisphere; at the border of the infarcted tissue. Taken together, the data suggest that brain region specific expression of gangliosides, particularly with respect to hydrocarbon length, may play a role in neuronal responses to injury.

  20. Imaging Mass Spectrometry Detection of Gangliosides Species in the Mouse Brain following Transient Focal Cerebral Ischemia and Long-Term Recovery

    PubMed Central

    Whitehead, Shawn N.; Chan, Kenneth H. N.; Gangaraju, Sandhya; Slinn, Jacqueline; Li, Jianjun; Hou, Sheng T.

    2011-01-01

    Gangliosides, a member of the glycosphingolipid family, are heterogeneously expressed in biological membranes and are particularly enriched within the central nervous system. Gangliosides consist of mono- or poly-sialylated oligosaccharide chains of variable lengths attached to a ceramide unit and are found to be intimately involved in brain disease development. The purpose of this study is to examine the spatial profile of ganglioside species using matrix-assisted laser desorption/ionization (MALDI) imaging (IMS) following middle cerebral artery occlusion (MCAO) reperfusion injury in the mouse. IMS is a powerful method to not only discriminate gangliosides by their oligosaccharide components, but also by their carbon length within their sphingosine base. Mice were subjected to a 30 min unilateral MCAO followed by long-term survival (up to 28 days of reperfusion). Brain sections were sprayed with the matrix 5-Chloro-2-mercaptobenzothiazole, scanned and analyzed for a series of ganglioside molecules using an Applied Biosystems 4800 MALDI TOF/TOF. Traditional histological and immunofluorescence techniques were performed to assess brain tissue damage and verification of the expression of gangliosides of interest. Results revealed a unique anatomical profile of GM1, GD1 and GT1b (d18∶1, d20∶1 as well as other members of the glycosphingolipid family). There was marked variability in the ratio of expression between ipsilateral and contralateral cortices for the various detected ganglioside species following MCAO-reperfusion injury. Most interestingly, MCAO resulted in the transient induction of both GM2 and GM3 signals within the ipsilateral hemisphere; at the border of the infarcted tissue. Taken together, the data suggest that brain region specific expression of gangliosides, particularly with respect to hydrocarbon length, may play a role in neuronal responses to injury. PMID:21687673

  1. 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.

  2. Effects of normobaric oxygen on the progression of focal cerebral ischemia in rats.

    PubMed

    Esposito, Elga; Mandeville, Emiri T; Hayakawa, Kazuhide; Singhal, Aneesh B; Lo, Eng H

    2013-11-01

    Normobaric oxygen (NBO) reduces infarction at 24-48 h in experimental models of focal cerebral ischemia. However, to be clinically relevant, longer term safety and efficacy must be explored. Here, we assessed the effects of NBO on glial activation, neurovascular recovery, and behavioral outcomes at 2 weeks after transient focal ischemia in rats. 100 min transient focal ischemia was induced by intraluminal occlusion of the middle cerebral artery in adult male Sprague-Dawley rats. Animals were randomized into sham, controls or 85'NBO started 15 min after ischemic onset. Infarct volumes and behavioral outcomes were blindly quantified. Immunohistochemistry was used to examine the effects of NBO on glial activation and neurovascular responses. After 2 weeks of reperfusion the infarct volume was marked reduced in animals subjected to NBO. They also had better outcomes in forelimb placement test and in body-swing test and weight loss reduction. After 14 days, NBO decreased expression of Iba1, a marker of activated microglia, and GFAP, a marker of activated astrocytes. NBO treatment had no detectable effect on angiogenesis. These results suggest that protective effects of NBO may persist for up to 2 weeks post-stroke.

  3. Effects of Normobaric Oxygen on the Progression of Focal Cerebral Ischemia in Rats

    PubMed Central

    Esposito, Elga; Mandeville, Emiri T.; Hayakawa, Kazuhide; Singhal, Aneesh B.; Lo, Eng H.

    2013-01-01

    Normobaric oxygen (NBO) reduces infarction at 24–48 hrs in experimental models of focal cerebral ischemia. However, to be clinically relevant, longer term safety and efficacy must be explored. Here, we assessed the effects of NBO on glial activation, neurovascular recovery, and behavioral outcomes at 2 weeks after transient focal ischemia in rats. 100 min transient focal ischemia was induced by intraluminal occlusion of the middle cerebral artery in adult male Sprague-Dawley rats. Animals were randomized into sham, controls or 85′NBO started 15 minutes after ischemic onset. Infarct volumes and behavioral outcomes were blindly quantified. Immunohistochemistry was used to examine the effects of NBO on glial activation and neurovascular responses. After 2 weeks of reperfusion the infarct volume was marked reduced in animals subjected to NBO. They also had better outcomes in forelimb placement test and in body-swing test and weight loss reduction. After 14 days, NBO decreased expression of Iba1, a marker of activated microglia, and GFAP, a marker of activated astrocytes. NBO treatment had no detectable effect on angiogenesis. These results suggest that protective effects of NBO may persist for up to 2 weeks post-stroke. PMID:23958492

  4. 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

  5. Sex differences in delayed cerebral ischemia after subarachnoid hemorrhage.

    PubMed

    Germans, Menno R; Jaja, Blessing N R; de Oliviera Manoel, Airton Leonardo; Cohen, Ashley H; Macdonald, R Loch

    2017-09-01

    OBJECTIVE In this study the authors sought to investigate the sex differences in the risk of delayed cerebral ischemia (DCI), delayed cerebral infarction, and the role of hormonal status. METHODS Ten studies included in the SAHIT (SAH International Trialists) repository were analyzed using a fitting logistic regression model. Heterogeneity between the studies was tested using I(2) statistics, and the results were pooled using a random-effects model. Multivariable analysis was adjusted for the effects of neurological status and fixed effect of study. An additional model was examined in which women and men were split into groups according to an age cut point of 55 years, as a surrogate to define hormonal status. RESULTS A pooled cohort of 6713 patients was analyzed. The risk of DCI was statistically significantly higher in women than in men (OR 1.29, 95% CI 1.12-1.48); no difference was found with respect to cerebral infarction (OR 1.17, 95% CI 0.98-1.40). No difference was found in the risk of DCI when comparing women ≤ 55 and > 55 years (OR 0.87, 95% CI 0.74-1.02; p = 0.08) or when comparing men ≤ 55 and > 55 years (p = 0.38). Independent predictors of DCI were World Federation of Neurosurgical Societies (WFNS) grade, Fisher grade, age, and sex. Independent predictors of infarction included WFNS grade, Fisher grade, and aneurysm size. CONCLUSIONS Female sex is associated with a higher risk of DCI. Sex differences may play a role in the pathogenesis of DCI but are not associated with menopausal status. The predictors of DCI and cerebral infarction were identified in a very large cohort and reflect experience from multiple institutions.

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

    PubMed Central

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

    2005-01-01

    AIM: To study the modulation of glutamate on post-ischemic intestinal and cerebral inflammatory responses in a ischemic and excitotoxic rat model. METHODS: Adult male rats were subjected to bilateral carotid artery occlusion for 15 min and injection of monosodium glutamate intraperitoneally, to decapitate them at selected time points. Tumor necrosis factor alpha (TNF-α) level and nuclear factor kappa B (NF-κB) activity were determined by enzyme-linked immunosorbant assay (ELISA) and electrophoretic mobility shift assay (EMSA), respectively. Hemodynamic parameters were monitored continuously during the whole process of cerebral ischemia and reperfusion. RESULTS: Monosodium glutamate (MSG) treated rats displayed statistically significant high levels of TNF-α in cerebral and intestinal tissues within the first 6 h of ischemia. The rats with cerebral ischemia showed a minor decrease of TNF-α production in cerebral and intestinal tissues. The rats with cerebral ischemia and treated with MSG displayed statistically significant low levels of TNF-α in cerebral and intestinal tissues. These results correlated significantly with NF-κB production calculated at the same intervals. During experiment, the mean blood pressure and heart rates in all groups were stable. CONCLUSION: Glutamate is involved in the mechanism of intestinal and cerebral inflammation responses. The effects of glutamate on cerebral and intestinal inflammatory responses after ischemia are up-regulated at the transcriptional level, through the NF-κB signal transduction pathway. PMID:15655833

  7. Neuroprotective effects of a traditional herbal prescription on transient cerebral global ischemia in gerbils.

    PubMed

    Cai, Mudan; Shin, Bum Young; Kim, Dong Hyun; Kim, Jong Min; Park, Se Jin; Park, Chan Sung; Won, Do Hee; Hong, Nam Doo; Kang, Dong Hyo; Yutaka, Yamamoto; Ryu, Jong Hoon

    2011-12-08

    Kyung-Ok-Ko (KOK), a traditional herbal prescription composed of Rehmannia glutinosa var. purpurae, Panax ginseng, Poria cocos, Lycium chinense, Aquillaria agallocha and honey, has been used to treat age-related symptoms, such as amnesia or dementia, and has been shown to ameliorate scopolamine-induced memory impairment in mice. However, the effects of KOK on transient cerebral global ischemia-induced brain damage are unclear. Transient cerebral global ischemia was induced by occluding the bilateral common carotid artery for 5 min followed by reperfusion for 7 days. KOK (0.25, 0.5, 1, or 2 g/kg) was administered orally immediately after reperfusion and once a day over the next 7 days. Y-maze or novel object recognition tasks were to analyze learning and memory capabilities at 4 or 5 days after reperfusion, respectively. Histochemistry and immunohistochemistry were used for evaluation of the effect of KOK on neuronal degeneration. Histochemical studies showed that KOK increased the number of viable cells detected by Nissl staining and decreased the number of degenerated neuronal cells detected by Fluoro-Jade B staining in the hippocampal CA1 region. In the immunohistochemical study, the sub-chronic KOK administration attenuated the ischemia-induced activation of microglia and astrocytes and the increase of cytokine IL-1β (P<0.05). In addition, KOK administration significantly attenuated the ischemia-induced cognitive impairments observed in the Y-maze and novel object recognition tasks (P<0.05). These findings suggest that the neuroprotective effects of KOK may be mediated by its anti-inflammatory activities, resulting in the attenuation of memory impairment. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  8. [The influences of ultrafiltration and alcohol sedimentation on protective effects of Radix Astragali and Radix Hedyseri against rat's cerebral ischemia].

    PubMed

    Liu, Yong-qi; Wang, Zhi-wang; Wei, Shu-chang; Yan, Chun-lu; Wang, Rui-qiong; Li, Ying-dong

    2015-03-01

    To investigate the influences of ultrafiltration and alcohol sedimentation on protective effects of Radix Astragali and Radix Hedyseri against rat's cerebral ischemia. Using dexamethasone (im.) and ligating common carotid artery, the rat stasis model combined transient cerebral ischemia was established to evaluate the effects of the ultrafiltration and alcohol sedimentation through detecting antioxidant system and other indexes in brain tissue. The results showed that the 6 g/kg water extract(crude drug), ultrafiltration and alcohol sedimentation of Radix Astragali and Radix Hedyseri could upgrade adenosine-triphosphate (ATP), superoxide dismutase (SOD) and catalase (CAT), and degrade malondialdehyde(MDA) and water content of brain tissue in rat stasis model combined transient cerebral ischemia, the water extract and ultrafiltration of them could degrade lactic acid (LD) of brain tissue, and the effects of alcohol sedimentation of Radix Astragali and Radix Hedyseri become weaker than water extract of them. The water extract, ultrafiltration and alcohol sedimentation of Radix Astragali and Radix Hedyseri have some protective effects on cerebral ischemia in rats, the effective differences of the extract through the same extraction method are not remarkable, and alcohol precipitation method has obvious influences effect on Radix Astragali and Radix Hedyseri.

  9. Prenatal cerebral ischemia triggers dysmaturation of caudate projection neurons

    PubMed Central

    McClendon, Evelyn; Chen, Kevin; Gong, Xi; Sharifnia, Elica; Hagen, Matthew; Cai, Victor; Shaver, Daniel C.; Riddle, Art; Dean, Justin M.; Gunn, Alistair J.; Mohr, Claudia; Kaplan, Joshua S.; Rossi, David J.; Kroenke, Christopher D.; Hohimer, A. Roger; Back, Stephen A.

    2014-01-01

    Objective Recently we reported that the neocortex displays impaired growth after transient cerebral hypoxia-ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry and Golgi staining defined CN growth, cell death, proliferation and dendritic maturation in preterm fetal sheep four weeks after HI. Patch-clamping recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI-defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Neither was there significant loss of calbindin-positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI-induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long-term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. PMID:24395459

  10. 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

  11. Histochemical characterization of cytotoxic brain edema. Potassium concentrations after cerebral ischemia and during the postmortem interval.

    PubMed

    Oehmichen, M; Ochs, U; Meissner, C

    2000-08-01

    Cytotoxic edema is a phenomenon of the ischemically damaged brain. In the present study we tested a histochemical method that detects this phenomenon based on potassium (K+) levels in the brain. In a first series focal cerebral ischemia was induced by arterial occlusion in 23 gerbils (Meriones unguiculatus). After survival times of 30, 60 and 120 min, the animals were killed and brain section histochemically stained for potassium and quantitatively evaluated with a morphometric method. The results were compared with those using physicochemical techniques. A distinct K+ depletion could be demonstrated in the area of the focal ischemia within a survival time of 30 min, the depletion growing thereafter with increasing survival time. In a second series histochemical and chemical methods were used to study the stability of K+ levels in undamaged brains of 15 healthy rats during postmortem intervals of 2.5 and 5 h. Within these intervals K+ levels were clearly depleted, apparently as a result of cerebral spinal fluid (CSF) diffusion. Even if neuronal injury can be demonstrated histochemically after very brief survival times of about 30 min, postmortem storage of the cadavers rendered detection impossible due to electrolyte and water diffusion. In autoptic human cases, therefore, this technique is of no practical utility in detecting cytotoxic brain edema in postmortem tissue.

  12. 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.

  13. OLIGODENDROCYTE DEGENERATION AND RECOVERY AFTER FOCAL CEREBRAL ISCHEMIA

    PubMed Central

    McIver, Sally R.; Muccigrosso, Megan; Gonzales, Ernesto R.; Lee, Jin-Moo; Roberts, Marie S.; Sands, Mark S.; Goldberg, Mark P.

    2013-01-01

    The vulnerability of oligodendrocytes to ischemic injury may contribute to functional loss in diseases of central white matter. Immunocytochemical methods to identify oligodendrocyte injury in experimental models rely on epitope availability, and fail to discriminate structural changes in oligodendrocyte morphology. We previously described the use of a lentiviral vector (LV) carrying eGFP under the myelin basic protein (MBP) promoter for selective visualization of oligodendrocyte cell bodies and processes. In this study, we used LV-MBP-eGFP to label oligodendrocytes in rat cerebral white matter prior to transient focal cerebral ischemia, and examined oligodendrocyte injury 24 hours, 48 hours and one week post-reperfusion by quantifying cell survival and assaying the integrity of myelin processes. There was progressive loss of GFP+ oligodendrocytes in ischemic white matter at 24 and 48 hrs. Surviving GFP+ cells had non-pyknotic nuclear morphology and were TUNEL-negative, but there was marked fragmentation of myelin processes as early as 24 hours after stroke. One week after stroke, we observed a restoration of GFP+ oligodendrocytes in ischemic white matter, reflected both by cell counts and by structural integrity of myelin processes. Proliferating cells were not the main source of GFP+ oligodendrocytes, as revealed by BrdU incorporation. These observations identify novel transient structural changes in oligodendrocyte cell bodies and myelinating processes, which may have consequences for white matter function after stroke. PMID:20621643

  14. Clinical and prognostic significance of hyperfibrinogenemia in cerebral ischemia.

    PubMed

    D'Erasmo, E; Pisani, D; Romagnoli, S; Ragno, A; Acca, M

    1998-01-01

    In order to evaluate the clinical and prognostic significance of early hyperfibrinogenemia in patients with transient ischemic attack (TIA) and ischemic cerebral infarction (ICI), we analyzed the relationships between plasma fibrinogen, brain damage severity, clinical status on admission and intra-hospital mortality. Vascular damage severity was estimated by measuring the necrotic area by computed axial tomography (CT) and indirectly by means of changes in some plasma enzymes (CK, LDH, GPT/ALT, and GOT/AST). Plasma fibrinogen levels were statistically higher in ICI than in TIA and control subjects (p < 0.0005; analysis of variance). Moreover, plasma fibrinogen was directly related to the extension of the necrotic area at CT scan (p < 0.05) and in ICI patients was positively correlated with CK (r = 0.50, p < 0.01), LDH (r = 0.41, p < 0.05) and GOT/AST (r = 0.42, p < 0.05) serum levels, but not with GPT/ALT. A higher plasma fibrinogen value was observed in patients with stupor or coma compared with those with alert consciousness (p < 0.05). In patients who died during hospitalization, fibrinogen levels were higher than those of subjects who were discharged (p < 0.005). The results indicate that in the early phase of cerebral ischemia, plasma fibrinogen levels are related to the severity of the clinical status and to the extension of the brain vascular damage, thus representing a negative clinical and prognostic factor of the disease.

  15. EFFECTS OF RAPAMYCIN ON CEREBRAL OXYGEN SUPPLY AND CONSUMPTION DURING REPERFUSION AFTER CEREBRAL ISCHEMIA

    PubMed Central

    CHI, O. Z.; BARSOUM, S.; VEGA-COTTO, N. M.; JACINTO, E.; LIU, X.; MELLENDER, S. J.; WEISS, H. R.

    2016-01-01

    Abstract—Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia–reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with and without rapamycin (20 mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5 ± 0.8% control vs. 21.5 ± 0.9% rapamycin). We also found that ischemia–reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia–reperfusion. PMID:26742793

  16. 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.

  17. Upregulation of cellular prion protein (PrPc) after focal cerebral ischemia and influence of lesion severity.

    PubMed

    Weise, Jens; Crome, Olaf; Sandau, Raoul; Schulz-Schaeffer, Walter; Bähr, Mathias; Zerr, Inga

    2004-11-30

    The pathological isoform of the prion protein (PrP(Sc)) has been identified to mediate transmissible spongiform encephalopathies like Creutzfeldt-Jakob disease (CJD). In contrast, the physiological function of the normal cellular prion protein (PrP(c)) is not yet understood. Recent findings suggest that PrP(c) may have neuroprotective properties and that its absence increases susceptibility to oxidative stress and neuronal injury. To determine whether PrP(c) is part of the cellular response to neuronal injury in vivo, we investigated PrP(c) regulation after severe and mild focal ischemic brain injury in mice using the thread occlusion stroke model. Western Blot and ELISA analysis showed a significant upregulation of PrP(c) in the ischemic hemisphere at 4 and 8h after onset of permanent focal ischemia, which was no longer detectable at 24h after lesion induction when compared to control animals. In contrast, transient focal ischemia (60 min) did only lead to slightly but not significantly elevated PrP(c) levels in the ischemic hemisphere when compared to controls. These results demonstrate that cerebral PrP(c) is upregulated early in response to focal cerebral ischemia. The extent of upregulation, however, seems to depend on the severity of ischemia and may therefore reflect the extent of ischemia induced neuronal damage. Given the known neuroprotective effects of PrP(c) in vitro, ischemia-induced upregulation of cerebral PrP(c) supports the hypothesis that, as part of an early adaptive cellular response to ischemic brain injury, PrP(c) may be involved in the regulation of ischemia-induced neuronal cell death in vivo.

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

    USDA-ARS?s Scientific Manuscript database

    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, ...

  19. Microembolic signals in acute posterior circulation cerebral ischemia: sources and consequences.

    PubMed

    Hwang, Jaechun; Kim, Suk Jae; Hong, Ji Man; Bang, Oh Young; Chung, Chin-Sang; Lee, Kwang Ho; Kim, Gyeong-Moon

    2012-03-01

    The clinical significance of microembolic signals (MES) in the posterior circulation remains unclear. The aim of this study was to investigate the sources and consequences of MES in acute posterior circulation cerebral ischemia. We evaluated a total of 140 consecutive patients (93 males, mean age 62.9 years) who had acute posterior circulation cerebral ischemia. The MES monitoring was conducted at the basilar artery through the suboccipital window for a 30-minute period. MES were detected in 18 (12.9%) of the 140 patients. Clinical characteristics and laboratory data did not differ between the MES-positive and MES-negative groups. Intracranial vertebrobasilar artery (VBA) stenosis was independently associated with the presence of MES (odds ratio, 9.85; 95% confidence interval, 1.22-79.48; P=0.032), whereas the patients with vertebral artery stenosis that was limited to the extracranial portion did not show an association. Microembolic signals occurred significantly more frequently in patients with severe degree of VBA stenosis compared to those with nonsignificant stenosis (odds ratio, 9.88; 95% confidence interval, 1.23-79.07; P=0.031). In a subgroup analysis of the 79 patients who had lesions on diffusion-weighted images and relevant VBA stenosis, the MES-positive group showed more frequent embolic infarction (P=0.010) and multiple lesion patterns (P=0.007) than single perforating infarctions. In acute posterior circulation cerebral ischemia, intracranial and severe VBA stenosis is associated with MES and may be its root causes. The presence of MES in VBA stenosis suggests that multiple and embolic type infarctions are the mechanisms of stroke.

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

    PubMed

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

    2017-01-01

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

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

    PubMed Central

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

    2017-01-01

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

  2. Neuroprotection of Ischemic Preconditioning is Mediated by Anti-inflammatory, Not Pro-inflammatory, Cytokines in the Gerbil Hippocampus Induced by a Subsequent Lethal Transient Cerebral Ischemia.

    PubMed

    Kim, Dong Won; Lee, Jae-Chul; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Chen, Bai Hui; Shin, Bich-Na; Tae, Hyun-Jin; Seo, Jeong Yeol; Cho, Jun Hwi; Kang, Il Jun; Hong, Seongkweon; Kim, Young-Myeong; Won, Moo-Ho; Kim, In Hye

    2015-09-01

    Ischemic preconditioning (IPC) induced by sublethal transient cerebral ischemia could reduce neuronal damage/death following a subsequent lethal transient cerebral ischemia. We, in this study, compared expressions of interleukin (IL)-2 and tumor necrosis factor (TNF)-α as pro-inflammatory cytokines, and IL-4 and IL-13 as anti-inflammatory cytokines in the gerbil hippocampal CA1 region between animals with lethal ischemia and ones with IPC followed by lethal ischemia. In the animals with lethal ischemia, pyramidal neurons in the stratum pyramidale (SP) of the hippocampal CA1 region were dead at 5 days post-ischemia; however, IPC protected the CA1 pyramidal neurons from lethal ischemic injury. Expressions of all cytokines were significantly decreased in the SP after lethal ischemia and hardly detected in the SP at 5 days post-ischemia because the CA1 pyramidal neurons were dead. IPC increased expressions of anti-inflammatory cytokines (IL-4 and IL-13) in the stratum pyramidale of the CA1 region following no lethal ischemia (sham-operation), and the increased expressions of IL-4 and IL-13 by IPC were continuously maintained is the SP of the CA1 region after lethal ischemia. However, pro-inflammatory cytokines (IL-2 and TNF-α) in the SP of the CA1 region were similar those in the sham-operated animals with IPC, and the IL-4 and IL-13 expressions in the SP were maintained after lethal ischemia. In conclusion, this study shows that anti-inflammatory cytokines significantly increased and longer maintained by IPC and this might be closely associated with neuroprotection after lethal transient cerebral ischemia.

  3. In Vivo Ischemia Detection by Luminescent Nanothermometers.

    PubMed

    Ximendes, Erving Clayton; Rocha, Uéslen; Del Rosal, Blanca; Vaquero, Alberto; Sanz-Rodríguez, Francisco; Monge, Luis; Ren, Fuqiang; Vetrone, Fiorenzo; Ma, Dongling; García-Solé, José; Jacinto, Carlos; Jaque, Daniel; Fernández, Nuria

    2017-02-01

    There is an urgent need to develop new diagnosis tools for real in vivo detection of first stages of ischemia for the early treatment of cardiovascular diseases and accidents. However, traditional approaches show low sensitivity and a limited penetration into tissues, so they are only applicable for the detection of surface lesions. Here, it is shown how the superior thermal sensing capabilities of near infrared-emitting quantum dots (NIR-QDs) can be efficiently used for in vivo detection of subcutaneous ischemic tissues. In particular, NIR-QDs make possible ischemia detection by high penetration transient thermometry studies in a murine ischemic hindlimb model. NIR-QDs nanothermometers are able to identify ischemic tissues by means of their faster thermal dynamics. In addition, they have shown to be capable of monitoring both the revascularization and damage recovery processes of ischemic tissues. This work demonstrates the applicability of fluorescence nanothermometry for ischemia detection and treatment, as well as a tool for early diagnosis of cardiovascular disease.

  4. Lyophilized Powder of Catalpol and Puerarin Protected Cerebral Vessels from Ischemia by Its Anti-apoptosis on Endothelial Cells

    PubMed Central

    Liu, Yang; Tang, Qing; Shao, Siying; Chen, Yi; Chen, Weihai; Xu, Xiaoyu

    2017-01-01

    Catalpol and puerarin are two monomers of Rehmannia glutinosa and Lobed Kudzuvine Root, which are two herbs commonly used together in ancient prescriptions of traditional Chinese medicine for cerebral ischemia. Our previous study shows that the lyophilized powder of the two monomers improved the outcome of cerebral ischemia excellently in rodents. However, if it protects vessels from ischemia is unknown. The present research studied the protection of lyophilized powder of catalpol and puerarin (CP) on endothelial cells and the relative mechanism in vivo and in vitro. Middle cerebral artery occlusion (MCAO) rats were used to study the improvement of CP on neurological deficiency, regional cerebral blood flow (rCBF), and infarct volume. The morphology of vessels and the apoptosis of brain vascular endothelial cells (BVECs) were observed and detected by immunohistochemistry approaches. To study how CP protected primary BVECs (pBVECs) from ischemic penumbra, oxygen glucose deprivation (OGD)-damaged pBVECs were cultured in the condition of insufficient nutrition and low oxygen which recapitulate the low perfusion of ischemic penumbra. Using the cell model, the mechanism by which CP protected pBVECs was studied by shRNA and pathway inhibitors. CP at the dose of 65.4 mg/kg increased regional cerebral blood flow (rCBF), reduced infarct volume, protected vessel integrity and inhibited endothelial cell apoptosis in vivo. But it only improved rCBF, vessel integrity and BVECs apoptosis at the dose of 32.7 mg/kg. In vitro, the protection of CP on pBVECs was proved to be ERK/HIF-1a- and PI3K/AKT/mTOR/HIF-1a-dependent. This study indicates a possibility of CP being a new drug for cerebral ischemia. Besides, this research provides an alternative cell model for penumbra ECs study. PMID:28367097

  5. Cerebroprotective activity of Wedelia calendulacea on global cerebral ischemia in rats.

    PubMed

    Prakash, T; Kotresha, D; Rama Rao, N

    2011-12-01

    The present study was to investigate the effect of W. calendulacea on ischemia and reperfusion-induced cerebral injury. Cerebral ischemia was induced by occluding right and left common carotid arteries (global cerebral ischemia) for 30 min followed by reperfusion for 1 h and 4 h individually. Various biochemical alterations, produced subsequent to the application of bilateral carotid artery occlusion (BCAO) followed by reperfusion viz. increase in lipid peroxidation (LPO), hydrogen peroxide (H2O2), and decrease in reduced glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD), level in the brain tissue, Western blot analysis (Cu-Zn-SOD and CAT) and assessment of cerebral infarct size were measured. All those enzymes are markedly reversed and restored to near normal level in the groups pretreated with W. calendulacea (250 and 500 mg/kg given orally in single and double dose/day for 10 days) in dose-dependent way. The effect of W. calendulacea had increased significantly the protein expression of copper/zinc superoxide dismutase (Cu-Zn-SOD) and CAT in cerebral ischemia. W. claendulacea was markedly decrease cerebral infarct damages but results are not statistically significant. It can be concluded that W. calendulacea possesses a neuroprotective activity against cerebral ischemia in rat.

  6. Neuroprotective effects of gallic acid against hypoxia/reoxygenation-induced mitochondrial dysfunctions in vitro and cerebral ischemia/reperfusion injury in vivo.

    PubMed

    Sun, Jing; Li, Yun-Zi; Ding, Yin-Hui; Wang, Jin; Geng, Ji; Yang, Huan; Ren, Jie; Tang, Jin-Yan; Gao, Jing

    2014-11-17

    Oxidative stress and mitochondrial dysfunction are frequently implicated in the pathology of secondary neuronal damage following cerebral ischemia/reperfusion. Recent evidence suggests that gallic acid (GA) reverses oxidative stress in rat model of streptozotocin-induced dementia, but the roles and mechanisms of GA on cerebral ischemia/reperfusion injury remain unknown. Here we investigated the potential roles and mechanisms of GA in hypoxia/reoxygenation induced by sodium hydrosulfite (Na2S2O4) in vitro and cerebral ischemia/reperfusion induced by middle cerebral artery occlusion (MCAO) in vivo. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay, 5, 5', 6, 6'-tetrachloro-1, 1', 3, 3'-tetraethylbenzimidazol carbocyanine iodide (JC-1), Dichlorofluorescin diacetate (DCF-DA) and MitoSOX fluorescent assay, Clark-type oxygen electrode, firefly luciferase assay, and calcium-induced mitochondrial swelling were conducted to detect cell death, mitochondrial membrane potential (MMP), intracellular and mitochondrial reactive oxygen species (ROS), oxygen consumption, ATP level, and mitochondrial permeability transition pore (MPTP) viability. We firstly find that modulation of the mitochondrial dysfunction is an important mechanism by GA attenuating hypoxia/reoxygenation insult. To further assess the effects of GA on cerebral ischemia/reperfusion injury, 2, 3, 5-triphenyl-tetrazolium chloride (TTC) staining, dUTP nick-end labeling (TUNEL) assay, and Cytochrome C (Cyt C) release were performed in MCAO rats. The results support that GA is useful against cerebral ischemia/reperfusion injury as a potential protective agent.

  7. [Molecular mechanism of protective effect of puerarin solid lipid nanoparticle on cerebral ischemia-reperfusion injury in gerbils].

    PubMed

    Zhu, Liu; Luo, Cheng-Feng; Yuan, Mu; Chen, Min-Sheng; Ji, Hong

    2010-12-01

    To investigate the effects of puerarin solid lipid nanoparticle on fore brain ischemic-reperfusion injury in gerbils and it's mechanisms. Gerbils were randomly divided into 4 groups: sham group, cerebral ischemia-reperfusion injury group, puerarin solid lipid nanoparticle group and puerarin injection control group. The gerbils' cerebral ischemia-reperfusion injury model was constructed with ligating bilater carotids method. The histomorphology and Bcl-2, Caspase-3 and HSP70 expressions were detected by HE dyeing and immunohistochemical method. After 24 h ischemia and reperfusion in gerbils, the level of Bcl-2 and HSP70 expressions in puerarin solid lipid nanoparticle group increased (P < 0.01) compared with the ischemic-reperfusion model group, and the level of Caspase-3 expression decreased (P < 0.01). The same results was consistent in puerarin injection control group. Puerarin solid lipid nanoparticle group can protect the cerebral ischemia-reperfusion injury in gerbils, which may be related to the upregulation of Bcl-2 and HSP70 expression and downregulation of Caspase-3 expression.

  8. Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats.

    PubMed

    Naderi, Yazdan; Sabetkasaei, Masoumeh; Parvardeh, Siavash; Moini Zanjani, Taraneh

    2017-04-01

    Cerebral ischemia leads to memory impairment that is associated with loss of hippocampal CA1 pyramidal neurons. Neuroinflammation and oxidative stress may be implicated in the pathogenesis of ischemia/reperfusion damage. Minocycline has anti-inflammatory and antioxidant properties. We investigated the neuroprotective effects of minocycline in rats subjected to cerebral ischemia/reperfusion injury. Thirty male rats were divided into three groups: control, sham, and minocycline-pretreated group. Minocycline (40 mg/kg) was injected intraperitoneally immediately before surgery, and then ischemia was induced by occlusion of common carotid arteries for 20 min. Seven days after reperfusion, the Morris water-maze task was used to evaluate memory. Nissl staining was also performed to analyze pyramidal cell damage. We measured the contents of malondialdehyde and proinflammatory cytokines in the hippocampus by the thiobarbituric acid method and enzyme-linked immunosorbent assay, respectively. Microglial activation was also investigated by Iba1 immunostaining. The results showed that pretreatment with minocycline prevented memory impairment induced by cerebral ischemia/reperfusion. Minocycline pretreatment also significantly attenuated ischemia-induced pyramidal cell death and microglial activation in the CA1 region and reduced the levels of malondialdehyde and proinflammatory cytokines (interleukin-1β and tumor necrosis factor-α) in the hippocampus of ischemic rats. Minocycline showed neuroprotective effects on cerebral ischemia-induced memory deficit probably through its anti-inflammatory and antioxidant activities.

  9. The Neuroprotective Effect of Glycyrrhizic Acid on an Experimental Model of Focal Cerebral Ischemia in Rats.

    PubMed

    Akman, Tarık; Guven, Mustafa; Aras, Adem Bozkurt; Ozkan, Adile; Sen, Halil Murat; Okuyucu, Ali; Kalkan, Yildiray; Sehitoglu, Ibrahim; Silan, Coskun; Cosar, Murat

    2015-08-01

    Cerebral ischemia is still one of the most important topics in neurosciences. Our study aimed to investigate the neuroprotective and anti-oxidant effects of glycyrrhizic acid on focal cerebral ischemia in rats. Twenty-four rats were divided equally into three groups. A middle cerebral artery occlusion model was performed in this study where sham and glycyrrhizic acid were administered intraperitoneally following middle cerebral artery occlusion. Group I was evaluated as control. Malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear respiratory factor-1 (NRF1) levels were analyzed biochemically on the right cerebral hemisphere, while ischemic histopathological studies were completed to investigate the anti-oxidant status. Biochemical results showed that SOD and NRF1 levels were significantly increased in the glycyrrhizic acid group compared with the sham group while MDA levels were significantly decreased. On histopathological examination, cerebral edema, vacuolization, degeneration, and destruction of neurons were decreased in the glycyrrhizic acid group compared with the sham group. Cerebral ischemia was attenuated by glycyrrhizic acid administration. These observations indicate that glycyrrhizic acid may have potential as a therapeutic agent in cerebral ischemia by preventing oxidative stress.

  10. Ischemia-Reperfusion Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

    PubMed Central

    Virgintino, Daniela; Girolamo, Francesco; Rizzi, Marco; Ahmedli, Nigar; Sadowska, Grazyna B.; Stopa, Edward G.; Zhang, Jiyong; Stonestreet, Barbara S.

    2014-01-01

    Information is limited regarding the effects of injury on neovascularization in the immature brain. We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices. PMID:24806298

  11. 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".

  12. Selective Estrogen Receptor Modulators (SERMs) Enhance Neurogenesis and Spine Density Following Focal Cerebral Ischemia

    PubMed Central

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

    2014-01-01

    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. PMID:24815952

  13. Transplantation of human amniotic mesenchymal stem cells in the treatment of focal cerebral ischemia.

    PubMed

    Li, Fang; Miao, Zong-Ning; Xu, Yun-Yun; Zheng, Shi-Ying; Qin, Ming-De; Gu, Yan-Zheng; Zhang, Xue-Guang

    2012-09-01

    Cerebrovascular injury is one of the three major causes of death and is the leading cause of adult disability. Despite the increasing progress in emergency treatment and early rehabilitation in patients with cerebrovascular injury, treatment options for neurological dysfunction that presents at a later stage are lacking. This study examined the potential of human amniotic mesenchymal stem cell (hAMSC) transplantation in the repair of neurological deficits in an experimental focal cerebral ischemia model. Following the isolation of hAMSCs, growth characteristics and surface antigen expression were observed. Butylated hydroxyanisole (BHA) was used to induce the cultured cells into neuron-like cells, which were identified by immunocytochemistry. The suture model was used to induce focal cerebral ischemia in rats, which were subsequently randomly divided into experimental and control groups for treatment with BrdU-labeled hAMSCs or PBS, respectively. Neurological deficits were assessed following transplantation using the neurological severity score, beam balance test and elevated body swing test. Eight weeks later, rat brain tissue was analyzed with H&E staining and BrdU immunohistochemistry, and the survival and spatial distribution of the transplanted hAMSCs were determined. The hAMSCs proliferated in vitro, and it was found that neuron-specific enolase (NSE) was expressed in neurons, whereas glial fibrillary acidic protein (GFAP) was expressed in astrocytes. The focal ischemia model caused varying degrees of left limb hemiplegia accompanied by right sided Horner's Syndrome. When examined 1, 3, 6 and 8 weeks later, significant recovery in neurological behavior was detected in the rats treated with hAMSC transplantation compared with the control (P<0.01). BrdU-labeled hAMSCs were concentrated near the graft site and surrounding areas, in certain cases migrating towards the ischemic lesion. Local gliosis and lymphocytic infiltration were not detected. hAMSCs exhibit

  14. [The correlation of tolerance to cerebral ischemia and body temperature with glutathione concentration].

    PubMed

    Kulinskiĭ, V I; Kolesnichenko, L S; Kovtun, V Iu; Sotnikova, G V

    2003-01-01

    Methodic approaches for the purposeful changes of glutathione concentration in the brain and liver by administration of glutathione depletors and prodrugs have been modified. Two different depletors (diethylmaleate and buthionine sulfoximine) cause considerable increase of tolerance to the complete global cerebral ischemia and hypothermia development which correlate closely with the decrease of GSH concentration. Five GSH prodrugs (GSH esters and oxothiazolidine carboxilate) and GSH itself usually decrease slightly body temperature but do not influence tolerance to ischemia in the most of series. The increase of tolerance to the complete global cerebral ischemia is connected not with GSH accumulation, but with its decrease. Evidently one of the two opposite GSH effects, sensitizing or protecting one, can predominate in different forms of cerebral ischemia.

  15. 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.

  16. 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.

  17. Are bone marrow regenerative cells ideal seed cells for the treatment of cerebral ischemia?★

    PubMed Central

    Li, Yi; Hua, Xuming; Hua, Fang; Mao, Wenwei; Wan, Liang; Li, Shiting

    2013-01-01

    Bone marrow cells for the treatment of ischemic brain injury may depend on the secretion of a large number of neurotrophic factors. Bone marrow regenerative cells are capable of increasing the secretion of neurotrophic factors. In this study, after tail vein injection of 5-fluorouracil for 7 days, bone marrow cells and bone marrow regenerative cells were isolated from the tibias and femurs of rats, and then administered intravenously via the tail vein after focal cerebral ischemia. Immunohistological staining and reverse transcription-PCR detection showed that transplanted bone marrow cells and bone marrow regenerative cells could migrate and survive in the ischemic regions, such as the cortical and striatal infarction zone. These cells promote vascular endothelial cell growth factor mRNA expression in the ischemic marginal zone surrounding the ischemic penumbra of the cortical and striatal infarction zone, and have great advantages in promoting the recovery of neurological function, reducing infarct size and promoting angiogenesis. Bone marrow regenerative cells exhibited stronger neuroprotective effects than bone marrow cells. Our experimental findings indicate that bone marrow regenerative cells are preferable over bone marrow cells for cell therapy for neural regeneration after cerebral ischemia. Their neuroprotective effect is largely due to their ability to induce the secretion of factors that promote vascular regeneration, such as vascular endothelial growth factor. PMID:25206414

  18. Fastigial nucleus electrostimulation reduces the expression of repulsive guidance molecule, improves axonal growth following focal cerebral ischemia.

    PubMed

    Jiang, Fan; Yin, Honglei; Qin, Xinyue

    2012-09-01

    The role of repulsive guidance molecule A (RGMa) in cerebral ischemia remains unclear. In the study, we examined the expression of RGMa in ischemic brain tissues following focal cerebral ischemia/reperfusion (IR) in rats. An established middle cerebral artery suture occlusion model was employed. A dipolar electrode was placed into the cerebellum to stimulate the cerebellar fastigial nucleus for 1 h at 2 h after ischemia. Reverse transcription-polymerase chain reaction was used to measure the mRNA RGMa and its downstream mediator, Ras homolog A (RhoA). Immunohistochemistry was applied to detect RGMa and RhoA expressions and to evaluate axonal regeneration by optical density analysis of 200 kDa neurofilaments. We found that both mRNA and protein levels of RGMa and RhoA were increased in the ischemic cortex and hippocampus 48 h following cerebral IR and these elevated levels were maintained for 2 weeks. Electrostimulation of the fastigial nucleus reduced the expression of RGMa and RhoA at 24 h and 2 weeks following cerebral IR. In addition, axonal growth was enhanced in the fastigial nucleus electrostimulated group compared to non-stimulated ischemic animals (P < 0.05). RGMa/RhoA expression was negatively correlated with the growth of axons (P < 0.05). Therefore, we concluded that RGMa and RhoA could be another key molecule and might inhibit axonal regeneration during cerebral IR injury. Electrostimulation of the fastigial nucleus enhances axonal growth, possibly by reducing the expression of RGMa and RhoA after cerebral IR.

  19. Ischemic damage and subsequent proliferation of oligodendrocytes in focal cerebral ischemia.

    PubMed

    Mandai, K; Matsumoto, M; Kitagawa, K; Matsushita, K; Ohtsuki, T; Mabuchi, T; Colman, D R; Kamada, T; Yanagihara, T

    1997-04-01

    In order to achieve a better understanding of the pathophysiology of ischemic white matter lesions, oligodendrocytic degeneration and subsequent proliferation were examined in the mouse model of middle cerebral artery occlusion. In situ hybridization histochemistry for proteolipid protein messenger RNA was employed as a sensitive and specific marker of oligodendrocytes, and immunohistochemistry for myelin basic protein was used as a compact myelin marker. Immunohistochemistry for microtubule-associated protein 2 and albumin was employed to monitor neuronal degeneration and the breakdown of the blood brain barrier, respectively. In the ischemic core of the caudoputamen, the immunoreactivity for microtubule-associated protein 2 disappeared and massive albumin extravasation occurred several hours after vessel occlusion, while proteolipid protein messenger RNA signals remained relatively strong at this time. The messenger RNA signals began to attenuate 12 h after ischemia and were hardly detectable 24 h after ischemia in the whole ischemic lesion. In situ end-labeling of fragmented DNA showed some cells with proteolipid protein messenger RNAs to have DNA fragmentation at this period. In contrast to proteolipid protein messenger RNA signals, the immunoreactivity for myelin basic protein was detected as long as five days after ischemia. An apparent increase in the cells possessing strong proteolipid protein messenger RNA signals was found five days after ischemia, mainly in the corpus callosum and the cortex bordering the infarcted areas. A double simultaneous procedure with in situ hybridization for proteolipid protein messenger RNA and immunohistochemistry for glial fibrillary acid protein or lectin histochemistry for macrophages/microglia showed proliferating oligodendrocytes to be co-localized with reactive astrocytes and macrophages/microglia. These findings show that oligodendrocytic damage occurred following ischemic neuronal damage and the breakdown of the blood

  20. The role of carotid artery stenting for recent cerebral ischemia.

    PubMed

    Bosiers, M; Callaert, J; Deloose, K; Verbist, J; Keirse, K; Peeters, P

    2010-06-01

    Patients with cerebral ischemia as a result of acute cervical internal carotid artery occlusion are generally considered to have a poor prognosis. Despite maximal medical treatment, a better treatment for patients with acute ischemic stroke who present with serious neurologic symptoms on admission or continue to deteriorate neurologically due to a total occlusion, a dissection or a high-grade stenosis of the internal carotid artery is required. An effective intervention to improve their neurologic symptoms and clinical outcome has not yet been established and represents a challenging and complex problem. Treatment of acute symptomatic occlusion of the cervical internal carotid artery includes intravenous administration of thrombolytic agent, carotid endarterectomy and an interventional approach (intra-arterial administration of thrombolytic agent, transluminal angioplasty with or without stenting). The endovascular interventional approach is becoming a part of the stroke therapy armamentarium for intracranial occlusion. It may also now be considered in select patients with acute internal carotid artery occlusion. Stenting and angioplasty for acute internal carotid artery occlusion appears to be feasible, safe and may be associated with early neurological improvement. The encouraging preliminary results await confirmation from prospective, randomized studies.

  1. Cell therapy for neonatal hypoxia-ischemia and cerebral palsy.

    PubMed

    Bennet, Laura; Tan, Sidhartha; Van den Heuij, Lotte; Derrick, Matthew; Groenendaal, Floris; van Bel, Frank; Juul, Sandra; Back, Stephen A; Northington, Frances; Robertson, Nicola J; Mallard, Carina; Gunn, Alistair Jan

    2012-05-01

    Perinatal hypoxic-ischemic brain injury remains a major cause of cerebral palsy. Although therapeutic hypothermia is now established to improve recovery from hypoxia-ischemia (HI) at term, many infants continue to survive with disability, and hypothermia has not yet been tested in preterm infants. There is increasing evidence from in vitro and in vivo preclinical studies that stem/progenitor cells may have multiple beneficial effects on outcome after hypoxic-ischemic injury. Stem/progenitor cells have shown great promise in animal studies in decreasing neurological impairment; however, the mechanisms of action of stem cells, and the optimal type, dose, and method of administration remain surprisingly unclear, and some studies have found no benefit. Although cell-based interventions after completion of the majority of secondary cell death appear to have potential to improve functional outcome for neonates after HI, further rigorous testing in translational animal models is required before randomized controlled trials should be considered. Copyright © 2011 American Neurological Association.

  2. [Effects of combined ischemic postconditioning, remote ischemic postconditioning and naloxone postconditioning on focal cerebral ischemia-reperfusion injury in rats].

    PubMed

    Liu, Yi; Liao, Xu; Xue, Fu-shan; Xu, Ya-chao; Xiong, Jun; Yuan, Yu-jing; Wang, Qiang; Liu, Jian-hua; Zhao, Jia-xun

    2011-06-07

    To assess the effects of ischemic postconditioning, remote ischemic postconditioning and naloxone postconditioning on focal cerebral ischemia-reperfusion injury in rats. A total of 110 adult SD rats were randomly divided into 5 groups (n = 22 each). The focal cerebral ischemia-reperfusion injury was induced by a 90-minute occlusion of right middle cerebral artery (MCA) and a 24-hour reperfusion sequentially. Group 1 was of ischemia-reperfusion control; Group 2 ischemic postconditioning induced by three 30-second cycles of MCA occlusion followed by a 30-second reperfusion; Group 3 remote ischemic postconditioning performed via a transient occlusion of right femoral artery at 5 min before the initiation of reperfusion; Group 4 naloxone postconditioning with naloxone 10 mg/kg intraperitoneally injected at the initiation of reperfusion; Group 5 combined ischemic, remote ischemic & naloxone postconditioning performed simultaneously in accordance with the methods used in Groups 2, 3 & 4. The neurologic deficit scores (NDS) were obtained at 2 h & 24 h post-reperfusion. At 24 h post-reperfusion, the anesthetized rat was sacrificed by decapitation and the brain rapidly extracted to assess the size of cerebral infarct (n = 10), detect the cerebral expression of microtubule-associated protein-2 (MAP2) (n = 6), measure the plasma volume of cerebral tissues and quantify the diameter and segment length of cerebral microvessel (n = 6). There were no significant differences in the heart rate (HR) and mean arterial pressure (MAP) among the above five groups at all observed time points (P > 0.05). At 24 h post-reperfusion, the percentage of ischemic cerebral infarct size was 43% ± 6%, 31% ± 4%, 32% ± 5%, 28% ± 6% & 21% ± 7% in ipsilateral hemisphere area (i.e., cerebral infarct severity) in Groups 1-5 respectively. Compared with Group 1, the levels of NDS and cerebral infarct severity significantly decreased at ischemic side in Groups 2-5 (P < 0.05). And the cerebral expression

  3. Consistent delayed unilateral neuronal death after modified transient focal cerebral ischemia in mice that mimics neuronal injury after transient global cerebral ischemia.

    PubMed

    Nishijima, Yasuo; Niizuma, Kuniyasu; Fujimura, Miki; Akamatsu, Yosuke; Shimizu, Hiroaki; Tominaga, Teiji

    2015-07-01

    Numerous studies have attempted to reveal the pathophysiology of ischemic neuronal injury using a representative transient global cerebral ischemia (tGCI) model in rodents; however, most of them have used gerbil or rat models. Recent advances in transgene and gene-knockout technology have enabled the precise molecular mechanisms of ischemic brain injury to be investigated. Because the predominant species for the study of genetic mutations is the mouse, a representative mouse model of tGCI is of particular importance. However, simple mouse models of tGCI are less reproducible; therefore, a more complex process or longer duration of ischemia, which causes a high mortality rate, has been used in previous tGCI models in mice. In this study, the authors aimed to overcome these problems and attempted to produce consistent unilateral delayed hippocampal CA1 neuronal death in mice. C57BL/6 mice were subjected to short-term unilateral cerebral ischemia using a 4-mm silicone-coated intraluminal suture to obstruct the origin of the posterior cerebral artery (PCA), and regional cerebral blood flow (rCBF) of the PCA territory was measured using laser speckle flowmetry. The mice were randomly assigned to groups of different ischemic durations and histologically evaluated at different time points after ischemia. The survival rate and neurological score of the group that experienced 15 minutes of ischemia were also evaluated. Consistent neuronal death was observed in the medial CA1 subregion 4 days after 15 minutes of ischemia in the group of mice with a reduction in rCBF of < 65% in the PCA territory during ischemia. Morphologically degenerated cells were mostly positive for terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and cleaved caspase 3 staining 4 days after ischemia. The survival rates of the mice 24 hours (n = 24), 4 days (n = 15), and 7 days (n = 7) after being subjected to 15 minutes of ischemia were 95.8%, 100%, and 100

  4. Lateral intracerebroventricular injection of Apelin-13 inhibits apoptosis after cerebral ischemia/reperfusion injury

    PubMed Central

    Yan, Xiao-ge; Cheng, Bao-hua; Wang, Xin; Ding, Liang-cai; Liu, Hai-qing; Chen, Jing; Bai, Bo

    2015-01-01

    Apelin-13 inhibits neuronal apoptosis caused by hydrogen peroxide, yet apoptosis following cerebral ischemia-reperfusion injury has rarely been studied. In this study, Apelin-13 (0.1 μg/g) was injected into the lateral ventricle of middle cerebral artery occlusion model rats. TTC, TUNEL, and immunohistochemical staining showed that compared with the cerebral ischemia/reperfusion group, infarct volume and apoptotic cell number at the ischemic penumbra region were decreased in the Apelin-13 treatment group. Additionally, Apelin-13 treatment increased Bcl-2 immunoreactivity and decreased caspase-3 immunoreactivity. Our findings suggest that Apelin-13 is neuroprotective against cerebral ischemia/reperfusion injury through inhibition of neuronal apoptosis. PMID:26109951

  5. Impaired cerebral autoregulation is associated with vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage.

    PubMed

    Otite, Fadar; Mink, Susanne; Tan, Can Ozan; Puri, Ajit; Zamani, Amir A; Mehregan, Aujan; Chou, Sherry; Orzell, Susannah; Purkayastha, Sushmita; Du, Rose; Sorond, Farzaneh A

    2014-03-01

    Cerebral autoregulation may be impaired in the early days after subarachnoid hemorrhage (SAH). The purpose of this study was to examine the relationship between cerebral autoregulation and angiographic vasospasm (aVSP) and radiographic delayed cerebral ischemia (DCI) in patients with SAH. Sixty-eight patients (54±13 years) with a diagnosis of nontraumatic SAH were studied. Dynamic cerebral autoregulation was assessed using transfer function analysis (phase and gain) of the spontaneous blood pressure and blood flow velocity oscillations on days 2 to 4 post-SAH. aVSP was diagnosed using a 4-vessel conventional angiogram. DCI was diagnosed from CT. Decision tree models were used to identify optimal cut-off points for clinical and physiological predictors of aVSP and DCI. Multivariate logistic regression models were used to develop and validate a risk scoring tool for each outcome. Sixty-two percent of patients developed aVSP, and 19% developed DCI. Patients with aVSP had higher transfer function gain (1.06±0.33 versus 0.89±0.30; P=0.04) and patients with DCI had lower transfer function phase (17.5±39.6 versus 38.3±18.2; P=0.03) compared with those who did not develop either. Multivariable scoring tools using transfer function gain>0.98 and phase<12.5 were strongly predictive of aVSP (92% positive predictive value; 77% negative predictive value; area under the receiver operating characteristic curve, 0.92) and DCI (80% positive predictive value; 91% negative predictive value; area under the curve, 0.94), respectively. Dynamic cerebral autoregulation is impaired in the early days after SAH. Including autoregulation as part of the initial clinical and radiographic assessment may enhance our ability to identify patients at a high risk for developing secondary complications after SAH.

  6. Time-course changes in immunoreactivities of glucokinase and glucokinase regulatory protein in the gerbil hippocampus following transient cerebral ischemia.

    PubMed

    Park, Joon Ha; Lee, Choong Hyun; Kim, In Hye; Ahn, Ji Hyeon; Cho, Jeong-Hwi; Yan, Bing Chun; Lee, Jae-Chul; Lee, Tae Hun; Seo, Jeong Yeol; Cho, Jun Hwi; Won, Moo-Ho; Kang, Il-Jun

    2013-12-01

    Glucose is a main energy source for normal brain functions. Glucokinase (GK) plays an important role in glucose metabolism as a glucose sensor, and GK activity is modulated by glucokinase regulatory protein (GKRP). In this study, we examined the changes of GK and GKRP immunoreactivities in the gerbil hippocampus after 5 min of transient global cerebral ischemia. In the sham-operated-group, GK and GKRP immunoreactivities were easily detected in the pyramidal neurons of the stratum pyramidale of the hippocampus. GK and GKRP immunoreactivities in the pyramidal neurons were distinctively decreased in the hippocampal CA1 region (CA), not CA2/3, 3 days after ischemia-reperfusion (I-R). Five days after I-R, GK and GKRP immunoreactivities were hardly detected in the CA1, not CA2/3, pyramidal neurons; however, at this point in time, GK and GKRP immunoreactivities were newly expressed in astrocytes, not microglia, in the ischemic CA1. In brief, GK and GKRP immunoreactivities are changed in pyramidal neurons and newly expressed in astrocytes in the ischemic CA1 after transient cerebral ischemia. These indicate that changes of GK and GKRP expression may be related to the ischemia-induced neuronal damage/death.

  7. Ischemic Transient Neurological Events Identified by Immune Response to Cerebral Ischemia

    PubMed Central

    Jickling, Glen C; Zhan, Xinhua; Stamova, Boryana; Ander, Bradley P; Tian, Yingfang; Liu, Dazhi; Sison, Shara-Mae; Verro, Piero; Johnston, S. Claiborne; Sharp, Frank R

    2012-01-01

    Background and Purpose Deciphering whether a transient neurological event (TNE) is of ischemic or nonischemic etiology can be challenging. Ischemia of cerebral tissue elicits an immune response in stroke and transient ischemic attack (TIA). This response, as detected by RNA expressed in immune cells, could potentially distinguish ischemic from nonischemic TNE. Methods Analysis of 208 TIAs, ischemic strokes, controls and TNE was performed. RNA from blood was processed on microarrays. TIAs (n=26) and ischemic strokes (n=94) were compared to controls (n=44) to identify differentially expressed genes (FDR<0.05, fold change ≥∣1.2∣). Genes common to TIA and stroke were used predict ischemia in TIA-DWI positive / minor-stroke (n=17), nonischemic TNE (n=13) and TNE of unclear etiology (n=14). Results Seventy-four genes expressed in TIA were common to those in ischemic stroke. Functional pathways common to TIA and stroke related to activation of innate and adaptive immune systems, involving granulocytes and B-cells. A prediction model using 26 of the 74 ischemia genes distinguished TIA and stroke subjects from controls with 89% sensitivity and specificity. In the validation cohort, 17/17 TIA-DWI positive / minor-strokes were predicted to be ischemic, and 10/13 nonischemic TNE were predicted to be nonischemic. In TNE of unclear etiology, 71% were predicted to be ischemic. These subjects had higher ABCD2 scores. Conclusions A common molecular response to ischemia in TIA and stroke was identified, relating to activation of innate and adaptive immune systems. TNE of ischemic etiology were identified based upon gene profiles that may be of clinical utility once validated. PMID:22308247

  8. Changes of hypoxia-inducible factor-1 signaling and the effect of cilostazol in chronic cerebral ischemia

    PubMed Central

    Chen, Han; Wei, Aixuan; He, Jinting; Yu, Ming; Mang, Jing; Xu, Zhongxin

    2013-01-01

    Hypoxia-inducible factor-1 and its specific target gene heme oxygenase-1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol (30 mg/kg) for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semi-quantitative PCR and western blot analysis showed that hypoxia-inducible factor-1α and heme oxygenase-1 expression levels increased after chronic cerebral ischemia, with hypoxia-inducible factor-1α expression peaking at 3 weeks and heme oxygenase-1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxia-inducible factor-1α may upregulate heme oxygenase-1 expression following chronic cerebral ischemia and that the hypoxia-inducible factor-1/heme oxygenase-1 signaling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxia-inducible factor-1α and heme oxygenase-1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an anti-apoptotic mechanism. PMID:25206477

  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. Molecular mechanisms of skeletal muscle atrophy in a mouse model of cerebral ischemia.

    PubMed

    Desgeorges, Marine Maud; Devillard, Xavier; Toutain, Jérome; Divoux, Didier; Castells, Josiane; Bernaudin, Myriam; Touzani, Omar; Freyssenet, Damien Gilles

    2015-06-01

    Loss of muscle mass and function is a severe complication in patients with stroke that contributes to promoting physical inactivity and disability. The deleterious consequences of skeletal muscle mass loss underline the necessity to identity the molecular mechanisms involved in skeletal muscle atrophy after cerebral ischemia. Transient focal cerebral ischemia (60 minutes) was induced by occlusion of the right middle cerebral artery in C57BL/6J male mice. Skeletal muscles were removed 3 days later and analyzed for the regulation of critical determinants of muscle mass homeostasis (Akt/mammalian target of rapamycin pathway, myostatin-Smad2/3 and bone morphogenetic protein-Smad1/5/8 signaling pathways, ubiquitin-proteasome and autophagy-lysosome proteolytic pathways). Cerebral ischemia induced severe sensorimotor deficits associated with muscle mass loss of the paretic limbs. Mechanistically, cerebral ischemia repressed Akt/mammalian target of rapamycin pathway and increased expression of key players of ubiquitin-proteasome pathway (MuRF1 [muscle RING finger-1], MAFbx [muscle atrophy F-box], Musa1 [muscle ubiquitin ligase of SCF complex in atrophy-1]), together with a marked increase in myostatin expression, in both paretic and nonparetic skeletal muscles. The Smad1/5/8 pathway was also activated. Our data fit with a model in which a repression of Akt/mammalian target of rapamycin pathway and an increase in the expression of key players of ubiquitin-proteasome pathway are critically involved in skeletal muscle atrophy after cerebral ischemia. Cerebral ischemia also caused an activation of bone morphogenetic protein-Smad1/5/8 signaling pathway, suggesting that compensatory mechanisms are also concomitantly activated to limit the extent of skeletal muscle atrophy. © 2015 American Heart Association, Inc.

  11. The intrinsic PEDF is regulated by PPARγ in permanent focal cerebral ischemia of rat.

    PubMed

    Zhu, Chunhua; Zhang, Xiangjian; Qiao, Huimin; Wang, Lina; Zhang, Xiaolin; Xing, Yinxue; Wang, Chaohui; Dong, Lipeng; Ji, Ye; Cao, Xiaoyun

    2012-10-01

    Inflammatory damage plays a pivotal role in cerebral ischemia and may represent a target for treatment. Pigment epithelium-derived factor (PEDF) is proven to possess neuroprotective property. But there is little known about the intrinsic PEDF after cerebral ischemia. This study evaluated the time course expression of the intrinsic PEDF and its underlying regulation mechanisms after cerebral ischemia. Male Sprague-Dawley rats were subjected to permanent middle cerebral artery occlusion. Telmisartan (PPARγ agonist) and GW9662 (PPARγ antagonist) were systemically administered to explore the effect on PPARγ, PEDF, NF-κB and MMP-9 expression at 24 h after cerebral ischemia by western blot and qRT-PCR. The neurological deficits, brain water content and infarct volume were measured. Compared with normal group, the expressions of PEDF and PPARγ decreased, and the expression of NF-κB and MMP-9 increased at early stage after ischemia (P < 0.05). Compared with the vehicle group, the decrease of PEDF and PPARγ was significantly up-regulated and the increase of NF-κB and MMP-9 was down-regulated by telmisartan at 24 h (P < 0.05). The neurological deficits, brain water content and infarct volume were dramatically alleviated by telmisartan (P < 0.05). Telmisartan's effects were reversed by GW9662 co-administration (P < 0.05). The expression of intrinsic PEDF was down-regulated at the early stage of cerebral ischemia. The protective effects of intrinsic PEDF by activating PPARγ pathway may be one of the strategic targets for cerebral ischemic therapies.

  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. An immunohistochemical study of parvalbumin containing interneurons in the gerbil hippocampus after cerebral ischemia.

    PubMed

    Araki, T; Kato, H; Liu, X H; Kogure, K; Kato, K; Itoyama, Y

    1994-09-01

    We investigated postischemic changes of non-pyramidal neurons in the gerbil hippocampus 1 h - 7 days after 10 min of cerebral ischemia, with parvalbumin and microtubule-associated protein 2 (MAP2)-immunohistochemistry. Parvalbumin-immunoreactive interneurons in the hippocampus were unaffected up to 24 h after ischemia. A slight reduction of the immunoreactivity in neuronal processes was seen in the hippocampal CA1 sector 48 h after ischemia. Seven days after ischemia, a marked loss of parvalbumin-immunoreactive interneurons was observed in the hippocampal CA1 and CA3 sectors. Furthermore, reduced staining in the dentate granular and molecular layers was observed. MAP2-immunoreactive pyramidal neurons in the hippocampus were unchanged up to 48 h after ischemia. Seven days after ischemia, a severe loss of MAP2 immunoreactivity was found in the hippocampal CA1 and CA3 neurons and dentate hilar neurons. However, scattered CA1 neurons, most likely interneurons, preserved MAP2 immunoreactivity. The results demonstrate that transient cerebral ischemia can cause a loss of parvalbumin-immunoreactive interneurons in the hippocampus. Furthermore, some interneurons seem to lose parvalbumin synthesis. Although dentate granule cells are resistant to ischemia, considerable reductions of afferent input was suggested by parvalbumin staining.

  14. DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats.

    PubMed

    Li, Zhen; Cui, Shengzhong; Zhang, Zhuo; Zhou, Rong; Ge, Yingbin; Sokabe, Masahiro; Chen, Ling

    2009-02-01

    Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-D-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca(2+) influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (sigma(1)) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.

  15. 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. Copyright © 2016 the American Physiological Society.

  16. 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.

  17. Free Fatty acids and delayed cerebral ischemia after subarachnoid hemorrhage.

    PubMed

    Badjatia, Neeraj; Seres, David; Carpenter, Amanda; Schmidt, J Michael; Lee, Kiwon; Mayer, Stephan A; Claassen, Jan; Connolly, E Sander; Elkind, Mitchell S

    2012-03-01

    The purpose of this study was to understand factors related to increases in serum free fatty acid (FFA) levels and association with delayed cerebral ischemia (DCI) after subarachnoid hemorrhage. We performed serial measurement of systemic oxygen consumption by indirect calorimetry and FFA levels by liquid chromatography/mass spectrometry in the first 14 days after ictus in 50 consecutive patients with subarachnoid hemorrhage. Multivariable generalized estimating equation models identified associations with FFA levels in the first 14 days after SAH and Cox proportional hazards model used to identified associations with time to DCI. There were 187 measurements in 50 patients with subarachnoid hemorrhage (mean age, 56±14 years old; 66% women) with a median Hunt-Hess score of 3. Adjusting for Hunt-Hess grade and daily caloric intake, n-6 and n-3 FFA levels were both associated with oxygen consumption and the modified Fisher score. Fourteen (28%) patients developed DCI on median postbleed Day 7. The modified Fisher score (P=0.01), mean n-6:n-3 FFA ratio (P=0.02), and mean oxygen consumption level (P=0.04) were higher in patients who developed DCI. In a Cox proportional hazards model, the mean n-6:n-3 FFA ratio (P<0.001), younger age (P=0.05), and modified Fisher scale (P=0.004) were associated with time to DCI. Injury severity and oxygen consumption hypermetabolism are associated with higher n-FFA levels and an increased n-6:n-3 FFA ratio is associated with DCI. This may indicate a role for interventions that modulate both oxygen consumption and FFA levels to reduce the occurrence of DCI.

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

    PubMed Central

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

    2015-01-01

    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 affect BCL-2 family proteins in the setting of cerebral ischemia.

    PubMed

    Ouyang, Yi-Bing; Giffard, Rona G

    2014-11-01

    The BCL-2 family is centrally involved in the mechanism of cell death after cerebral ischemia. It is well known that the proteins of the BCL-2 family are key regulators of apoptosis through controlling mitochondrial outer membrane permeabilization. Recent findings suggest that many BCL-2 family members are also directly involved in controlling transmission of Ca(2+) from the endoplasmic reticulum (ER) to mitochondria through a specialization called the mitochondria-associated ER membrane (MAM). Increasing evidence supports the involvement of microRNAs (miRNAs), some of them targeting BCL-2 family proteins, in the regulation of cerebral ischemia. In this mini-review, after highlighting current knowledge about the multiple functions of BCL-2 family proteins and summarizing their relationship to outcome from cerebral ischemia, we focus on the regulation of BCL-2 family proteins by miRNAs, especially miR-29 which targets multiple BCL-2 family proteins. Copyright © 2013 Elsevier Ltd. All rights reserved.

  20. 3′-Daidzein sulfonate sodium improves mitochondrial functions after cerebral ischemia/reperfusion injury

    PubMed Central

    Yuan, Wa; Chen, Qin; Zeng, Jing; Xiao, Hai; Huang, Zhi-hua; Li, Xiao; Lei, Qiong

    2017-01-01

    3′-Daidzein sulfonate sodium is a new synthetic water-soluble compound derived from daidzein (an active ingredient of the kudzu vine root). It has been shown to have a protective effect on cerebral ischemia/reperfusion injury in rats. We plan to study the mechanism of its protective effect. 3′-Daidzein sulfonate sodium was injected in rats after cerebral ischemia/reperfusion injury. Results showed that 3′-daidzein sulfonate sodium significantly reduced mitochondrial swelling, significantly elevated the mitochondrial membrane potential, increased mitochondrial superoxide dismutase and glutathione peroxidase activities, and decreased mitochondrial malondialdehyde levels. 3′-Daidzein sulfonate sodium improved the structural integrity of the blood-brain barrier and reduced blood-brain barrier permeability. These findings confirmed that 3′-daidzein sulfonate sodium has a protective effect on mitochondrial functions after cerebral ischemia/reperfusion injury, improves brain energy metabolism, and provides protection against blood-brain barrier damage. PMID:28400805

  1. Cerebral ischemia during carotid artery cross-clamping: predictive value of phase-contrast magnetic resonance imaging.

    PubMed

    Bagan, Patrick; Vidal, Renaud; Martinod, Emmanuel; Destable, Marie-Dominique; Tremblay, Bruno; Dumas, Jean Luc; Azorin, Jacques F

    2006-11-01

    The goal of this prospective study was to determine the utility of preoperative cerebral magnetic resonance imaging (MRI) in predicting cerebral ischemia during carotid artery cross-clamping for endarterectomy. Between January 2000 and December 2003, a total of 121 patients (95 men, 26 women) underwent three-dimensional phase-contrast MRI to assess collateral function prior to carotid endarterectomy. During regional anesthesia, patients were monitored to detect ischemic events and their timing in relation to cross-clamping and to determine mean intraoperative arterial pressure. These findings were then correlated with the collateral variations observed in the circle of Willis on preoperative MRI. Patients were classified into three groups according to neurological tolerance: normal tolerance (n = 106), immediate severe deficit (n = 9), and late deficit associated with arterial hypotension (n = 6). In the second group, a significant correlation was found between the absence of collateral circulation and neurological deficit (p < .0001). These results indicated that three-dimensional phase-contrast MRI is useful for predicting cerebral ischemia during carotid cross-clamping and selecting indications for shunting. Absence of visible collaterals of the circle of Willis on MRI is significantly predictive of early ischemia and an indication for systematic shunt placement.

  2. [Mechanism of heart and lung injury induced by cerebral ischemia/reperfusion in both young and old mice].

    PubMed

    Lyu, Yanni; Fu, Longsheng; Qian, Yisong; Jiang, Mingjin; He, Libiao; Ouyang, Aijun; Zheng, Yu

    2017-06-01

    Objective To study the mechanism of heart and lung injury after cerebral ischemia/reperfusion in mice. Methods C57BL/6J mice were divided into young and old groups according to their ages, the former being 5-6 months old and the latter being 20-21 months old. Each group was divided into five subgroups subjected to sham operation, middle cerebral artery occlusion for 1-hour ischemia followed by 1-, 12-, 24-, 48-hour reperfusion. At different reperfusion time, HE and TUNEL staining were used to observe the morphological changes of heart and lung tissues; meanwhile, chemical colorimetry was performed to determine the changes of cardiac Na(+)-K(+)-ATPase and Ca(2+)-ATPase; the lung indexes were evaluated; the levels of nuclear factor (NF)-κBp65, p-NF-κBp65, IκBα, p-IκBα were detected by Western blotting; the levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) were determined by ELISA; and the release of NO was examined by colorimetry. Results We observed inflammatory responses in the lung tissues of young and old mice at 24-hour reperfusion and 1-hour reperfusion, respectively, and hemorrhage in the heart tissues of young and old mice at 24-hour reperfusion and 12-hour reperfusion, respectively.Lung tissues showed earlier response to the stimulation of cerebral ischemia/reperfusion than heart tissues did. Meanwhile, the results of Na(+)-K(+)-ATPase, Ca(2+)-ATPase, lung index, NF-κB signaling pathway and inflammatory cytokines in young and old mice were consistent with histological changes of heart and lung tissues. Conclusion Cerebral ischemia/reperfusion can cause heart and lung tissue injury in the old mice, and energy metabolism and inflammation cascade are the main mechanisms of the injury.

  3. Magnesium sulfate fails to reduce infarct volume following transient focal cerebral ischemia in rats.

    PubMed

    Zhu, Hong-Dong; Martin, Rosemary; Meloni, Bruno; Oltvolgyi, Csongor; Moore, Stephen; Majda, Bernadette; Knuckey, Neville

    2004-07-01

    Studies on the neuroprotective effect of magnesium treatment in animal models of focal and global cerebral ischemia have produced inconsistent results. Nevertheless, two magnesium acute stroke phase III trials (IMAGES and FAST-MAG) have either been completed or are planned. Therefore, we decided to re-evaluate the efficacy of magnesium following focal cerebral ischaemia in rats. Two experiments were carried out in two independent laboratories based in Australia. Both used the intraluminal thread method to induce focal cerebral ischemia in the rat. In the Perth study the middle cerebral artery (MCA) was occluded for 45 min and body temperature was controlled during and after ischemia. In the Canberra laboratory the MCA was occluded for 2 h and body temperature was only controlled during surgery. Three different doses (180, 360, or 720 micromol/kg) of MgSO4 in the Perth study and two different MgSO4 doses (370 or 740 micromol/kg) in the Canberra study were intravenously or intra-arterially administered immediately before ischemia. Control animals were given an equal volume of normal saline just before ischemia in both studies. Twenty-four or 72 h post-ischemia, infarct volume was determined following 2',3',5'-triphenyl-2H-tetrazolium chloride (TTC) staining. No significant differences (P > 0.05) in total, cortical and striatal infarct volumes between saline and MgSO4 treated animals were observed in either study. We conclude MgSO4 does not reduce infarct volume when administered before focal cerebral ischemia in rats.

  4. 3',4'-Dihydroxyflavonol attenuates spatial learning and memory impairments in global cerebral ischemia.

    PubMed

    Oz, Mehmet; Demir, Enver Ahmet; Caliskan, Merve; Mogulkoc, Rasim; Baltaci, Abdulkerim Kasım; Nurullahoglu Atalik, K Esra

    2017-02-01

    In the present study, effects of 3',4'-dihydroxyflavonol (DiOHF) on anxiety-like behavior, and learning and memory were investigated in a model of transient global cerebral ischemia and reperfusion. The animals were assigned to sham-operated, ischemia, and two DiOHF-treated (10 mg/kg i.p.) groups. DiOHF was administered at 1 hour before and immediately after the ischemia. Male rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 20 minutes, followed by reperfusion for 7 days. The openfield, elevated plus maze (EPM), and Morris water maze tests were used to evaluate the effects of DiOHF treatment on ischemia-induced locomotor activity, anxiety-like behavior, and spatial and recognition memory impairments, respectively. In the open field test, locomotor activity in the ischemic rats was not altered 6 days after the ischemia, nor was anxiety-like behavior, which was evaluated with the EPM (P > 0.05). In the water-maze test, cerebral ischemia significantly decreased the exploration time in the target quadrant, and the platform crossing counts were lower (P < 0.05) in the probe trial test; this memory impairment was significantly improved by DiOHF applied 1 hour before and immediately after ischemia (P < 0.05). All together, these findings suggest that DiOHF reverses spatial learning and memory deficits resulting from transient global ischemia but has no significant effect on anxiety-like behavior.

  5. 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.

  6. Evaluation of MR derived cerebral oxygen metabolic index in experimental hyperoxic hypercapnia, hypoxia and ischemia

    PubMed Central

    An, Hongyu; Liu, Qingwei; Chen, Yasheng; Lin, Weili

    2009-01-01

    Background and Purpose A non-invasive MRI method to measure cerebral oxygen metabolism has the potential to assess tissue viability during cerebral ischemia. The purposes of this study were 1) to validate MR oxygenation measurements across a wide range of global cerebral oxygenation; and 2) to examine the spatiotemporal evolution of oxygen metabolism during focal middle cerebral artery occlusion (MCAO) in rats. Methods A group of rats (n=28) under normal, hyperoxic hypercapnia and hypoxia were studied to compare MR measured cerebral oxygen saturation (O2SatMRv) with blood gas oximetry measurements in the jugular vein (O2SatJV) and superior sagittal sinus (O2SatSSS). In a separate group of rats (n=31), MR measured cerebral oxygen metabolic index (MR_COMI) was acquired at multiple time-points during MCAO. Histogram analysis was performed on the normalized MR_COMI (rMR_COMI) to examine evolution of oxygen metabolism during acute ischemia. Results Highly linear relationships were obtained between O2SatMRv and O2SatJV/O2SatSSS in rats under global cerebral oxygenation alterations. In the focal ischemia study, rMR_COMI values were significantly lower within the areas of eventual infarction than other regions. Moreover, the rMR_COMI values within the ischemic territory decreased with time, concomitant with an increase in the number of voxels with severely impaired oxygen metabolism. Conclusion Accurate estimates of O2SatMRv can be obtained across a broad and physiologically relevant range of cerebral oxygenation. Furthermore, this method demonstrates a dynamic alteration of cerebral oxygen metabolism during acute ischemia in rats. PMID:19359642

  7. The effects of oxiracetam (CT-848) on local cerebral glucose utilization after focal cerebral ischemia in rats.

    PubMed

    Hokonohara, T; Sako, K; Shinoda, Y; Tomabechi, M; Yonemasu, Y

    1992-02-01

    The effects of oxiracetam on the reduction of brain metabolism induced by focal cerebral ischemia were investigated by measuring local cerebral glucose utilization (LCGU) in rats 24 hr after left middle cerebral artery occlusion. Focal cerebral ischemia reduced LCGU in the entire ipsilateral cortex, the greatest reduction being in the lateral parts of the frontoparietal cortex. LCGU was slightly reduced in the contralateral cortex; this reduction was considered to be caused by diaschisis. Oxiracetam was administered intraperitoneally for 3 days prior to middle cerebral artery occlusion. In the ipsilateral cortex, LCGU reduction was minimized in the ischemic center areas by oxiracetam at a dose of 400 mg/kg and in more extensive areas, by a dose of 800 mg/kg. Moreover, oxiracetam at a dose of 800 mg/kg enhanced metabolism impaired by diaschisis in the caudal areas of the contralateral cortex. These findings suggest that oxiracetam minimizes the reduction of brain function induced by ischemia and may therefore be useful in the treatment of cerebrovascular disease.

  8. [Comparative proteome analysis of blood plasma of patients with early-stage chronic cerebral ischemia].

    PubMed

    Kisrieva, Y S; Petushkova, N A; Samenkova, N F; Kuznetsova, G P; Larina, O V; Zavialova, M G; Teryaeva, N B; Belyaev, A Y; Karuzina, I I

    2016-07-01

    In the present study, we explored the technology of liquid chromatography-mass spectrometry (HPLC-MS/MS) for the proteome analysis of blood plasma of patients with early chronic cerebral ischemia. Analysis of mass-spectrometer data carried out in automatic mode using the software Progenesis LS-MS. As a result of this study identified 43 proteins. The differences identified in the study group compared with the control in 7 proteins. It was found that in the early stages of chronic cerebral ischemia proteome changes in blood plasma affect proteins related to the immune system, the system for the maintenance of hemostasis and lipid metabolism.

  9. The role of microglia and myeloid immune cells in acute cerebral ischemia

    PubMed Central

    Benakis, Corinne; Garcia-Bonilla, Lidia; Iadecola, Costantino; Anrather, Josef

    2015-01-01

    The immune response to acute cerebral ischemia is a major contributor to stroke pathobiology. The inflammatory response is characterized by the participation of brain resident cells and peripheral leukocytes. Microglia in the brain and monocytes/neutrophils in the periphery have a prominent role in initiating, sustaining and resolving post-ischemic inflammation. In this review we aim to summarize recent literature concerning the origins, fate and role of microglia, monocytes and neutrophils in models of cerebral ischemia and to discuss their relevance for human stroke. PMID:25642168

  10. [Animal models of cerebral ischemia--testing therapeutic strategies in vivo].

    PubMed

    Erdô, Franciska; Hossmann, Konstantin-Alexander

    2007-09-30

    Acute cerebral ischemia is one of the leading causes of mortality and chronic disability worldwide. Animal models of focal (stroke-type) and global (cardiac arrest-type) ischemia have been established to investigate the morphological, functional and molecular consequences and to design therapeutic strategies for the improvement of ischemic injury. Despite highly beneficial effects in experimental studies, most human clinical trials were disappointing, suggesting inefficacies in the design and/or translation of animal experiments. In this review the pathophysiologically relevant specifics of ischemia models will be discussed to provide a rational basis for the proper selection of animal models for testing therapeutic strategies under experimental conditions.

  11. Neuroprotective Effects of Poly(ADP-ribose)polymerase Inhibitor Olaparib in Transient Cerebral Ischemia.

    PubMed

    Teng, Fei; Zhu, Ling; Su, Junhui; Zhang, Xi; Li, Ning; Nie, Zhiyu; Jin, Lingjing

    2016-07-01

    Olaparib was the first poly(ADP-ribose)polymerase inhibitor approved by Food and Drug Administration for oncology treatment. However, its neuroprotective effects have not been elucidated. This study aimed to evaluate the effects of olaparib in transient cerebral ischemia. A mouse model of transient middle cerebral artery occlusion was used. Reperfusion was performed at 2 h after ischemia. Different doses of olaparib (1, 3, 5, 10 and 25 mg/kg) were administered intraperitoneally immediately after reperfusion. Twenty-four hours after ischemia, the neurological score was assessed, and grip and string tests were performed to evaluate the behavioral deficits in the mice. Cresyl violet staining was used to assess cerebral edema and the lesion volume. Immunohistochemistry was performed to evaluate the expression of blood-brain barrier proteins collagen IV and claudin-5, as well as extravasation of IgG. Ischemia induced a neurological deficit, which was significantly ameliorated by olaparib at 3 and 5 mg/kg. However, this neuroprotective effect was not observed in mice treated with either low-dose or high-dose olaparib. Both 3 and 5 mg/kg olaparib markedly reduced cerebral infarction volume, but not cerebral edema. The expression of collagen IV decreased after cerebral ischemia, which was improved by olaparib at 3 and 5 mg/kg. These results were confirmed by the reduction of IgG extravasation with olaparib. Olaparib showed clear neuroprotective effects in transient ischemic mice mainly through the reduction of cerebral infarction and blood-brain barrier damage.

  12. Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia

    PubMed Central

    Gu, Yu-Huan; Kanazawa, Masato; Hung, Stephanie Y; Wang, Xiaoyun; Fukuda, Shunichi; Koziol, James A; del Zoppo, Gregory J

    2015-01-01

    During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage. PMID:26198177

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

    PubMed

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

    2014-06-01

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

  14. Antioxidant N-acetylcysteine and AMPA/KA receptor antagonist DNQX inhibited mixed lineage kinase-3 activation following cerebral ischemia in rat hippocampus.

    PubMed

    Tian, Hui; Zhang, Quanguang; Li, Hongchun; Zhang, Guangyi

    2003-09-01

    We measured the MLK3 expression, activity and backphosphorylation following cerebral ischemia. Our data showed that MLK3 protein levels were unalterable during ischemia and reperfusion. However, during ischemia MLK3 activity gradually increased and reached its peak at 30 min of ischemia. While its backphosphorylation reduced from 5 min of ischemia to 30 min of ischemia. In addition, we also detected MLK3 alteration at various time points of reperfusion after 15 min of ischemia, which showed that MLK3 activity increased twice, whereas MLK3 backphosphorylation was similarly consistent with its activity during reperfusion. To further analyze the reason of MLK3 activation, antioxidant N-acetylcysteine (NAC) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3(1H, 4H)-dione (DNQX) were given to the rats 20 min prior to ischemia. The results illustrated that NAC preferably inhibited the MLK3 activation during the ischemia and the early reperfusion, whereas DNQX effectively attenuated the MLK3 activation of the late reperfusion. We think that MLK3 activation is certainly associated with reactive oxygen species (ROS) and AMPA/KA receptor in response to ischemic insult.

  15. Chronic oleoylethanolamide treatment improves spatial cognitive deficits through enhancing hippocampal neurogenesis after transient focal cerebral ischemia.

    PubMed

    Yang, Li-Chao; Guo, Han; Zhou, Hao; Suo, Da-Qin; Li, Wen-Jun; Zhou, Yu; Zhao, Yun; Yang, Wu-Shuang; Jin, Xin

    2015-04-15

    Oleoylethanolamide (OEA) has been shown to have neuroprotective effects after acute cerebral ischemic injury. The aim of this study was to investigate the effects of chronic OEA treatment on ischemia-induced spatial cognitive impairments, electrophysiology behavior and hippocampal neurogenesis. Daily treatments of 30 mg/kg OEA significantly ameliorated spatial cognitive deficits and attenuated the inhibition of long-term potentiation (LTP) in the middle cerebral artery occlusion (MCAO) rat model. Moreover, OEA administration improved cognitive function in a manner associated with enhanced neurogenesis in the hippocampus. Further study demonstrated that treatment with OEA markedly increased the expressions of brain-derived neurotrophic factor (BDNF) and peroxisome proliferator-activated receptors α (PPARα). Our data suggest that chronic OEA treatment can exert functional recovery of cognitive impairments and neuroprotective effects against cerebral ischemic insult in rats via triggering of neurogenesis in the hippocampus, which supports the therapeutic use of OEA for cerebral ischemia. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. 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

  17. Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats.

    PubMed

    Hartman, Richard E; Lee, Jin M; Zipfel, Greg J; Wozniak, David F

    2005-05-10

    The 2-vessel-occlusion + hypotension (2VO + H) model of transient global cerebral ischemia results in neurodegeneration within the CA1 field of the hippocampus, but previous research has failed to demonstrate robust or reliable learning/memory deficits in rats subjected to this treatment. In the present study, sensitive behavioral protocols were developed in an effort to characterize the cognitive impairments following 2VO + H more precisely. Adult rats were exposed to 10 min of bilateral carotid occlusion with simultaneous hypotension. Following recovery, 2VO + H and control rats were subjected to a series of behavioral tests (locomotor activity, sensorimotor battery, water maze [cued, place, learning set], object recognition, and radial arm maze) over an extended recovery period followed by an assessment of neuronal loss in the dorsal hippocampus. The 2VO + H treatment was associated with long-lasting spatial learning deficits in the absence of other behavioral impairments and with neurodegeneration in dorsal hippocampal CA1. Water maze protocols that placed higher memory demands upon the rats (relatively "hard" vs. "easy") were more sensitive for detecting ischemia-induced deficits. We have shown that the use of appropriate behavioral tests (e.g., a relatively difficult place learning task) allowed for the observation of robust spatial learning deficits in a model previously shown to induce relatively subtle behavioral effects. Thus, the 2VO + H model induces both hippocampal neuronal loss and long-term learning deficits in rats, providing a potentially useful model for evaluating therapeutic efficacy.

  18. 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.

  19. 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. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Impact of hyperthermia before and during ischemia-reperfusion on neuronal damage and gliosis in the gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Kim, Min Joung; Cho, Jun Hwi; Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Tae, Hyun-Jin; Cho, Geum-Sil; Yan, Bing Chun; Hwang, In Koo; Lee, Choong Hyun; Bae, Eun Joo; Won, Moo-Ho; Lee, Jae-Chul

    2015-01-15

    Hyperthermia can exacerbate the brain damage produced by ischemia. In the present study, we investigated the effects of hyperthermia before and during ischemia-reperfusion on neuronal damage and glial changes in the gerbil hippocampus following transient cerebral ischemia using cresyl violet staining, NeuN immunohistochemistry and Fluoro-Jade B histofluorescence staining. The animals were randomly assigned to 4 groups: (1) sham-operated animals with normothermia (normothermia + sham group); (2) ischemia-operated animals with normothermia (normothermia + ischemia group); (3) sham-operated animals with hyperthermia (hyperthermia + sham group); and (4) ischemia-operated animals with hyperthermia (hyperthermia + ischemia group). Hyperthermia (39.5 ± 0.2°C) was induced by exposing the gerbils to a heating pad connected to a rectal thermistor for 30 min before and during ischemia-reperfusion. In the normothermia+ischemia groups, a significant delayed neuronal death was observed in the stratum pyramidale (SP) of the hippocampal CA1 region (CA1) 5 days after ischemia-reperfusion. In the hyperthermia+ischemia groups, neuronal death in the SP of the CA1 occurred at 1 day post-ischemia, and neuronal death was observed in the SP of the CA2/3 region at 2 days post-ischemia. In addition, we examined activations of astrocytes and microglia using immunohistochemistry for anti-glial fibrillary acidic protein (GFAP) and anti-ionized calcium-binding adapter molecule 1 (Iba-1). GFAP-positive astrocytes and Iba-1-positive microglia in the ischemic hippocampus were activated much earlier and much more accelerated in the hyperthermia+ischemia groups than those in the normothermia+ischemia groups. Based on our findings, we suggest that an experimentally hyperthermic pre-condition before cerebral ischemic insult produces more extensive neuronal damage and glial activation in the ischemic hippocampus.

  1. Role of cannabinoids and endocannabinoids in cerebral ischemia

    PubMed Central

    Hillard, Cecilia J.

    2008-01-01

    The human costs of stroke are very large and growing; it is the third largest cause of death in the United States and survivors are often faced with loss of ability to function independently. There is a large need for therapeutic approaches that act to protect neurons from the injury produced by ischemia and reperfusion. The goal of this review is to introduce and discuss the available data that endogenous cannabinoid signaling is altered during ischemia and that it contributes to the consequences of ischemia-induced injury. Overall, the available data suggest that inhibition of CB1 receptor activation together with increased CB2 receptor activation produces beneficial effects. PMID:18781985

  2. Association of nosocomial infections with delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage.

    PubMed

    Foreman, Paul M; Chua, Michelle; Harrigan, Mark R; Fisher, Winfield S; Vyas, Nilesh A; Lipsky, Robert H; Walters, Beverly C; Tubbs, R Shane; Shoja, Mohammadali M; Griessenauer, Christoph J

    2016-12-01

    OBJECTIVE Delayed cerebral ischemia (DCI) is a recognized complication of aneurysmal subarachnoid hemorrhage (aSAH) that contributes to poor outcome. This study seeks to determine the effect of nosocomial infection on the incidence of DCI and patient outcome. METHODS An exploratory analysis was performed on 156 patients with aSAH enrolled in the Cerebral Aneurysm Renin Angiotensin System study. Clinical and radiographic data were analyzed with univariate analysis to detect risk factors for the development of DCI and poor outcome. Multivariate logistic regression was performed to identify independent predictors of DCI. RESULTS One hundred fifty-three patients with aSAH were included. DCI was identified in 32 patients (20.9%). Nosocomial infection (odds ratio [OR] 3.5, 95% confidence interval [CI] 1.09-11.2, p = 0.04), ventriculitis (OR 25.3, 95% CI 1.39-458.7, p = 0.03), aneurysm re-rupture (OR 7.55, 95% CI 1.02-55.7, p = 0.05), and clinical vasospasm (OR 43.4, 95% CI 13.1-143.4, p < 0.01) were independently associated with the development of DCI. Diagnosis of nosocomial infection preceded the diagnosis of DCI in 15 (71.4%) of 21 patients. Patients diagnosed with nosocomial infection experienced significantly worse outcomes as measured by the modified Rankin Scale score at discharge and 1 year (p < 0.01 and p = 0.03, respectively). CONCLUSIONS Nosocomial infection is independently associated with DCI. This association is hypothesized to be partly causative through the exacerbation of systemic inflammation leading to thrombosis and subsequent ischemia.

  3. [Differential effects of isoflurane and nitrous oxide on cerebral blood flow, metabolism and electrocorticogram after incomplete cerebral ischemia in the rat].

    PubMed

    Ishikawa, T; Maekawa, T; Shinohara, K; Sakabe, T; Takeshita, H

    1989-07-01

    Differential effects of isoflurane (ISOF) and N2O on cerebral blood flow, metabolism and electrocorticogram (ECoG) were examined in rats subjected to 15 min-incomplete cerebral ischemia. In the first study, regional cerebral blood flow (rCBF) and ECoG were measured during and after ischemia. In the second study, local cerebral blood flow (LCBF) and glucose utilization (LCGU) were determined at 60 min after reperfusion. In the N2O group, rCBF in both the cerebral cortex and hippocampus decreased significantly to less than 10% of the pre-ischemic value during ischemia, and it increased to 170% at 10 min after reperfusion. The ECoG became flat during ischemia and reappeared at 21 min after reperfusion. In the ISOF group, rCBF decreased significantly to 25% during ischemia and returned to the preischemic value after reperfusion. The ECoG became flat during ischemia and reappeared at 14 min. In the N2O group, LCBFs decreased significantly to 40-50% of the pre-ischemic values in the forebrain. LCGUs decreased significantly to 30-50% in all structures of the forebrain. In the ISOF group, LCBFs decreased significantly to 60-80% in the forebrain, but were not different in other structures. LCGUs did not differ from pre-ischemic values in all structures except for in the thalamus and habenula. These results may indicate cerebral protective effects of ISOF on incomplete cerebral ischemia in rats.

  4. 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

  5. Neuroprotective effect of humic Acid on focal cerebral ischemia injury: an experimental study in rats.

    PubMed

    Ozkan, Adile; Sen, Halil Murat; Sehitoglu, Ibrahim; Alacam, Hasan; Guven, Mustafa; Aras, Adem Bozkurt; Akman, Tarik; Silan, Coşkun; Cosar, Murat; Karaman, Handan Isin Ozisik

    2015-02-01

    Stroke is still a major cause of death and permanent neurological disability. As humic acids are well-known antioxidant molecules, the purpose of this study was to investigate the potential neuroprotective effects of humic acid in a focal cerebral ischemia model. Twenty-four rats were divided equally into three groups. A middle cerebral artery occlusion model was performed in this study where control (group II) and humic acid (group III) were administered intraperitoneally following an ischemic experimental procedure. Group I was evaluated as sham. Malondialdehyde (MDA), superoxide dismutase (SOD), and nuclear respiratory factor-1 (NRF-1) levels were analyzed biochemically on the right side of the ischemic cerebral hemisphere, while ischemic histopathological studies were completed on the left side to investigate the antioxidant status. Biochemical results showed that SOD and NRF-1 levels were significantly increased in the humic acid group (III) compared with the control group (II) while MDA levels were significantly decreased. On histopathological examination, cerebral edema, vacuolization, degeneration, and destruction of neural elements were decreased in the humic acid group (III) compared with the control group (II). Cerebral ischemia was attenuated by humic acid administration. These observations indicate that humic acid may have potential as a therapeutic agent in cerebral ischemia by preventing oxidative stress.

  6. Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation

    PubMed Central

    Cho, Kyu Suk; Jeon, Se Jin; Kwon, Oh Wook; Jang, Dae Sik; Kim, Sun Yeou; Ryu, Jong Hoon; Choi, Ji Woong

    2017-01-01

    Microglial activation and its-driven neuroinflammation are characteristic pathogenetic features of neurodiseases, including focal cerebral ischemia. The Artemisia asiatica (Asteraceae) extract and its active component, eupatilin, are well-known to reduce inflammatory responses. But the therapeutic potential of eupatilin against focal cerebral ischemia is not known, along with its anti-inflammatory activities on activated microglia. In this study, we investigated the neuroprotective effect of eupatilin on focal cerebral ischemia through its anti-inflammation, particularly on activated microglia, employing a transient middle cerebral artery occlusion/reperfusion (tMCAO), combined with lipopolysaccharide-stimulated BV2 microglia. Eupatilin exerted anti-inflammatory responses in activated BV2 microglia, in which it reduced secretion of well-known inflammatory markers, including nitrite, IL-6, TNF-α, and PGE2, in a concentration-dependent manner. These observed in vitro effects of eupatilin led to in vivo neuroprotection against focal cerebral ischemia. Oral administration of eupatilin (10 mg/kg) in a therapeutic paradigm significantly reduced brain infarction and improved neurological functions in tMCAO-challenged mice. The same benefit was also observed when eupatilin was given even within 5 hours after MCAO induction. In addition, the neuroprotective effects of a single administration of eupatilin (10 mg/kg) immediately after tMCAO challenge persisted up to 3 days after tMCAO. Eupatilin administration reduced the number of Iba1-immunopositive cells across ischemic brain and induced their morphological changes from amoeboid into ramified in the ischemic core, which was accompanied with reduced microglial proliferation in ischemic brain. Eupatilin suppressed NF-κB signaling activities in ischemic brain by reducing IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation. Overall, these data indicate that eupatilin is a neuroprotective agent against

  7. 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

  8. Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion.

    PubMed

    Abd-Elsameea, A A; Moustaf, A A; Mohamed, A M

    2014-08-01

    Oxidative stress plays a major role in the pathogenesis of ischemic and reperfusion injury to many organs, including the brain. Chronic metformin treatment is associated with a lower risk of stroke in clinical populations. The aim of the present study was to investigate the effect of metformin on the oxidative stress induced in experimental model of incomplete global cerebral ischemia and ischemia/reperfusion in adult male Wistar rats. Metformin was administered to rats orally by gavage 500 mg/kg once daily for one week before induction of cerebral ischemia (rats were subjected to 30 min of ischemia before decapitation) and ischemia/reperfusion (rats were subjected to 30 min of ischemia then 60 minutes of reperfusion before decapitation). The selected parameters for oxidative stress were the activities of the antioxidant enzymes: glutathione peroxidase (GSHPx), superoxide dismutase (SOD), and catalase as well as malondialdehyde (MDA) levels. Metformin reduced the elevated activites of GSHPx, SOD and catalase as well as MDA levels in cerebrum of rats exposed to ischemia and ischemia/reperfusion injures. Metformin improved the oxidative stress induced by ischemia and ischemia/reperfusion injuries. This may be a mechanism that explains the cerebroprotective effect of the drug.

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

    PubMed

    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

    2015-10-20

    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.

  10. Autophagy: a double-edged sword for neuronal survival after cerebral ischemia

    PubMed Central

    Chen, Wenqi; Sun, Yinyi; Liu, Kangyong; Sun, Xiaojiang

    2014-01-01

    Evidence suggests that autophagy may be a new therapeutic target for stroke, but whether activation of autophagy increases or decreases the rate of neuronal death is still under debate. This review summarizes the potential role and possible signaling pathway of autophagy in neuronal survival after cerebral ischemia and proposes that autophagy has dual effects. PMID:25206784

  11. 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

  12. CD38 Exacerbates Focal Cytokine Production, Postischemic Inflammation and Brain Injury after Focal Cerebral Ischemia

    PubMed Central

    Gelderblom, Mathias; Ludewig, Peter; Leypoldt, Frank; Koch-Nolte, Friedrich; Gerloff, Christian; Magnus, Tim

    2011-01-01

    Background Converging evidence suggests that inflammatory processes significantly influence brain injury and clinical impairment in ischemic stroke. Although early studies suggested a key role of lymphocytes, recent data has emphasized the orchestrating function of innate immunity, i.e., macrophages and microglia. The bifunctional receptor and ectoenzyme CD38 synthesizes calcium-mobilizing second messengers (e.g., cyclic ADP-ribose), which have been shown to be necessary for activation and migration of myeloid immune cells. Therefore, we investigated the dynamics of CD38 in stroke and the impact of CD38-deficiency on cytokine production, inflammation and cerebral damage in a mouse model of cerebral ischemia-reperfusion. Methodology/Principal Findings We show that the local expression of the chemokine MCP-1 was attenuated in CD38-deficient mice compared with wildtype mice after focal cerebral ischemia and reperfusion. In contrast, no significant induction of MCP-1 expression was observed in peripheral blood after 6 hours. Flow cytometry analysis revealed less infiltrating macrophages and lymphocytes in the ischemic hemisphere of CD38-deficient mice, whereas the amount of resident microglia was unaltered. An up-regulation of CD38 expression was observed in macrophages and CD8+ cells after focal cerebral ischemia in wildtype mice, whereas CD38 expression was unchanged in microglia. Finally, we demonstrate that CD38-deficiency decreases the cerebral ischemic injury and the persistent neurological deficit after three days of reperfusion in this murine temporary middle cerebral artery occlusion (tMCAO) model. Conclusion/Significance CD38 is differentially regulated following stroke and its deficiency attenuates the postischemic chemokine production, the immune cell infiltration and the cerebral injury after temporary ischemia and reperfusion. Therefore CD38 might prove a therapeutic target in ischemic stroke. PMID:21625615

  13. 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.

  14. [The comparison of volume of ischemia zone in CT examination with neurological and functional status of patients after cerebral ischemia].

    PubMed

    Bartynowska, Karolina

    2013-01-01

    The aim of this work was to establish the correlation between volume of ischemic zone in CT examination and neurological and functional (Barthel index) disorders after cerebral ischemia. The retrospective study was performed. The 30 patients (the median age was 73 years; 14 woman and 16 man) were examined. The medial cerebral artery stroke was recognised in CT. CT examinations without contrast media injection, neurological and functional (Barthel index) diagnostic tests were performed directly and 18 months after ischemia. The evolution of ischemic zone in CT and neurological and functional disorders were estimated. The correlation between volume of ischemic zone in CT, neurological parameters and Barthel index results was examined. The statistical correlation between ischemic zone volumetry and physiological reactions was ascertained. In acute phase the greater volume of ischemic zone responds to neurological dysfunctions. The same tendency, without statistical significance, was observed between volume of ischemic zone and Barthel index result (inversely proportional). 18 months after cerebral stroke the statistical correlation was significant only for comparison of volume of the ischemic zone and Barthel index result. The greater volume of ischemic zone responded to lower Barthel index. Ischemic stroke volumetry in CT examination can facilitate neurological (physiological reactions disorders) and functional (Barthel index) status assessment.

  15. 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.

  16. 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

  17. Flutamide Enhances Neuroprotective Effects of Testosterone during Experimental Cerebral Ischemia in Male Rats

    PubMed Central

    Fanaei, Hamed; Sadeghipour, Hamid Reza; Karimian, Seyed Morteza; Hassanzade, Gholamreza

    2013-01-01

    Testosterone has been shown to worsen histological and neurological impairment during cerebral ischemia in animal models. Cell culture studies revealed that testosterone is implicated in protecting neural and glial cells against insults, and they started to elucidate testosterone pathways that underlie these protective effects. These studies support the hypothesis that testosterone can be neuroprotective throughout an episode of cerebral ischemia. Therefore, we evaluated the mechanisms underlying the shift between testosterone protective and deleterious effects via block testosterone aromatization and androgen receptors in rats subjected to 60-minute middle cerebral artery occlusion. Fifty rats were divided into five equal groups: gonadally intact male; castrated male; intact male + flutamide; intact male + letrozole; intact male + combination flutamide and letrozole. Our results indicated that castration has the ability to reduce histological damage and to improve neurological score 24 hours after middle cerebral artery occlusion. Moreover, flutamide improved histologic and neurological impairment better than castration. Letrozole induced increases in striatal infarct volume and seizures in gonadally intact rats. Combination of flutamide and letrozole showed that letrozole can reverse beneficial effects of flutamide. In conclusion, it seems that the beneficial effects of flutamide are the prevention of the deleterious effects and enhancement of neuroprotective effects of testosterone during cerebral ischemia. PMID:23401794

  18. 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

    2015-01-20

    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.

  19. 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

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

    PubMed

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

    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.

  1. 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.

  2. Interruption of perivascular sympathetic nerves of cerebral arteries offers neuroprotection against ischemia.

    PubMed

    Lee, Reggie H; Couto E Silva, Alexandre; Lerner, Francesca M; Wilkins, Carl S; Valido, Stephen E; Klein, Daniel D; Wu, Celeste Y; Neumann, Jake T; Della-Morte, David; Koslow, Stephen H; Minagar, Alireza; Lin, Hung Wen

    2017-01-01

    Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia. Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory. Copyright © 2017 the American Physiological Society.

  3. [Effectiveness of mesoglycan in the prevention of cerebral ischemia].

    PubMed

    Bettini, R; Maino, C; Gorini, M

    2003-01-01

    40 subjects who had a transitory ischemic cerebral attack were treated with Mesoglycan and controlled for two consecutive years. Only four patients showed relapse of ischemic cerebral attacks. There was also noted a positive effect on the patients' quality of life, examined using psycometric scales.

  4. Fish oil prevents oxidative stress and exerts sustained antiamnesic effect after global cerebral ischemia.

    PubMed

    Bacarin, Cristiano Correia; de Sá-Nakanishi, Anacharis Babeto; Bracht, Adelar; Matsushita, Makoto; Santos Previdelli, Isolde; Mori, Marco Aurélio; de Oliveira, Rúbia Maria Weffort; Milani, Humberto

    2015-01-01

    Transient, global cerebral ischemia (TGCI) causes hippocampal/cortical damage and the persistent loss of welltrained, long-term memory (retrograde amnesia). Fish oil (FO), a rich source of omega-3 polyunsaturated fatty acids, abolishes such amnesia in the absence of neurohistological protection. The present study investigated whether FO prevents ischemia-induced oxidative stress and whether such an action contributes to the lasting effect of FO on memory recovery. In a first experiment, FO was administered for 4 days prior to ischemia, and antioxidant status was subsequently measured after 24 h of reperfusion. In another experiment, naive rats were trained in an eight-arm radial maze until they achieved asymptotic performance and then subjected to TGCI. One group of rats received FO as in the first experiment (i.e., 4 days prior to ischemia), whereas another group received FO for 4 days prior to ischemia plus 6 days postischemia. Retrograde memory performance was assessed 2-5 weeks after ischemia. TGCI depleted the level of antioxidant enzymes and increased the amount of protein carbonylation, indicating oxidative damage. Fish oil reversed oxidative damage to control levels. The same treatment that attenuated oxidative stress after 24 h of reperfusion also prevented retrograde amnesia assessed several weeks later. This antiamnesic effect afforded by short preischemia treatment was comparable to 10 days of treatment but not as consistent. These data indicate that an antioxidant action in the hyperacute phase of ischemia/reperfusion may contribute to the long-term, antiamnesic effect of FO.

  5. Effect of isoflurane on neuronal apoptosis in rats subjected to focal cerebral ischemia.

    PubMed

    Kawaguchi, Masahiko; Drummond, John C; Cole, Daniel J; Kelly, Paul J; Spurlock, Mark P; Patel, Piyush M

    2004-03-01

    Although isoflurane can reduce ischemic neuronal injury after short postischemic recovery intervals, this neuroprotective efficacy is not sustained. Neuronal apoptosis can contribute to the gradual increase in infarct size after ischemia. This suggests that isoflurane, although capable of reducing early neuronal death, may not inhibit ischemia-induced apoptosis. We investigated the effects of isoflurane on markers of apoptosis in rats subjected to focal ischemia. Fasted Wistar-Kyoto rats were anesthetized with isoflurane and randomly allocated to awake (n = 40) or isoflurane (n = 40) groups. Animals in both groups were subjected to focal ischemia by filament occlusion of the middle cerebral artery for 70 min. Pericranial temperature was servo-controlled at 37 degrees C +/- 0.2 degrees C throughout the experiment. In the awake group, isoflurane was discontinued and the animals were allowed to awaken. In the isoflurane group, isoflurane anesthesia was maintained at 1.5 MAC (minimum alveolar anesthetic concentration). Animals were killed 7 h, 1 day, 4 days, or 7 days after reperfusion (n = 10/group/time point). The area of cerebral infarction was measured by image analysis in a hematoxylin and eosin stained section. In three adjacent sections, apoptotic neurons were identified by TUNEL staining and immunostaining for active caspase-9 and caspase-3. Infarct size was smaller in the isoflurane group than the awake group 7 h, 1 day, and 4 days after reperfusion (P < 0.05). However, this difference was absent 7 days after reperfusion. The number of apoptotic (TUNEL, caspase-3, and caspase-9 positive) cells 1 day after ischemia was significantly more in the awake versus isoflurane group. After a recovery period of 4 or 7 days, the number of apoptotic cells in the isoflurane group was more than in the awake group. After 7 days, the number of caspase-3 and -9 positive neurons was more in the isoflurane group (P < 0.05). The data indicate that isoflurane delays but does not

  6. Cerebral microvascular dysfunction in metabolic syndrome is exacerbated by ischemia-reperfusion injury.

    PubMed

    Obadia, Nathalie; Lessa, Marcos Adriano; Daliry, Anissa; Silvares, Raquel Rangel; Gomes, Fabiana; Tibiriçá, Eduardo; Estato, Vanessa

    2017-09-08

    Metabolic syndrome (MetS) is associated with an increased risk of cerebrovascular diseases, including cerebral ischemia. Microvascular dysfunction is an important feature underlying the pathophysiology of cerebrovascular diseases. In this study, we aimed to investigate the impacts of ischemia and reperfusion (IR) injury on the cerebral microvascular function of rats with high-fat diet-induced MetS. We examined Wistar rats fed a high-fat diet (HFD) or normal diet (CTL) for 20 weeks underwent 30 min of bilateral carotid artery occlusion followed by 1 h of reperfusion (IR) or sham surgery. Microvascular blood flow was evaluated on the parietal cortex surface through a cranial window by laser speckle contrast imaging, functional capillary density, endothelial function and endothelial-leukocyte interactions by intravital videomicroscopy. Lipid peroxidation was assessed by TBARs analysis, the expression of oxidative enzymes and inflammatory markers in the brain tissue was analyzed by real-time PCR. The cerebral IR in MetS animals induced a functional capillary rarefaction (HFD IR 117 ± 17 vs. CTL IR 224 ± 35 capillary/mm(2); p < 0.05), blunted the endothelial response to acetylcholine (HFD IR -16.93% vs. CTL IR 16.19% from baseline inner diameter p < 0.05) and increased the endothelial-leukocyte interactions in the venules in the brain. The impact of ischemia on the cerebral microvascular blood flow was worsened in MetS animals, with a marked reduction of cerebral blood flow, exposing brain tissue to a higher state of hypoxia. Our results demonstrate that during ischemia and reperfusion, animals with MetS are more susceptible to alterations in the cerebral microcirculation involving endothelial dysfunction and oxidative stress events.

  7. Neuroprotective activity of Stereospermum suaveolens against global cerebral ischemia rat model.

    PubMed

    Shalavadi, M H; Chandrashekhar, V M; Ramkishan, A; Nidavani, R B; Biradar, B S

    2013-08-01

    Stereospermum suaveolens DC. (Bignoniaceae) is a medicinal tree species native to India. Traditionally, the whole plant is used for various diseases including neuronal disorders. The present study evaluated the neuroprotective activity of Stereospermum suaveolens against global cerebral ischemia in a rat model. Neuroprotective activity was carried out by global cerebral ischemia on Sprague-Dawley rats and divided into five groups of eight rats each; sham and control groups received normal saline (10 ml/kg) and treated groups received methanol extract of Stereospermum suaveolens (MES) orally (125, 250, and 500 mg/kg) for 10 days prior to the experiment. Global cerebral ischemia was induced by bilateral carotid artery (BCA) occlusion for 30 min followed by 4-h reperfusion. The antioxidant enzymatic and non-enzymatic levels were estimated by UV spectroscopic method along with cerebral infarction area; histopathological studies were carried out. LD₅₀ of MES was found to be 5000 mg/kg of body weight. The entire test was performed at dose levels 125, 250, and 500 mg/kg of body weight. The results of the study indicate that the Stereospermum suaveolens methanol extract showed neuroprotective activity by a significant decrease in lipid peroxidation (p < 0.001) and an increase in superoxide dismutase (p < 0.01), catalase (p < 0.01), glutathione (p < 0.001), and total thiol (p < 0.001) levels in extract-treated groups as compared to control group. Measurement of cerebral infarction area and histopathological studies further supported the protective effect of the extract. These findings suggest a potential protective role of Stereospermum suaveolens against global cerebral ischemia/reperfusion-induced brain injury.

  8. Mechanisms of estrogens' dose-dependent neuroprotective and neurodamaging effects in experimental models of cerebral ischemia.

    PubMed

    Strom, Jakob O; Theodorsson, Annette; Theodorsson, Elvar

    2011-01-01

    Ever since the hypothesis was put forward that estrogens could protect against cerebral ischemia, numerous studies have investigated the mechanisms of their effects. Despite initial studies showing ameliorating effects, later trials in both humans and animals have yielded contrasting results regarding the fundamental issue of whether estrogens are neuroprotective or neurodamaging. Therefore, investigations of the possible mechanisms of estrogen actions in brain ischemia have been difficult to assess. A recently published systematic review from our laboratory indicates that the dichotomy in experimental rat studies may be caused by the use of insufficiently validated estrogen administration methods resulting in serum hormone concentrations far from those intended, and that physiological estrogen concentrations are neuroprotective while supraphysiological concentrations augment the damage from cerebral ischemia. This evidence offers a new perspective on the mechanisms of estrogens' actions in cerebral ischemia, and also has a direct bearing on the hormone replacement therapy debate. Estrogens affect their target organs by several different pathways and receptors, and the mechanisms proposed for their effects on stroke probably prevail in different concentration ranges. In the current article, previously suggested neuroprotective and neurodamaging mechanisms are reviewed in a hormone concentration perspective in an effort to provide a mechanistic framework for the dose-dependent paradoxical effects of estrogens in stroke. It is concluded that five protective mechanisms, namely decreased apoptosis, growth factor regulation, vascular modulation, indirect antioxidant properties and decreased inflammation, and the proposed damaging mechanism of increased inflammation, are currently supported by experiments performed in optimal biological settings.

  9. Neuroprotection of antioxidant enzymes against transient global cerebral ischemia in gerbils

    PubMed Central

    Lee, Jae-Chul

    2014-01-01

    Experimentally transient global cerebral ischemia using animal models have been thoroughly studied and numerous reports suggest the involvement of oxidative stress in the pathogenesis of neuronal death in ischemic lesions. In animal models, during the reperfusion period after ischemia, increased oxygen supply results in the overproduction of reactive oxygen species (ROS), which are involved in the process of cell death. ROS, such as superoxide anions, hydroxyl free radicals, hydrogen peroxide and nitric oxide are produced as a consequence of metabolic reactions and central nervous system activity. These reactive species are directly involved in the oxidative damage of cellular macromolecules such as nucleic acids, lipids and proteins in ischemic tissues, which can lead to cell death. Antioxidant enzymes are believed to be among the major mechanisms by which cells counteract the deleterious effect of ROS after cerebral ischemia. Consequently, antioxidant strategies have been long suggested as a therapy for experimental ischemic stroke; however, clinical trials have not yet been able to promote the translation of this concept into patient treatment regimens. This article focuses on the contribution of oxidative stress or antioxidants to the post-ischemic neuronal death following transient global cerebral ischemia by using a gerbil model. PMID:25276473

  10. Deciphering of mitochondrial cardiolipin oxidative signaling in cerebral ischemia-reperfusion

    PubMed Central

    Ji, Jing; Baart, Sophie; Vikulina, Anna S; Clark, Robert SB; Anthonymuthu, Tamil S; Tyurin, Vladimir A; Du, Lina; St Croix, Claudette M; Tyurina, Yulia Y; Lewis, Jesse; Skoda, Erin M; Kline, Anthony E; Kochanek, Patrick M; Wipf, Peter; Kagan, Valerian E; Bayır, Hülya

    2015-01-01

    It is believed that biosynthesis of lipid mediators in the central nervous system after cerebral ischemia-reperfusion starts with phospholipid hydrolysis by calcium-dependent phospholipases and is followed by oxygenation of released fatty acids (FAs). Here, we report an alternative pathway whereby cereberal ischemia-reperfusion triggered oxygenation of a mitochondria-specific phospholipid, cardiolipin (CL), is followed by its hydrolysis to yield monolyso-CLs and oxygenated derivatives of fatty (linoleic) acids. We used a model of global cerebral ischemia-reperfusion characterized by 9 minutes of asphyxia leading to asystole followed by cardiopulmonary resuscitation in postnatal day 17 rats. Global ischemia and cardiopulmonary resuscitation resulted in: (1) selective oxidation and hydrolysis of CLs, (2) accumulation of lyso-CLs and oxygenated free FAs, (3) activation of caspase 3/7 in the brain, and (4) motor and cognitive dysfunction. On the basis of these findings, we used a mitochondria targeted nitroxide electron scavenger, which prevented CL oxidation and subsequent hydrolysis, attenuated caspase activation, and improved neurocognitive outcome when administered after cardiac arrest. These data show that calcium-independent CL oxidation and subsequent hydrolysis represent a previously unidentified pathogenic mechanism of brain injury incurred by ischemia-reperfusion and a clinically relevant therapeutic target. PMID:25407268

  11. 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

  12. 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.

  13. 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

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

    PubMed

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

    2015-08-01

    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. 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. 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. 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.

  15. 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

  16. A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice.

    PubMed

    Miyanohara, Jun; Shirakawa, Hisashi; Sanpei, Kazuaki; Nakagawa, Takayuki; Kaneko, Shuji

    2015-11-20

    Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca(2+) permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia.

  17. A pathophysiological role of TRPV1 in ischemic injury after transient focal cerebral ischemia in mice

    SciTech Connect

    Miyanohara, Jun; Shirakawa, Hisashi; Sanpei, Kazuaki; Nakagawa, Takayuki; Kaneko, Shuji

    2015-11-20

    Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca{sup 2+} permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia. - Highlights: • We investigated whether TRPV1 is involved in transient ischemic brain damage in mice. • Neurological deficits and infarct volumes were lower in TRPV1-KO mice than in WT mice. • Injection of a TRPV1 antagonist, capsazepine, attenuated neurological deficits and improved infarct size. • No differences in astrocytic or microglial activation were observed between WT and TRPV1-KO mice.

  18. 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.

  19. Different mechanisms of secondary neuronal damage in thalamic nuclei after focal cerebral ischemia in rats.

    PubMed

    Dihné, Marcel; Grommes, Christian; Lutzenburg, Michael; Witte, Otto W; Block, Frank

    2002-12-01

    After focal cerebral ischemia, depending on its localization and extent, secondary neuronal damage may occur that is remote from the initial lesion. In this study differences in secondary damage of the ventroposterior thalamic nucleus (VPN) and the reticular thalamic nucleus (RTN) were investigated with the use of different ischemia models. Transient middle cerebral artery occlusion (MCAO) leads to cortical infarction, including parts of the basal ganglia such as the globus pallidus, and to widespread edema. Photothrombotic ischemia generates pure cortical infarcts sparing the basal ganglia and with only minor edema. Neuronal degeneration was quantified within the ipsilateral RTN and VPN 14 days after ischemia. Glial reactions were studied with the use of immunohistochemistry. MCAO resulted in delayed neuronal cell loss of the ipsilateral VPN and RTN. Glial activation occurred in both nuclei beginning after 24 hours. Photothrombotic ischemia resulted in delayed neuronal cell loss only within the VPN. Even 2 weeks after photothrombotic ischemia, glial activation could only be seen within the VPN. Pure cortical infarcts after photothrombotic ischemia, without major edema and without effects on the globus pallidus of the basal ganglia, only lead to secondary VPN damage that is possibly due to retrograde degeneration. MCAO, which results in infarction of cortex and globus pallidus and which causes widespread edema, leads to secondary damage in the VPN and RTN. Thus, additional RTN damage may be due to loss of protective GABAergic input from the globus pallidus to the RTN or due to the extensive edema. Retrograde degeneration is not possible because the RTN, in contrast to the VPN, has no efferents to the cortex.

  20. Syringaldehyde exerts neuroprotective effect on cerebral ischemia injury in rats through anti-oxidative and anti-apoptotic properties

    PubMed Central

    Bozkurt, Aras Adem; Mustafa, Guven; Tarık, Akman; Adile, Ozkan; Murat, Sen Halil; Mesut, Kılıcoglu; Yıldıray, Kalkan; Coskun, Silan; Murat, Cosar

    2014-01-01

    There are few studies on the neuroprotective effects of syringaldehyde in a rat model of cerebral ischemia. The study aimed to elucidate the mechanisms underlying the neuroprotective effects of syringaldehyde on ischemic brain cells. Rat models of cerebral ischemia were intraperitoneally administered syringaldehyde. At 6 and 24 hours after syringaldehyde administration, cell damage in the brain of cerebral ischemia rats was obviously reduced, superoxide dismutase activity and nuclear respiratory factor 1 expression in the brain tissue were markedly increased, malondiadehyde level was obviously decreased, apoptosis-related cysteine peptidase caspase-3 and -9 immunoreactivity was obviously decreased, and neurological function was markedly improved. These findings suggest that syringaldehyde exerts neuroprotective effects on cerebral ischemia injury through anti-oxidation and anti-apoptosis. PMID:25558237

  1. 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.

  2. Excessive Supraventricular Ectopic Activity Is Indicative of Paroxysmal Atrial Fibrillation in Patients with Cerebral Ischemia

    PubMed Central

    Weber-Krüger, Mark; Gröschel, Klaus; Mende, Meinhard; Seegers, Joachim; Lahno, Rosine; Haase, Beatrice; Niehaus, Cord-Friedrich; Edelmann, Frank; Hasenfuß, Gerd

    2013-01-01

    Background Detecting paroxysmal atrial fibrillation (PAF) in patients with cerebral ischemia is challenging. Frequent premature atrial complexes (PAC/h) and the longest supraventricular run on 24-h-Holter (SV-run24 h), summarised as excessive supraventricular ectopic activity (ESVEA), may help selecting patients for extended ECG-monitoring, especially in combination with echocardiographic marker LAVI/a’ (left atrial volume index/late diastolic tissue Doppler velocity). Methods Retrospective analysis from the prospective monocentric observational trial Find-AF (ISRCTN-46104198). Patients with acute stroke or TIA were enrolled at the University Hospital Göttingen, Germany. Those with sinus rhythm at presentation received 7-day Holter-monitoring. ESVEA was quantified in one 24-hour interval free from PAF. Echocardiographic parameters were assessed prospectively. Results PAF was detected in 23/208 patients (11.1%). The median was 4 [IQR 1; 22] for PAC/h and 5 [IQR 0; 9] for SV-run24 h. PAF was more prevalent in patients with ESVEA: 19.6% vs. 2.8% for PAC/h >4 vs. ≤4 (p<0.001); 17.0% vs. 4.9% for SV-run24 h >5 vs. ≤5 beats (p = 0.003). Patients with PAF showed more supraventricular ectopic activity: 29 PAC/h [IQR 9; 143] vs. 4 PAC/h [1]; [14] and longest SV-run24 h = 10 [5]; [21] vs. 0 [0; 8] beats (both p<0.001). Both markers discriminated between the PAF- and the Non-PAF-group (area under receiver-operator-characteristics-curve 0.763 [95% CI 0.667; 0.858] and 0.716 [0.600; 0.832]). In multivariate analyses log(PAC/h) and log(SV-run24 h) were independently indicative of PAF. In Patients with PAC/h ≤4 and normal LAVI/a’ PAF was excluded, whereas those with PAC/h >4 and abnormal LAVI/a’ showed high PAF-rates. Conclusions ESVEA discriminated PAF from non-PAF beyond clinical factors including LAVI/a’ in patients with cerebral ischemia. Normal LAVI/a’+PAC/h ≤4 ruled out PAF, while prevalence was high in those with abnormal LAVI/a’+PAC/h >4. PMID

  3. Serial magnetic resonance imaging of evolving focal cerebral ischemia in the CAT

    SciTech Connect

    Barnett, G.H.; Lorig, R.J.; Jones, S.C.; Friel, H.T.; Modic, M.T.; Little, J.R.

    1985-05-01

    Magnetic resonance imaging (MRI) is recognized as a sensitive medium for detecting lesions within the central nervous system. Three cats were scanned under light pentobarbital anesthesia using various MRI techniques before and after right middle cerebral artery (MCA) occlusion. Scanning began as early as four minutes after MCA occlusion and continued 8 to 10 hours. The animals were subsequently perfused with a colloidal carbon and phosphate buffered formalin. Brains were removed and sliced for histopathologic examination. The sharpest images were produced with a single spin-echo, multi-slice technique using a 0.6 Tesla (T) FIELD, 0.4 cm slice thickness, and a surface coil. Changes were apparent within 1 hr after MCA occlusion with T2 weighting (TR 2000 msec, TE 120 msec). Increased signal with this technique correlated with areas of decreased colloidal carbon perfusion. One animal with a large cortical infarction showed increased cortical signal at the time of the first MRI scan completed in the first 20 min. An animal with only mild cortical changes and severe ischemic changes in the dorsal thalamus nuclei had similar MRI results. T1 weighted images (TR 500 msec, TE 30 msec) revealed changes in hemispheric contour possibly corresponding to edema at 4 hours post occlusion. One animal imaged with almost double the slice thickness (0.75 cm) and with a 1.5 T field showed poor image quality using the above techniques but without a surface coil. MRI is sensitive in detecting changes due to cerebral ischemia within 30 minutes of onset. Increased MRI signal correlated with areas of decreased colloidal carbon perfusion, demonstrated at later times.

  4. [Comparative evaluation of the neuroprotective activity of phenibut and piracetam under experimental cerebral ischemia conditions in rats].

    PubMed

    Tiurenkov, I N; Bagmetov, M N; Epishina, V V; Borodkina, L E; Voronkov, A V

    2006-01-01

    The neuroprotective properties of phenibut and piracetam were studied in rats with cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in brain cortex under ischemic injury conditions were studied. Phenibut and (to a lower extent) piracetam reduced a neuralgic deficiency, amnesia, and the degree of cerebral circulation drop, and improved the spontaneous movement and research activity deteriorated by brain ischemia.

  5. Tetracycline inhibits local inflammation induced by cerebral ischemia via modulating autophagy.

    PubMed

    Jiang, Yongjun; Zhu, Juehua; Wu, Li; Xu, Gelin; Dai, Jianwu; Liu, Xinfeng

    2012-01-01

    Tetracycline exerts neuroprotection via suppressing the local inflammation induced by cerebral ischemia. However, the underlying mechanism is not completely clear. The mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and the number of activated microglia were measured to detect the inflammatory process in the ischemic hemisphere. The key proteins of nuclear factor kappa B pathway and the binding activity of nuclear factor kappa B were also measured. Two key components of autophagy, Beclin 1 and LC3, were detected by western blotting. Pretreatment with tetracycline inhibited the mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and decreased the numbers of activated and phagocytotic microglia. Tetracycline down regulated the total and phosphorylated expressions of IKK, IκB and p65 (P<0.05). The autophagy inhibitor, 3-methyladenine, inhibited inflammation and activation of nuclear factor kappa B pathway. The levels of Beclin 1 and LC3 were decreased by 3-methyladenine and tetracycline. Our data suggested that pretreatment of tetracycline may inhibit autophagy in the ischemic stroke brain and then suppress the inflammatory process via inhibiting the activation of nuclear factor kappa B pathway.

  6. Tetracycline Inhibits Local Inflammation Induced by Cerebral Ischemia via Modulating Autophagy

    PubMed Central

    Jiang, Yongjun; Zhu, Juehua; Wu, Li; Xu, Gelin; Dai, Jianwu; Liu, Xinfeng

    2012-01-01

    Background Tetracycline exerts neuroprotection via suppressing the local inflammation induced by cerebral ischemia. However, the underlying mechanism is not completely clear. Methodology/Principal Findings The mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and the number of activated microglia were measured to detect the inflammatory process in the ischemic hemisphere. The key proteins of nuclear factor kappa B pathway and the binding activity of nuclear factor kappa B were also measured. Two key components of autophagy, Beclin 1 and LC3, were detected by western blotting. Pretreatment with tetracycline inhibited the mRNA and protein expressions of tumor necrosis factor α and interleukin 6 and decreased the numbers of activated and phagocytotic microglia. Tetracycline down regulated the total and phosphorylated expressions of IKK, IκB and p65 (P<0.05). The autophagy inhibitor, 3-methyladenine, inhibited inflammation and activation of nuclear factor kappa B pathway. The levels of Beclin 1 and LC3 were decreased by 3-methyladenine and tetracycline. Conclusions/Significance Our data suggested that pretreatment of tetracycline may inhibit autophagy in the ischemic stroke brain and then suppress the inflammatory process via inhibiting the activation of nuclear factor kappa B pathway. PMID:23144925

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

    PubMed

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

    2013-11-01

    Although propofol has been reported to offer neuroprotection against cerebral ischemia injury, its impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of propofol post-treatment on blood-brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), and hypoxia inducible factor (HIF)-1α. Cerebral ischemia was induced in male Sprague-Dawley rats (n = 78) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol, 1 mg kg(-1) min(-1) of propofol was administered for 1 h from the start of reperfusion. Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, and MMP-9 was determined 24 h after reperfusion and the expression of HIF-1α was determined 8 h after reperfusion. Propofol post-treatment significantly reduced cerebral edema (P < 0.05) and BBB disruption (P < 0.05) compared with the saline-treated control. The expression of AQP-1, AQP-4, MMP-2, and MMP-9 at 24 h and of HIF-1α at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P < 0.05). Propofol post-treatment attenuated cerebral edema after transient cerebral ischemia, in association with reduced expression of AQP-1, AQP-4, MMP-2, and MMP-9. The decreased expression of AQPs and MMPs after propofol post-treatment might result from suppression of HIF-1α expression.

  8. Leukotrienes, Prostaglandins, and Granulocyte Accumulation in Cerebral Ischemia

    DTIC Science & Technology

    1987-01-01

    model of multifocal ischemia induced by air embolism f9l.,This ac- cumulation could theoretically aggravate and extend the initial tissue injury...skull, stainless steel screw electrodes were positioned over the right sensorimotor cortex and the nasal bones (reference electrode). Electrode...their participation in postischemic reperfusion injury. Romson et al. [28] and Mullane et al. [251 reported results from models of myocardial infarction

  9. Modulation of cerebral RAGE expression following nitric oxide synthase inhibition in rats subjected to focal cerebral ischemia.

    PubMed

    Greco, Rosaria; Demartini, Chiara; Zanaboni, Anna Maria; Blandini, Fabio; Amantea, Diana; Tassorelli, Cristina

    2017-04-05

    The receptor for advanced glycation endproducts (RAGE) is a key mediator of neuroinflammation following cerebral ischemia. Nitric oxide (NO) plays a dualistic role in cerebral ischemia, depending on whether it originates from neuronal, inducible or endothelial synthase. Although a dynamic interplay between RAGE and NO pathways exists, its relevance in ischemic stroke has not been investigated. The aim of this study is to evaluate the effect of the NO synthase (NOS) inhibition on RAGE expression in rats subjected to transient middle cerebral artery occlusion (tMCAo). Full-length (fl-RAGE) gene expression was elevated in the striatum and, to a lesser extent, in the cortex of rats undergone tMCAo. The exacerbation of cortical damage caused by systemic administration of L-N-(1-iminoethyl)ornithine (L-NIO), a relatively selective inhibitor of endothelial NOS (eNOS), was associated with elevated mRNA levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α and fl-RAGE in both the cortex and the striatum. Conversely, NG-nitro-l-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, decreased cortical damage, did not affect cerebral cytokine mRNA levels, while it increased fl-RAGE mRNA expression only in the striatum. Fl-RAGE striatal protein levels varied accordingly with observed mRNA changes in the striatum, while in the cortex, RAGE protein levels were reduced by tMCAo and further decreased following L-NIO treatment. Modulation of RAGE expression by different inhibitors of NOS may have opposite effects on transient cortical ischemia: the non selective inhibition of NOS activity is protective, while the selective inhibition of eNOS is harmful, probably via the activation of inflammatory pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Rosiglitazone Promotes White Matter Integrity and Long-Term Functional Recovery After Focal Cerebral Ischemia.

    PubMed

    Han, Lijuan; Cai, Wei; Mao, Leilei; Liu, Jia; Li, Peiying; Leak, Rehana K; Xu, Yun; Hu, Xiaoming; Chen, Jun

    2015-09-01

    Oligodendrogenesis is essential for white matter repair after stroke. Although agonists of peroxisome proliferator-activated receptors γ confer neuroprotection in models of cerebral ischemia, it is not known whether this effect extends to white matter protection. This study tested the hypothesis that the peroxisome proliferator-activated receptors γ agonist rosiglitazone enhances oligodendrogenesis and improves long-term white matter integrity after ischemia/reperfusion. Male adult C57/BL6 mice (25-30 g) were subjected to 60-minute middle cerebral artery occlusion and reperfusion. Rosiglitazone (3 mg/kg) was injected intraperitoneally once daily for 14 days beginning 2 hours after reperfusion. Sensorimotor and cognitive functions were evaluated ≤21 days after middle cerebral artery occlusion. Immunostaining was used to assess infarct volume, myelin loss, and microglial activation. Bromodeoxyuridine (BrdU) was injected for measurements of proliferating NG2(+) oligodendrocyte precursor cells (OPCs) and newly generated adenomatous polyposis coli(+) oligodendrocytes. Mixed glial cultures were used to confirm the effect of rosiglitazone on oligodendrocyte differentiation and microglial polarization. Rosiglitazone significantly reduced brain tissue loss, ameliorated white matter injury, and improved sensorimotor and cognitive functions for at least 21 days after middle cerebral artery occlusion. Rosiglitazone enhanced OPC proliferation and increased the numbers of newly generated mature oligodendrocytes after middle cerebral artery occlusion. Rosiglitazone treatment also reduced the numbers of Iba1(+)/CD16(+) M1 microglia and increased the numbers of Iba1(+)/CD206(+) M2 microglia after stroke. Glial culture experiments confirmed that rosiglitazone promoted oligodendrocyte differentiation, perhaps by promoting microglial M2 polarization. Rosiglitazone treatment improves long-term white matter integrity after cerebral ischemia, at least, in part, by promoting

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

    PubMed

    Han, Jing; Xiao, Qing; Lin, Yan-Hua; Zheng, Zhen-Zhu; He, Zhao-Dong; Hu, Juan; Chen, Li-Dian

    2015-12-01

    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.

  12. 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.

  13. Chrysophanol Inhibits NALP3 Inflammasome Activation and Ameliorates Cerebral Ischemia/Reperfusion in Mice

    PubMed Central

    Zhang, Nan; Liu, Xiaoxia; Wang, Hong; Xue, Jing; Yu, Jingying; Kang, Ning; Wang, Xiaolu

    2014-01-01

    The most effective way to contain cerebral ischemic injury is reperfusion; however, reperfusion itself may result in tissue injury, for which inflammatory damage is one of the main causative factors. NALP3 inflammasome is a multiprotein complex. It consists of NALP3, ASC, and caspase-1, whose function is to switch on the inflammatory process. Chrysophanol is an extract from plants of Rheum genus and it possesses many pharmacological effects including its anti-inflammation activity. In this study, the effects of chrysophanol in cerebral ischemia/reperfusion and the potential mechanisms were investigated. Male CD1 mice were subject to transient middle cerebral artery occlusion (tMCAO). The NALP3 inflammasome activation status and its dynamic expression during the natural inflammatory response induced by tMCAO were first profiled. The neuroprotective effects of chrysophanol were then assessed and the potential mechanisms mediating the observed neuroprotection were then explored. Physical parameters including neurological deficit, infarct size, brain edema, and BBB permeability were measured at 24 h after tMCAO. Confocal microscopy, Western blotting, immunohistochemistry, and qRT-PCR techniques were utilized to analyze the expression of NALP3 inflammasome and IL-1β. Our results indicated that the brain tissue damage during cerebral ischemia/reperfusion is accompanied by NALP3 inflammasome activation. Chrysophanol could inhibit the activation of NALP3 inflammasome and protect cerebral ischemic stroke. PMID:24876671

  14. [Cardioprotective effect of drugs with antioxidant activity in acute cerebral ischemia].

    PubMed

    Stoliarova, V V

    2001-01-01

    The bioelectric cardiac activity was studied in the experiments on white mice with an acute cerebral blood circulation disorder. It was found that he resulting EEG changes possess a specific character, with the sympathoadrenal system stimulation playing an important role in the acute cerebrocardiac syndrome development. The antioxidant-type agents such as emoxypine (50 mg/kg), mexidol (50 mg/kg), and cytochrome C (10 mg/kg) produce a significant cardioprotective effect in the test animals with experimental cerebral ischemia, which was comparable with the effect of propranolol (obsidane) (0.1 mg/kg).

  15. Influence of changes in glutathione concentration on body temperature and tolerance to cerebral ischemia.

    PubMed

    Kolesnichenko, L S; Kulinsky, V I; Sotnikova, G V; Kovtun, V Yu

    2003-05-01

    Two compounds that deplete glutathione (buthionine sulfoximine and diethyl maleate) with different mechanisms of action decrease body temperature and increase tolerance to complete global cerebral ischemia, both correlating closely with the glutathione concentration decrease. Glutathione apparently participates in the regulations of these functional parameters. GSH diethyl ester does not influence the latter, though it increases moderately the GSH concentration. Injection of GSH ester into the cerebral ventricles or subcutaneously selectively increases the GSH level in the brain and liver. An influence of the brain on the glutathione system in the liver was revealed. Diethyl maleate and GSH ester increase the activity of glutathione metabolizing enzymes under certain conditions.

  16. 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.

  17. Protective effect of ginkgo proanthocyanidins against cerebral ischemia/reperfusion injury associated with its antioxidant effects

    PubMed Central

    Cao, Wang-li; Huang, Hai-bo; Fang, Ling; Hu, Jiang-ning; Jin, Zhu-ming; Wang, Ru-wei

    2016-01-01

    Proanthocyanidins have been shown to effectively protect ischemic neurons, but its mechanism remains poorly understood. Ginkgo proanthocyanidins (20, 40, 80 mg/kg) were intraperitoneally administered 1, 24, 48 and 72 hours before reperfusion. Results showed that ginkgo proanthocyanidins could effectively mitigate neurological disorders, shorten infarct volume, increase superoxide dismutase activity, and decrease malondialdehyde and nitric oxide contents. Simultaneously, the study on grape seed proanthocyanidins (40 mg/kg) confirmed that different sources of proanthocyanidins have a similar effect. The neurological outcomes of ginkgo proanthocyanidins were similar to that of nimodipine in the treatment of cerebral ischemia/reperfusion injury. Our results suggest that ginkgo proanthocyanidins can effectively lessen cerebral ischemia/reperfusion injury and protect ischemic brain tissue and these effects are associated with antioxidant properties. PMID:28123420

  18. 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

  19. TLR2 and TLR4 in the Brain Injury Caused by Cerebral Ischemia and Reperfusion

    PubMed Central

    Wang, Ying; Zhu, Yuhong

    2013-01-01

    Brain injury caused by cerebral ischemia/reperfusion is a complicated pathophysiological course, in which inflammation is thought to play an important role. Toll-like receptors are a type of transmembrane proteins, which can recognize either exogenous pathogen-associated molecular patterns or endogenous stress or damage-associated molecular patterns in the innate immune system and initiate inflammatory responses. Among Toll-like receptors, TLR2 and TLR4 are found to be more important than others in the pathological progression of cerebral injury due to ischemia and reperfusion. This review will focus on the biological characteristics and functions of TLR2 and TLR4 and their downstream signal pathways. PMID:23864765

  20. 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

  1. Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury

    PubMed Central

    Wu, Peng-fei; Zhang, Zui; Wang, Fang; Chen, Jian-guo

    2010-01-01

    More and more attention in the field of drug discovery has been focused on the neuroprotection of natural compounds from traditional medicinal herbs. Cerebral ischemia is a complex pathological process involving a series of mechanisms, and a framework for the development of neuroprotectants from traditional herb medicine is a promising treatment for cerebral ischemia. Natural compounds with the effects of anti-oxidation, anti-inflammation, calcium antagonization, anti-apoptosis, and neurofunctional regulation exhibit preventive or therapeutic effects on experimental ischemic brain injury. According to the pharmacological mechanisms underlying neuroprotection, we evaluated natural products from traditional medicinal herbs that exhibit protective effects on ischemic brain injury and characterized the promising targets. PMID:21127495

  2. [Adenosine Al Receptor Mediated Neuroprotection of Shenmai Injection on Rat Cerebral Ischemia/Reperfusion Injury: an Experimental Study].

    PubMed

    Lu, Hua-rong; Song, Sheng-wen; Han, Kun-yuan; Liu, Hai-peng; Chen, Shuang-dong; Wang, Jun-lu; Dai, Qin-xue

    2015-09-01

    To observe whether adenosine Al receptor (Al R) mediated neuroprotection of Shenmai Injection (SI) on rat cerebral ischemia/reperfusion (I/R) injury. The focal cerebral I/R model was established by middle cerebral artery occlusion (MCAO). Totally 60 successfully modeled rats was divided into 5 groups according to randomized block principle, i.e., the model group, the SI group, the SI + AlR antagonist (1,3-dipropyl-8-cyclopentylxanthine, DPCPX) group, the AlR antagonist control group, and the dimethyl sulfoxide (DMSO) control group, 12 in each group. Besides, a sham-operation group was set up (n =12). SI at 15 mL/kg was peritoneally injected to mice in the SI group immediately after cerebral I/R. Equal volume of normal saline was injected to mice in the model group and the sham-operation group. DPCPX at 1 mg/mL was peritoneally injected to mice in the Al R antagonist control group 30 min before peritoneal injecting SI. DPCPX at 1 mg/kg and DMSO at 1 mL/kg were peritoneally injected to mice in the AlR antagonist control group and the DMSO control group 30 min immediately before cerebral I/R. Rats' neurobehavioral scores were assessed after 24 h reperfusion. The volume of cerebral infarction and Bcl-2 protein expression of cerebral infarction penumbra were also detected. Results Compared with the sham-operation group, neurobehavioral scores, the volume of cerebral infarction, and Bcl-2 protein expression increased (all P <0. 05). Compared with the model group, neurobehavioral scores and the volume of cerebral infarction obviously decreased, but Bcl-2 protein expression increased in the SI group (all P <0. 05). Compared with the SI group, neurobehavioral scores increased, the volume of cerebral infarction was obviously enlarged, and Bcl-2 protein expression was obviously reduced in the A1R antagonist control group (all P <0. 05). SI's neurobehavioral scores could be partially reversed in the Al R antagonist control group, the volume of cerebral infarction and Bcl-2

  3. Intravenous injection of neural progenitor cells improved depression-like behavior after cerebral ischemia

    PubMed Central

    Moriyama, Y; Takagi, N; Tanonaka, K

    2011-01-01

    Poststroke depression (PSD) occurs in approximately one-third of stroke survivors and is one of the serious sequelae of stroke. The onset of PSD causes delayed functional recovery by rehabilitation and also increases cognitive impairment. However, appropriate strategies for the therapy against ischemia-induced depression-like behaviors still remain to be developed. Such behaviors have been associated with a reduced level of brain-derived neurotrophic factor (BDNF). In addition, accumulating evidence indicates the ability of stem cells to improve cerebral ischemia-induced brain injuries. However, it remains to be clarified as to the effect of neural progenitor cells (NPCs) on PSD and the association between BDNF level and PSD. Using NPCs, we investigated the effect of intravenous injection of NPCs on PSD. We showed that injection of NPCs improved ischemia-induced depression-like behaviors in the forced-swimming test and sucrose preference test without having any effect on the viable area between vehicle- and NPC-injected ischemic rats. The injection of NPCs prevented the decrease in the level of BDNF in the ipsilateral hemisphere. The levels of phosphorylated CREB, ERK and Akt, which have been implicated in events downstream of BDNF signaling, were also decreased after cerebral ischemia. NPC injection inhibited these decreases in the phosphorylation of CREB and ERK, but not that of Akt. Our findings provide evidence that injection of NPCs may have therapeutic potential for the improvement of depression-like behaviors after cerebral ischemia and that these effects might be associated with restoring BDNF-ERK-CREB signaling. PMID:22832603

  4. 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

  5. [Biochemical and pharmacological mechanisms of different types of hypoxic preconditioning in cerebral ischemia in mice].

    PubMed

    Kulinskiĭ, V I; Gavrilina, T V; Minakina, L N; Kovtun, V Iu

    2006-01-01

    Different types of hypoxic preconditioning (hypoxic, circulatory, hemic and tissue hypoxia) increase the tolerance to complete global cerebral ischemia at early terms (hours). Biochemico-pharmacological analysis with the use of selective agonists and antagonists showed the importance of adenosine A1-receptors and K+(ATP)-channels in the mechanisms of the neuroprotective effect and natural tolerance. The general scheme of the investigated mechanisms of different types of hypoxic preconditioning has been proposed.

  6. Let-7f Regulates the Hypoxic Response in Cerebral Ischemia by Targeting NDRG3.

    PubMed

    Yao, Yaobing; Wang, Weiwei; Jing, Lijun; Wang, Yiwen; Li, Mingzhe; Hou, Xiaocan; Wang, Jing; Peng, Tao; Teng, Junfang; Jia, Yanjie

    2017-02-01

    microRNAs are a class of non-coding RNAs including approximately 22 nucleotides in length and play a pivotal role in post-transcriptional gene regulation. Currently, the role of miRNAs in the pathophysiology of ischemic stroke has been the subject of recent investigations. In particular, antagomirs to microRNA (miRNA) let-7f have been found to be neuroprotective in vivo, although the detailed function of let-7f during cerebral ischemia has not been fully illustrated. NDRG3 is an N-myc downstream-regulated gene (NDRG) family member that has been observed in the nuclei in most brain cells. Recently, a NDRG3-mediated lactate signaling, in which stabilized NDRG3 protein can promote angiogenesis and cell growth by activating the Raf-ERK pathway in hypoxia was discovered. In this study, we preliminarily explored the change in the expression of the NDRG3 protein which indicated that NDRG3 protein is an oxygen-regulated protein in neurons in rat cerebral ischemia in vivo and in vitro. We further identified let-7f as an upstream regulator of NDRG3 by the lentiviral transfection of rat cortical neurons and the dual luciferase analysis of human genes. In addition, a dual-color fluorescence in situ hybridization assay showed that when the expression of let-7f was elevated, the expression of NDRG3 mRNA was accordingly reduced in rat cerebral ischemia. Taken together, our results identify a new regulatory mechanism of let-7f on NDRG3 expression in the hypoxic response of cerebral ischemia and raise the possibility that the let-7f/NDRG3 pathway may serve as a potential target for the treatment of ischemic stroke.

  7. [Acute cerebral ischemia: an unusual clinical presentation of isolated left ventricular noncompaction in an adult patient].

    PubMed

    Fiorencis, Andrea; Quadretti, Laura; Bacich, Daniela; Chiodi, Elisabetta; Mele, Donato; Fiorencis, Roberto

    2013-01-01

    Isolated left ventricular noncompaction in adults is uncommon. The most frequent clinical manifestations are heart failure due to left ventricular systolic dysfunction and supraventricular and ventricular arrhythmias, which may be sustained and associated with sudden death. Thromboembolic complications are also possible. We report the case of an adult patient with isolated left ventricular noncompaction who came to our observation because of acute cerebral ischemia, an initial presentation of the disease only rarely described.

  8. Transient Enhancement of Inhibitory Synaptic Transmission in Hippocampal CA1 Pyramidal Neurons after Cerebral Ischemia

    PubMed Central

    Liang, Rui; Pang, Zhi-Ping; Deng, Ping; Xu, Zao C.

    2009-01-01

    Pyramidal neurons in hippocampal CA1 regions are highly sensitive to cerebral ischemia. Alterations of excitatory and inhibitory synaptic transmission may contribute to the ischemia-induced neuronal degeneration. However, little is known about the changes of GABAergic synaptic transmission in the hippocampus following reperfusion. We examined the GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal neurons 12 hours and 24 hours after transient forebrain ischemia. The amplitudes of evoked IPSCs (eIPSCs) were increased significantly 12 hours after ischemia and returned to control levels 24 hours following reperfusion. The potentiation of eIPSCs was accompanied by an increase of miniature IPSCs (mIPSCs) amplitude, and an enhanced response to exogenous application of GABA, indicating the involvement of postsynaptic mechanisms. Furthermore, there was no obvious change of the paired-pulse ratio (PPR) of eIPSCs and the frequency of mIPSCs, suggesting that the potentiation of eIPSCs might not be due to the increased presynaptic release. Blockade of adenosine A1 receptors led to a decrease of eIPSCs amplitude in post-ischemic neurons but not in control neurons, without affecting the frequency of mIPSCs and the PPR of eIPSCs. Thus, tonic activation of adenosine A1 receptors might, at least in part, contribute to the enhancement of inhibitory synaptic transmission in CA1 neurons after forebrain ischemia. The transient enhancement of inhibitory neurotransmission might temporarily protect CA1 pyramidal neurons, and delay the process of neuronal death after cerebral ischemia. PMID:19258028

  9. 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.

  10. How long is sufficient for optimal neuroprotection with cerebral cooling after ischemia in fetal sheep?

    PubMed

    Davidson, Joanne O; Draghi, Vittoria; Whitham, Sean; Dhillon, Simerdeep K; Wassink, Guido; Bennet, Laura; Gunn, Alistair J

    2017-01-01

    The optimal duration of mild "therapeutic" hypothermia for neonates with hypoxic-ischemic encephalopathy is surprisingly unclear. This study assessed the relative efficacy of cooling for 48 h versus 72 h. Fetal sheep (0.85 gestation) received sham ischemia (n = 9) or 30 min global cerebral ischemia followed by normothermia (n = 8) or delayed hypothermia from 3 h to 48 h (n = 8) or 72 h (n = 8). Ischemia was associated with profound loss of electroencephalogram (EEG) power, neurons in the cortex and hippocampus, and oligodendrocytes and myelin basic protein expression in the white matter, with increased Iba-1-positive microglia and proliferation. Hypothermia for 48 h was associated with improved outcomes compared to normothermia, but a progressive deterioration of EEG power after rewarming compared to 72 h of hypothermia, with impaired neuronal survival and myelin basic protein, and more microglia in the white matter and cortex. These findings show that head cooling for 48 h is partially neuroprotective, but is inferior to cooling for 72 h after cerebral ischemia in fetal sheep. The close association between rewarming at 48 h, subsequent deterioration in EEG power and increased cortical inflammation strongly suggests that deleterious inflammation can be reactivated by premature rewarming.

  11. Assessment of the Relative Contribution of COX-1 and COX-2 Isoforms to Ischemia-induced Oxidative Damage and Neurodegeneration Following Transient Global Cerebral Ischemia

    PubMed Central

    Candelario-Jalil, Eduardo; González-Falcón, Armando; García-Cabrera, Michel; Álvarez, Dalia; Al-Dalain, Said; Martínez, Gregorio; Sonia León, Olga; Springer, Joe E.

    2006-01-01

    We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor Rofecoxib (20 mg/kg) relative to the COX-1 inhibitor Valeryl Salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with Rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, selective inhibition of COX-2 with Rofecoxib or inhibition of COX-1 with Valeryl Salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia. PMID:12859668

  12. Assessment of the relative contribution of COX-1 and COX-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia.

    PubMed

    Candelario-Jalil, Eduardo; González-Falcón, Armando; García-Cabrera, Michel; Alvarez, Dalia; Al-Dalain, Said; Martínez, Gregorio; León, Olga Sonia; Springer, Joe E

    2003-08-01

    We investigated the relative contribution of COX-1 and/or COX-2 to oxidative damage, prostaglandin E2 (PGE2) production and hippocampal CA1 neuronal loss in a model of 5 min transient global cerebral ischemia in gerbils. Our results revealed a biphasic and significant increase in PGE2 levels after 2 and 24-48 h of reperfusion. The late increase in PGE2 levels (24 h) was more potently reduced by the highly selective COX-2 inhibitor rofecoxib (20 mg/kg) relative to the COX-1 inhibitor valeryl salicylate (20 mg/kg). The delayed rise in COX catalytic activity preceded the onset of histopathological changes in the CA1 subfield of the hippocampus. Post-ischemia treatment with rofecoxib (starting 6 h after restoration of blood flow) significantly reduced measures of oxidative damage (glutathione depletion and lipid peroxidation) seen at 48 h after the initial ischemic episode, indicating that the late increase in COX-2 activity is involved in the delayed occurrence of oxidative damage in the hippocampus after global ischemia. Interestingly, either selective inhibition of COX-2 with rofecoxib or inhibition of COX-1 with valeryl salicylate significantly increased the number of healthy neurons in the hippocampal CA1 sector even when the treatment began 6 h after ischemia. These results provide the first evidence that both COX isoforms are involved in the progression of neuronal damage following global cerebral ischemia, and have important implications for the potential therapeutic use of COX inhibitors in cerebral ischemia.

  13. The promotion of cerebral ischemia recovery in rats by laminin-binding BDNF.

    PubMed

    Han, Qianqian; Li, Bo; Feng, Hua; Xiao, Zhifeng; Chen, Bing; Zhao, Yannan; Huang, Jingchun; Dai, Jianwu

    2011-08-01

    Brain-derived neurotrophic factor (BDNF) has been shown to have therapeutic effects on cerebral ischemia. However, the delivery approach limits its application. Laminin is a rich extra cellular matrix in the central nervous system, and is highly expressed in the ischemic region after cerebral ischemia. We reported here by fusing with laminin-binding domain (LBD) to BDNF to construct laminin-binding BDNF (LBD-BDNF). LBD-BDNF could target accumulated laminin in the ischemic region and exert targeting therapy of injured neurons after ischemia. We examined the laminin-binding ability and neurotrophic bioactivity of LBD-BDNF in vitro, and assessed its targeting therapy using a rat permanent middle cerebral artery occlusion (MCAO) model in vivo. It was found that LBD-BDNF could specifically bind to laminin and maintain BDNF activity both in vitro and in vivo. LBD-BDNF treatment attenuated neural-degeneration after MCAO, and also resulted in a reduction of infarct volume that is associated with a parallel improvement in neurological functional outcome and neurogenesis in the dentate gyrus of hippocamp.

  14. Effect of cypermethrin on memory, movement activity and coordination in mice after transient incomplete cerebral ischemia.

    PubMed

    Nieradko-Iwanicka, Barbara; Borzecki, Andrzej

    2008-01-01

    Cypermethrin is a synthetic pyrethroid widely used as an insecticide. The aim of the present study was to investigate the possible effect of 0.1 LD50 of cypermethrin on memory, movement activity and co-ordination in mice exposed to transient incomplete cerebral ischemia. Transient occlusion of both carotid arteries (BCCA) in adult female mice was performed under ketamine + xylazine anesthesia. Intraperitoneal LD50 for cypermethrin was calculated to be 169.9 mg/kg. Memory retention was evaluated in a step-through passive avoidance task (PA), working spatial memory in a Y-maze, spontaneous movement activity in an automated device fitted with two photocells and a counter in two subsequent 30-min periods, and movement co-ordination on a rod spinning at the rate of 10 rotations/min. Neither memory nor movement co-ordination were significantly affected by transient incomplete cerebral ischemia or cypermethrin. BCCA itself did not impair movement activity in the examined mice. Cypermethrin decreased exploratory motor activity in the mice, and the effect was exacerbated by BCCA. These results show that transient incomplete cerebral ischemia combined with exposure to subtoxic doses of cypermethrin do not impair memory, but do affect behavior, producing transient reduction of spontaneous horizontal movement in mice.

  15. Neuroprotective activity of Wedelia calendulacea on cerebral ischemia/reperfusion induced oxidative stress in rats

    PubMed Central

    Prakash, Tigari; Kotresha, Dupadahalli; Nedendla, Rama Rao

    2011-01-01

    Objective: This study was undertaken to evaluate the neuroprotective activity of Wedelia calendulacea against cerebral ischemia/reperfusion induced oxidative stress in the rats. Materials and Methods: The global cerebral ischemia was induced in male albino Wistar rats by occluding the bilateral carotid arteries for 30 min followed by 1 h and 4 h reperfusion. At various times of reperfusion, the histopathological changes and the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione–s–transferase (GST), and hydrogen peroxide (H2O2) activity and brain water content were measured. Results: The ischemic changes were preceded by increase in concentration of MDA, hydrogen peroxide and followed by decreased GPx, GR, and GST activity. Treatment with W. calendulacea significantly attenuated ischemia–induced oxidative stress. W. calendulacea administration markedly reversed and restored to near normal level in the groups pre-treated with methanolic extract (250 and 500 mg/kg, given orally in single and double dose/day for 10 days) in dose-dependent way. Similarly, W. calendulacea reversed the brain water content in the ischemia reperfusion animals. The neurodegenaration also conformed by the histopathological changes in the cerebral-ischemic animals. Conclusion: The findings from the present investigation reveal that W. calendulacea protects neurons from global cerebral–ischemic injury in rat by attenuating oxidative stress. PMID:22144773

  16. The effect of ASK1 on vascular permeability and edema formation in cerebral ischemia.

    PubMed

    Song, Juhyun; Cheon, So Yeong; Lee, Won Taek; Park, Kyung Ah; Lee, Jong Eun

    2015-01-21

    Apoptosis signal-regulating kinase-1 (ASK1) is the mitogen-activated protein kinase kinase kinase (MAPKKK) and participates in the various central nervous system (CNS) signaling pathways. In cerebral ischemia, vascular permeability in the brain is an important issue because regulation failure of it results in edema formation and blood-brain barrier (BBB) disruption. To determine the role of ASK1 on vascular permeability and edema formation following cerebral ischemia, we first investigated ASK1-related gene expression using microarray analyses of ischemic brain tissue. We then measured protein levels of ASK1 and vascular endothelial growth factor (VEGF) in brain endothelial cells after hypoxia injury. We also examined protein expression of ASK1 and VEGF, edema formation, and morphological alteration through cresyl violet staining in ischemic brain tissue using ASK1-small interference RNA (ASK1-siRNA). Finally, immunohistochemistry was performed to examine VEGF and aquaporin-1 (AQP-1) expression in ischemic brain injury. Based on our findings, we propose that ASK1 is a regulating factor of vascular permeability and edema formation in cerebral ischemia.

  17. Neuronal and astrocytic interactions modulate brain endothelial properties during metabolic stresses of in vitro cerebral ischemia

    PubMed Central

    2014-01-01

    Neurovascular and gliovascular interactions significantly affect endothelial phenotype. Physiologically, brain endothelium attains several of its properties by its intimate association with neurons and astrocytes. However, during cerebrovascular pathologies such as cerebral ischemia, the uncoupling of neurovascular and gliovascular units can result in several phenotypical changes in brain endothelium. The role of neurovascular and gliovascular uncoupling in modulating brain endothelial properties during cerebral ischemia is not clear. Specifically, the roles of metabolic stresses involved in cerebral ischemia, including aglycemia, hypoxia and combined aglycemia and hypoxia (oxygen glucose deprivation and re-oxygenation, OGDR) in modulating neurovascular and gliovascular interactions are not known. The complex intimate interactions in neurovascular and gliovascular units are highly difficult to recapitulate in vitro. However, in the present study, we used a 3D co-culture model of brain endothelium with neurons and astrocytes in vitro reflecting an intimate neurovascular and gliovascular interactions in vivo. While the cellular signaling interactions in neurovascular and gliovascular units in vivo are much more complex than the 3D co-culture models in vitro, we were still able to observe several important phenotypical changes in brain endothelial properties by metabolically stressed neurons and astrocytes including changes in barrier, lymphocyte adhesive properties, endothelial cell adhesion molecule expression and in vitro angiogenic potential. PMID:24438487

  18. Anti-apoptotic and angiogenic effects of intelectin-1 in rat cerebral ischemia.

    PubMed

    Gu, Naibing; Dong, Yaru; Tian, Ye; Di, Zhengli; Liu, Zhiqin; Chang, Mingze; Jia, Xiaotao; Qian, Yihua; Zhang, Weiping

    2017-04-01

    Ischemic stroke is an acute life-threatening disease, which causes neurological dysfunction. The formation of new blood vessels around the infarct is vital to the restoration of perfusion and healing of brain tissue. Studies have shown that intelectin-1 (omentin) promotes endothelial cell function and angiogenesis in response to ischemia and inhibits apoptosis in rats with unilateral hind limb surgery. In the present study, we investigated the neuroprotective role of intelectin-1 following focal cerebral ischemia. We specifically assessed the effect of increased expression of intelectin-1 in promoting angiogenesis and reducing apoptosis. The treatment was administered using a lentiviral vector, 7 days prior to surgery. The surgery was performed using the established middle cerebral artery occlusion (MCAO) model in rats, and the outcome was evaluated 7 days after injury. Our results demonstrated a significant reduction in brain infarction volume following LV-intelectin-1 treatment. Additionally, CD34 and capillary density were increased in the cerebral ischemic penumbra. Real-time PCR and Western blot revealed an increased expression of intelectin-1, and phosphorylation of eNOS and AKT with enhanced expression of bcl-2 in brain tissues. These data suggest that the successful delivery of LV-intelectin-1 ameliorated ischemic brain injury. It promoted endothelial cell function and revasc ularization, and inhibited apoptosis in response to ischemia by stimulating the Akt-eNOS signaling pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Protective effect of buflomedil in a rat model of moderate cerebral ischemia.

    PubMed

    Briguglio, Francesco S; Mondello, Maria Rita; Galluzzo, Mariangela; Raneri, Eugenio; De Pasquale, Anna; Saija, Antonella; Trombetta, Domenico

    2005-01-01

    Buflomedil hydrochloride (CAS 55837-25-7) is a vasoactive drug with a variety of pharmacodynamic properties. Although a number of studies have been carried out to verify the beneficial effect of buflomedil in ischemic peripheral conditions, few data are reported to justify the efficacious employment of buflomedil in the treatment of cerebrovascular diseases. The aim of the present study was to better investigate the neuroprotective effect of buflomedil in normal pentobarbital-anaesthetized rats subjected to transient bilateral common artery occlusion (BCO) for 20 min. Buflomedil hydrochloride (10 mg/kg) was administered by slow intravenous infusion (90 min), starting 1 h after the onset of ischemia. The rats were sacrificed 48 h after carotid clamping. BCO caused dramatic death of hippocampal CA1 pyramidal neurons, and a significant increase in circulating levels of neuron-specific enolase (NSE) and lactate. Treatment with buflomedil attenuated ischemia-induced histological loss and damage of CA1 pyramidal cells. Furthermore, in ischemic rats, the drug restored blood lactate concentrations and serum NSE concentrations to near normal levels. These data clearly demonstrate that buflomedil is able to protect brain neurons against damage following moderate global cerebral ischemia. One could speculate that this protective effect could be related to the capability of buflomedil to improve cerebral blood flow and energy metabolism, or to a smooth muscle relaxant effect on cerebral blood vessels.

  20. Neuroprotection in focal cerebral ischemia owing to delayed treatment with melanocortins.

    PubMed

    Giuliani, Daniela; Ottani, Alessandra; Mioni, Chiara; Bazzani, Carla; Galantucci, Maria; Minutoli, Letteria; Bitto, Alessandra; Zaffe, Davide; Botticelli, Annibale R; Squadrito, Francesco; Guarini, Salvatore

    2007-09-10

    In gerbils subjected to transient global cerebral ischemia, melanocortin peptides produce long-lasting protection with a broad time window, and through the activation of central nervous system melanocortin MC(4) receptors. Here we aimed to investigate whether melanocortins are neuroprotective also in a rat model of focal cerebral ischemia induced by intrastriatal microinjection of endothelin-1. The vasoconstrictor agent endothelin-1 caused a significant impairment in spatial learning and memory, as well as in sensory-motor orientation and limb use, associated with severe striatal morphological damage including intense neuronal death and an almost complete myelin degradation. Treatment of ischemic rats with a nanomolar dose (340 microg/kg/day i.p. for 11 days, beginning 3 h or 9 h after endothelin-1 microinjection) of the melanocortin analog [Nle(4), D-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) significantly reduced striatal damage, and improved subsequent functional recovery, with all scheduled NDP-alpha-MSH treatments. Pharmacological blockade of melanocortin MC(4) receptors prevented the protective effect of NDP-alpha-MSH. Our findings give evidence that melanocortins are neuroprotective, with a broad time window, also in a severe model of focal cerebral ischemia, and suggest that melanocortin MC(4) receptor agonists could produce neuroprotection in different experimental models of ischemic stroke.

  1. Transient cerebral ischemia in an elderly patient with patent foramen ovale and atrial septal aneurysm.

    PubMed

    Merante, Alfonso; Gareri, Pietro; Castagna, Alberto; Marigliano, Norma Maria; Candigliota, Mafalda; Ferraro, Alessandro; Ruotolo, Giovanni

    2015-01-01

    Cerebrovascular disease is one of the most common causes of cerebrovascular morbidity and mortality in developed countries; up to 40% of acute ischemic strokes in young adults are cryptogenic in nature - that is, no cause is determined. However, in more than half of these patients, patent foramen ovale (PFO) is seen along with an increased incidence of atrial septal aneurysm (ASA). The following is a report of an interesting case: a 68-year-old man with ASA and transient cerebral ischemia. Transesophageal echocardiography (TEE) showed the presence of ASA; a test with microbubbles derived from a mixture of air and saline or colloids pointed out a shunt on the foramen ovale following Valsalva's maneuver. The patient underwent percutaneous transcatheter closure of the interatrial communication by an interventional cardiologist. TEE and transcranial Doppler or TEE with the microbubbles test are the recommended methods for detecting and quantifying intracardiac shunts, both at rest and following Valsalva's maneuver. In patients following the first event of transient ischemic attack, and without clinical and anatomical risk factors (such as the presence of ASA, PFO, and basal shunt), pharmacological treatment with antiplatelets or anticoagulants is closely recommended. On the contrary, in patients following the first event of transient ischemic attack, or a recurrent event during antiplatelet treatment, the percutaneous closure of PFO is recommended.

  2. Transient cerebral ischemia in an elderly patient with patent foramen ovale and atrial septal aneurysm

    PubMed Central

    Merante, Alfonso; Gareri, Pietro; Castagna, Alberto; Marigliano, Norma Maria; Candigliota, Mafalda; Ferraro, Alessandro; Ruotolo, Giovanni

    2015-01-01

    Cerebrovascular disease is one of the most common causes of cerebrovascular morbidity and mortality in developed countries; up to 40% of acute ischemic strokes in young adults are cryptogenic in nature – that is, no cause is determined. However, in more than half of these patients, patent foramen ovale (PFO) is seen along with an increased incidence of atrial septal aneurysm (ASA). The following is a report of an interesting case: a 68-year-old man with ASA and transient cerebral ischemia. Transesophageal echocardiography (TEE) showed the presence of ASA; a test with microbubbles derived from a mixture of air and saline or colloids pointed out a shunt on the foramen ovale following Valsalva’s maneuver. The patient underwent percutaneous transcatheter closure of the interatrial communication by an interventional cardiologist. TEE and transcranial Doppler or TEE with the microbubbles test are the recommended methods for detecting and quantifying intracardiac shunts, both at rest and following Valsalva’s maneuver. In patients following the first event of transient ischemic attack, and without clinical and anatomical risk factors (such as the presence of ASA, PFO, and basal shunt), pharmacological treatment with antiplatelets or anticoagulants is closely recommended. On the contrary, in patients following the first event of transient ischemic attack, or a recurrent event during antiplatelet treatment, the percutaneous closure of PFO is recommended. PMID:26379429

  3. Schisandrin B enhances cerebral mitochondrial antioxidant status and structural integrity, and protects against cerebral ischemia/reperfusion injury in rats.

    PubMed

    Chen, Na; Chiu, Po Yee; Ko, Kam Ming

    2008-07-01

    Schisandrin B (Sch B), a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis, has been shown to enhance mitochondrial antioxidant status in liver, heart and brain tissues in rodents. Whether or not long-term Sch B treatment can protect against oxidative stress-induced cerebral damage remains unclear. In the present study, the effect of long-term Sch B treatment (1-30 mg/kg/dx15) on cerebral ischemia/reperfusion (I/R) injury was examined in rats. Sch B treatment protected against I/R-induced cerebral damage, as evidenced by the significant increase in the percentage of 2,3,5-triphenyl tetrazolium chloride (TTC)-stained tissues in representative brain slices, when compared with the Sch B-untreated and I/R control. The cerebroprotection was associated with an enhancement in cerebral mitochondrial antioxidant status, as assessed by the level/activity of reduced glutathione, alpha-tocopherol and Mn-superoxide dismutase, as well as the improvement/preservation of mitochondrial structural integrity, as assessed by the extents of malondialdehyde production, Ca(2+) loading and cytochrome c release, as well as the sensitivity to Ca(2+)-induced permeability transition, in control and I/R-challenged rats. In conclusion, long-term Sch B treatment could enhance cerebral mitochondrial antioxidant status as well as improve mitochondrial structural integrity, thereby protecting against I/R injury.

  4. Intensive training accelerates the recovery of motor functions following cerebral ischemia-reperfusion in MCAO rats.

    PubMed

    Wang, Q; Wang, P-P; Meng, P-P; Han, C; Yue, S-W

    2016-09-01

    Cerebral ischemia-reperfusion is the major pathophysiological process in stroke and can cause severe and lasting sequel. However, an intensive exercise training can potentially effect a quick and efficient recovery. We used swimming training on rats with cerebral ischemia-reperfusion (CIR) and explore the underlying neuroprotective mechanism(s), including the effects of intensive training on the expression of semaphorin 3A (Sema3A) and its receptor Neuropilin-1 (NRP-1). The middle cerebral artery occlusion/reperfusion (MCAO/R) model was established by inserting a thread into the middle cerebral artery of Sprague-Dawley (SD) rats, and randomly dividing into the control group and training groups for different training intensities. The control group and the sham group received no training. All the rats in various groups were further randomly divided into three sub-groups for different postoperative time points (3, 7, and 14 days after operation). The apoptosis and the expression of Sema3A and NRP-1 were analyzed using immunohistochemistry (IHC), RT-PCR, and Western blotting methods respectively. The intensive training resulted in significant neurological function improvements at all the time points after MCAO, compared to that in the control group (p<0.05), with training group 3 (highest training intensity) showing the most remarkable recovery. The Sema3A and NP-1 expressions were significantly lower than those of the control group at all the time points (p<0.05), with training group 3 having the lowest levels (best recovery). Intensive training can reduce cerebral damage after ischemia and reperfusion in rats, inhibit the MCAO-induced Sema3A and NRP-1 expression, and accelerate the restoring process of motor nerve functions.

  5. Nimodipine prevents early loss of hippocampal CA1 parvalbumin immunoreactivity after focal cerebral ischemia in the rat.

    PubMed

    Benyó, Z; De Jong, G I; Luiten, P G

    1995-01-01

    The effect of focal cerebral ischemia induced by middle cerebral artery occlusion on hippocampal interneurons containing the calcium-binding protein parvalbumin (PV) was studied in rats. Four hours after the onset of ischemia, a reduced number of PV-immunoreactive (-ir) neurons was observed in the lateral part of the CA1 region, while PV-ir was not altered in the CA2 and CA3 areas. Pretreatment with the L-type Ca2+ channel blocker nimodipine prevented the ischemia-induced loss of PV-ir in the CA1, suggesting a role for L-type voltage sensitive calcium channels in the mechanism of early neuronal alterations in the hippocampus CA1 region after focal cerebral ischemia.

  6. 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.

  7. 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

    2012-02-09

    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.

  8. 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

  9. [Comparative evaluation of the neuroprotective activity of phenotropil and piracetam in laboratory animals with experimental cerebral ischemia].

    PubMed

    Tiurenkov, I N; Bagmetov, M N; Epishina, V V

    2007-01-01

    The neuroprotective properties of phenotropil and piracetam were studied in Wistar rats with low and high sensitivity with respect to cerebral ischemia caused by bilateral irreversible simultaneous occlusion of carotid arteries and gravitational overload in craniocaudal vector. In addition, the effects of both drugs on microcirculation in the brain cortex under ischemic injury conditions were studied. Phenotropil and (to a lower extent) piracetam reduced the extent of neuralgic deficiency manifestations, retained the locomotor, research, and memory functions in animals with gravitational cerebral ischemia, increased the survival of experimental animals, and favored the restoration of local cerebral flow upon the occlusion of carotid arteries.

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

    PubMed

    Zhang, Xiao-Xiao; He, Fen-Fen; Yan, Gui-Lin; Li, Ha-Ni; Li, Dan; Ma, Yan-Ling; Wang, Fang; Xu, Nan; Cao, Fei

    2016-04-01

    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.

  11. 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

  12. 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

  13. Precision Medicine of Aneurysmal Subarachnoid Hemorrhage – Vasospasm and Delayed Cerebral Ischemia

    PubMed Central

    Burrell, Christian; Avalon, Nicole E.; Siegel, Jason; Pizzi, Michael; Dutta, Tumpa; Charlesworth, M. Cristine; Freeman, William D.

    2017-01-01

    Introduction Precision medicine is an emerging paradigm aimed at providing individualized prevention and treatment of diseases through understanding and leveraging patient-to-patient variation. Aneurysmal subarachnoid hemorrhage (aSAH) carries tremendous morbidity and mortality with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) proving devastating and unpredictable. The paucity of effective treatment or prevention measures for these conditions could potentially be improved through implementation of precision medicine. Areas covered This review presents the basic pathophysiology of CV and DCI, current treatment guidelines, and evidence for the use of precision medicine in the prediction and prevention of poor outcomes following aSAH. An extensive PubMed literature search was performed using keywords cerebral vasospasm or delayed cerebral ischemia and either biomarkers, precision medicine, metabolomics, proteomics, or genomics. Over 200 peer-reviewed articles were reviewed. The studies presented focus on biomarkers identified as predictive markers or therapeutic targets following aSAH. Expert Commentary The array of novel biomarkers reviewed here, ranging from genotypes to metabolites, has been found to correlate with CV, DCI, and neurologic outcomes after aSAH. Though their practical use in the clinical management of aSAH is not well established, using these biomarkers as predictive tools or therapeutic targets demonstrates the potential of precision medicine in the treatment of aSAH. PMID:27314601

  14. Precision medicine of aneurysmal subarachnoid hemorrhage, vasospasm and delayed cerebral ischemia.

    PubMed

    Burrell, Christian; Avalon, Nicole E; Siegel, Jason; Pizzi, Michael; Dutta, Tumpa; Charlesworth, M Cristine; Freeman, William D

    2016-11-01

    Precision medicine provides individualized treatment of diseases through leveraging patient-to-patient variation. Aneurysmal subarachnoid hemorrhage carries tremendous morbidity and mortality with cerebral vasospasm and delayed cerebral ischemia proving devastating and unpredictable. Lack of treatment measures for these conditions could be improved through precision medicine. Areas covered: Discussed are the pathophysiology of CV and DCI, treatment guidelines, and evidence for precision medicine used for prediction and prevention of poor outcomes following aSAH. A PubMed search was performed using keywords cerebral vasospasm or delayed cerebral ischemia and either biomarkers, precision medicine, metabolomics, proteomics, or genomics. Over 200 peer-reviewed articles were evaluated. The studies presented cover biomarkers identified as predictive markers or therapeutic targets following aSAH. Expert commentary: The biomarkers reviewed here correlate with CV, DCI, and neurologic outcomes after aSAH. Though practical use in clinical management of aSAH is not well established, using these biomarkers as predictive tools or therapeutic targets demonstrates the potential of precision medicine.

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

    PubMed

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

    2015-01-01

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

  16. Ginger pharmacopuncture improves cognitive impairment and oxidative stress following cerebral ischemia.

    PubMed

    Jittiwat, Jinatta; Wattanathorn, Jintanaporn

    2012-12-01

    Recent findings have demonstrated that acupuncture and ginger can each improve memory impairment following cerebral ischemia. We hypothesized that ginger pharmacopuncture, a combination of these two treatments, could increase the beneficial effects. Due to the limitation of supporting evidence, we aimed to determine whether ginger pharmacopuncture could improve cognitive function and oxidative stress following cerebral ischemia. Male Wistar rats were induced by right middle cerebral artery occlusion (Rt. MCAO) and subjected to either acupuncture or ginger pharmacopuncture once daily over a period of 14 days after Rt. MCAO. Cognitive function was determined every 7 days, using escape latency and retention time as indices, and the oxidative stress status of the rats was determined at the end of the study. Rats subjected either to acupuncture or to ginger pharmacopuncture at GV20 demonstrated enhanced spatial memory, and the activities of catalase and glutathione peroxidase in both cerebral cortex and hippocampus were improved. Elevation of superoxide dismutase activity was observed only in the hippocampus. Cognitive enhancement was observed sooner with ginger pharmacopuncture than with acupuncture. The cognitive enhancing effect of acupuncture and ginger pharmacopuncture is likely to be at least partially attributable to decreased oxidative stress. However, other mechanisms may also be involved, and this requires further study.

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

    PubMed

    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.

  18. 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

  19. Cerebral inflammation and mobilization of the peripheral immune system following global hypoxia-ischemia in preterm sheep

    PubMed Central

    2013-01-01

    Background Hypoxic-ischemic encephalopathy (HIE) is one of the most important causes of brain injury in preterm infants. Preterm HIE is predominantly caused by global hypoxia-ischemia (HI). In contrast, focal ischemia is most common in the adult brain and known to result in cerebral inflammation and activation of the peripheral immune system. These inflammatory responses are considered to play an important role in the adverse outcomes following brain ischemia. In this study, we hypothesize that cerebral and peripheral immune activation is also involved in preterm brain injury after global HI. Methods Preterm instrumented fetal sheep were exposed to 25 minutes of umbilical cord occlusion (UCO) (n = 8) at 0.7 gestation. Sham-treated animals (n = 8) were used as a control group. Brain sections were stained for ionized calcium binding adaptor molecule 1 (IBA-1) to investigate microglial proliferation and activation. The peripheral immune system was studied by assessment of circulating white blood cell counts, cellular changes of the spleen and influx of peripheral immune cells (MPO-positive neutrophils) into the brain. Pre-oligodendrocytes (preOLs) and myelin basic protein (MBP) were detected to determine white matter injury. Electro-encephalography (EEG) was recorded to assess functional impairment by interburst interval (IBI) length analysis. Results Global HI resulted in profound activation and proliferation of microglia in the hippocampus, periventricular and subcortical white matter. In addition, non-preferential mobilization of white blood cells into the circulation was observed within 1 day after global HI and a significant influx of neutrophils into the brain was detected 7 days after the global HI insult. Furthermore, global HI resulted in marked involution of the spleen, which could not be explained by increased splenic apoptosis. In concordance with cerebral inflammation, global HI induced severe brain atrophy, region-specific preOL vulnerability

  20. Reversible recovery of neuronal structures depends on the degree of neuronal damage after global cerebral ischemia in mice.

    PubMed

    Zhu, Lirui; Wang, Lei; Ju, Furong; Khan, Akbar; Cheng, Xiaofeng; Zhang, Shengxiang

    2017-03-01

    It has been observed by in vivo imaging that damaged neuronal structures can be reversibly restored after ischemic insults with the application of timely therapeutic interventions. However, what degree of neuronal damage can be restored and the time frame for reversible recovery of neuronal structures remain unclear. Here, transcranial two-photon imaging, histological staining and electron microscopy were used to investigate the reversible recovery of neuronal structures from dendrites to soma after different durations of global cerebral ischemia in mice. Intravital imaging revealed that the damage to dendritic structures was reversible when ischemia time was <1h, but they became difficult to restore after >3h of ischemia. Data from fixed YFP brain slice and Golgi staining indicated that the damage of dendritic structures progressively extended to deeper dendritic shafts with the extension of ischemia time. Furthermore, longer duration of ischemia caused an increasing number of degenerating neurons. Importantly, significant chromatin margination and karyopyknosis of neuron were observed after 6h of ischemia. These data suggested that neuronal structures could be reversibly restored when ischemia time was <1h, but irreversible and progressive damage to neurons occurred with longer duration of ischemia. Consistently, behavioral performance of post-ischemic animals experienced an ischemia time-dependent recovery. Taken together, our data suggested that recovery of neuronal structures following ischemia was dependent on the duration of ischemia, and prevention of neuronal loss is a key target for therapeutic interventions in ischemic stroke.

  1. Expression and function of striatal enriched protein tyrosine phosphatase is profoundly altered in cerebral ischemia.

    PubMed

    Braithwaite, Steven P; Xu, Jian; Leung, John; Urfer, Roman; Nikolich, Karoly; Oksenberg, Donna; Lombroso, Paul J; Shamloo, Mehrdad

    2008-05-01

    Striatal enriched protein tyrosine phosphatase (STEP) acts in the central nervous system to dephosphorylate a number of important proteins involved in synaptic function including ERK and NMDA receptor subunits. These proteins are also linked to stroke, in which cerebral ischemia triggers a complex cascade of events. Here we demonstrate that STEP is regulated at both the transcriptional and the post-transcriptional levels in rat models of cerebral ischemia and that its regulation may play a role in the outcome of ischemic insults. After transient middle cerebral artery occlusion, there are profound decreases in the levels of STEP mRNA, whilst in global ischemia STEP mRNA is selectively down-regulated in areas susceptible to ischemic damage. In a neuroprotective preconditioning paradigm, and in regions of the brain that are relatively resistant to ischemic damage, STEP mRNA levels are increased. Furthermore, there is a significant processing of STEP after ischemia to generate a novel species, STEP(33), resulting in a redistribution of STEP from membrane-bound to soluble compartments. Concomitant with the cleavage of mature forms of STEP, there are changes in the phosphorylation state of ERK. We show that the cleavage of STEP leads to a catalytically active form, but this cleaved form no longer binds to and dephosphorylates its substrate pERK. Therefore, in response to ischemic insults, there are profound reductions in both the amount and the activity of STEP, its localization, as well as the activity of one of its key substrates, pERK. These changes in STEP may reflect a critical role in the outcomes of ischemic brain injury.

  2. 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

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

    PubMed

    Xu, Ai-Ling; Zheng, Guan-Yi; Wang, Zhi-Jian; Chen, Xiao-Dong; Jiang, Qiong

    2016-04-01

    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.

  4. Cost-effectiveness of 7-day-Holter monitoring alone or in combination with transthoracic echocardiography in patients with cerebral ischemia.

    PubMed

    Mayer, Felix; Stahrenberg, Raoul; Gröschel, Klaus; Mostardt, Sarah; Biermann, Janine; Edelmann, Frank; Liman, Jan; Wasem, Jürgen; Goehler, Alexander; Wachter, Rolf; Neumann, Anja

    2013-12-01

    Prolonged Holter monitoring of patients with cerebral ischemia increases the detection rate of paroxysmal atrial fibrillation (PAF); this leads to improved antithrombotic regimens aimed at preventing recurrent ischemic strokes. The aim of this study was to compare a 7-day-Holter monitoring (7-d-Holter) alone or in combination with prior selection via transthoracic echocardiography (TTE) to a standard 24-h-Holter using a cost-utility analysis. Lifetime cost, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICER) were estimated for a cohort of patients with acute cerebral ischemia and no contraindication to oral anticoagulation. A Markov model was developed to simulate the long-term course and progression of cerebral ischemia considering the different diagnostic algorithms (24-h-Holter, 7-d-Holter, 7-d-Holter after preselection by TTE). Clinical data for these algorithms were derived from the prospective observational Find-AF study (ISRCTN 46104198). Predicted lifelong discounted costs were 33,837 for patients diagnosed by the 7-d-Holter and 33,852 by the standard 24-h-Holter. Cumulated QALYs were 3.868 for the 7-d-Holter compared to 3.844 for the 24-h-Holter. The 7-d-Holter dominated the 24-h-Holter in the base-case scenario and remained cost-effective in extensive sensitivity analysis of key input parameter with a maximum of 8,354 /QALY gained. Preselecting patients for the 7-d-Holter had no positive effect on the cost-effectiveness. A 7-d-Holter to detect PAF in patients with cerebral ischemia is cost-effective. It increases the detection which leads to improved antithrombotic regimens; therefore, it avoids recurrent strokes, saves future costs, and decreases quality of life impairment. Preselecting patients by TTE does not improve cost-effectiveness.

  5. Physiologically relevant online electrochemical method for continuous and simultaneous monitoring of striatum glucose and lactate following global cerebral ischemia/reperfusion.

    PubMed

    Lin, Yuqing; Zhu, Ningning; Yu, Ping; Su, Lei; Mao, Lanqun

    2009-03-15

    This study demonstrates a new electroanalytical method with a high physiological relevance for simultaneous online monitoring of glucose and lactate in the striatum of the rat brain following global cerebral ischemia/reperfusion. The online analytical method is based on the efficient integration of in vivo microdialysis sampling with an online selective electrochemical detection with the electrochemical biosensors with dehydrogenases, i.e., glucose and lactate dehydrogenases, as recognition elements. The dehydrogenase-based electrochemical biosensors are developed onto the dual split-disk plastic carbon film (SPCF) electrodes with methylene green (MG) adsorbed onto single-walled carbon nanotubes (SWNTs) as the electrocatalyst for the oxidation of dihydronicotiamide adenine dinucleotide (NADH) at a low potential of 0.0 V (vs Ag/AgCl). Artificial cerebrospinal fluid (aCSF) containing NAD(+) is externally perfused from a second pump and online mixed with the brain microdialysates to minimize the variation of pH that occurred following the cerebral ischemia/reperfusion and to supply NAD(+) cofactor and O(2) for the enzymatic reactions of dehydrogenases and ascorbate oxidase, respectively. As a result, the developed online electroanalytical method exhibits a high selectivity against the electrochemically active species endogenously existing in the cerebral systems and a high tolerance against the variation of pH and O(2) following cerebral ischemia/reperfusion. This property, along with the good linearity and a high stability toward glucose and lactate as well as little cross-talk between two biosensors, substantially makes this method possible for the continuous, simultaneous, and online monitoring of glucose and lactate in the rat brain following global cerebral ischemia/reperfusion. This study establishes a new and effective platform for the investigation of the energy metabolism in physiological and pathological processes.

  6. 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

  7. Neurovascular protection conferred by 2-BFI treatment during rat cerebral ischemia.

    PubMed

    Han, Zhao; Cheng, Zhao-Hui; Liu, Shuang; Yang, Jin-Long; Xiao, Mei-Juan; Zheng, Rong-Yuan; Hou, Sheng-Tao

    2012-08-03

    Stroke is caused by vascular dysfunction and currently there are no effective therapeutics to stroke induced brain damage. In contrast to an intense emphasis on neuroprotection, relatively few studies have addressed means of vascular protection in cerebral ischemia. Here we discovered that the ligand to immidazolin receptor, 2-BFI, not only provided potent neuroprotection during middle cerebral artery occlusion in rat, which confirmed our previous reports, but also protected the integrity of the cerebral vasculature. Treatment with 2-BFI twice daily after the occlusion of the middle cerebral artery for 14 d significantly improved the neurological deficits, reduced brain infarction, and importantly, protected the cerebral vasculature as evidenced by the increased expression of an endothelial marker, von Willebrand factor, and better preservation of the cerebral vasculature, as viewed under a confocal microscope on rat brain perfused with FITC-labeled dextran. These results indicated that 2-BFI contributes to protection of neurovasculature. Understanding the molecular mechanisms could eventually lead to development of more effective therapies for stroke. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

  8. 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

  9. Spatial-temporal expression of NDRG2 in rat brain after focal cerebral ischemia and reperfusion.

    PubMed

    Li, Yan; Shen, Lan; Cai, Lei; Wang, Qiang; Hou, Wugang; Wang, Feng; Zeng, Yi; Zhao, Gang; Yao, Libo; Xiong, Lize

    2011-03-25

    N-myc downstream regulated gene 2 (NDRG2) was reported to be widely expressed in the nervous system. However, the expression and potential role of NDRG2 in focal cerebral ischemia brain remain unclear. Herein, we investigated spatial-temporal expression of NDRG2 in the rat brain following transient focal cerebral ischemia. Male Sprague-Dawley rats underwent a 120-min transient occlusion of middle cerebral artery. Rats were killed and brain samples were harvested at 4, 12, 24, and 72h after reperfusion. Expression of NDRG2 in the brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemical staining. Cellular apoptosis was assessed by TUNEL staining. The results showed that NDRG2 was expressed on cells with an astrocytes-like morphology in ischemic penumbra. NDRG2 mRNA and protein expression began to increase at 4h after reperfusion and peaked at 24h in the ischemic penumbra. By using immunofluorescence, NDRG2 signals were co-localized with GFAP-positive astrocytes, and NDRG2 expression in astrocytes translocated from a cytoplasm to a nuclear localization at 24h after reperfusion. Double immunofluorescent staining for TUNEL and NDRG2 showed that some NDRG2 signals co-localized with TUNEL-positive cells, and that the apoptotic cells increased with enhancement of NDRG2-positive signals. In conclusion, NDRG2 expression is up-regulated in ischemic penumbra following transient focal cerebral ischemia. NDRG2 expression in astrocytes may play important pathological roles in cell apoptosis after stroke. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. Cerebroprotective activity of Pentapetes phoenicea on global cerebral ischemia in rats

    PubMed Central

    Sravanthi, Koneru Naga; Rao, Nadendla Rama

    2016-01-01

    Objectives: The study was performed to evaluate the cerebroprotective activity of methanolic extract (ME) of Pentapetes phoenicea - a folk medicine used as anti-inflammatory and in central nervous system ailments. It has high phenolic and flavonoid contents including rutin. Materials and Methods: Global cerebral ischemia was induced in male albino Wistar rats by temporary bilateral carotid artery occlusion (BCAO) for 30 min, followed by 4 h reperfusion. Groups of rats were pretreated for 10 days with 100, 200, and 400 mg/kg of ME of P. phoenicea and 3 mg/kg of edaravone, a marketed cerebroprotective agent, as standard. Antioxidant enzymes such as, the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT) and hydrogen peroxide (H2O2), protein content, brain water content, cerebral infarct size and the histopathological changes were measured. Results: P. phoenicea-pretreated groups restored the biochemical parameters significantly in a dose-dependent manner. The ischemic changes were involved with an increase in the concentration of MDA and H2O2, followed by decreased SOD, CAT, GPx, GR, and GST activity in rat brain. The neurodegenaration and its attenuation by P. phoenicea were confirmed by examination of triphenyl tetrazolium chloride staining and histopathological changes in the cerebral ischemic rat brains. Similarly, P. phoenicea reversed the brain water content in the ischemia-reperfusion animals. Conclusion: The result of the study indicates that the treatment with P. phoenicea enhances the antioxidant defense against BCAO-induced global cerebral ischemia/reperfusion and exerts cerebroprotection. PMID:28066109

  11. Role of Neutrophils in Exacerbation of Brain Injury After Focal Cerebral Ischemia in Hyperlipidemic Mice.

    PubMed

    Herz, Josephine; Sabellek, Pascal; Lane, Thomas E; Gunzer, Matthias; Hermann, Dirk M; Doeppner, Thorsten R

    2015-10-01

    Inflammation-related comorbidities contribute to stroke-induced immune responses and brain damage. We previously showed that hyperlipidemia exacerbates ischemic brain injury, which is associated with elevated peripheral and cerebral granulocyte numbers. Herein, we evaluate the contribution of neutrophils to the exacerbation of ischemic brain injury. Wild-type mice fed with a normal chow and ApoE knockout mice fed with a high cholesterol diet were exposed to middle cerebral artery occlusion. CXCR2 was blocked using the selective antagonist SB225002 (2 mg/kg) or neutralizing CXCR2 antiserum. Neutrophils were depleted using an anti-Ly6G antibody. At 72 hours post ischemia, immunohistochemistry, flow cytometry, and real-time polymerase chain reaction were performed to determine cerebral tissue injury and immunologic changes in the blood, bone marrow, and brain. Functional outcome was assessed by accelerated rota rod and tight rope tests at 4, 7, and 14 days post ischemia. CXCR2 antagonization reduced neurological deficits and infarct volumes that were exacerbated in hyperlipidemic ApoE-/- mice. This effect was mimicked by neutrophil depletion. Cerebral neutrophil infiltration and peripheral neutrophilia, which were increased on ischemia in hyperlipidemia, were attenuated by CXCR2 antagonization. This downscaling of neutrophil responses was associated with increased neutrophil apoptosis and reduced levels of CXCR2, inducible nitric oxide synthase, and NADPH oxidase 2 expression on bone marrow neutrophils. Our data demonstrate a role of neutrophils in the exacerbation of ischemic brain injury induced by hyperlipidemia. Accordingly, CXCR2 blockade, which prevents neutrophil recruitment into the brain, might be an effective option for stroke treatment in patients with hyperlipidemia. © 2015 American Heart Association, Inc.

  12. Intranasal Administration of Interleukin-1 Receptor Antagonist in a Transient Focal Cerebral Ischemia Rat Model

    PubMed Central

    Lee, Jae Hoon; Kam, Eun Hee; Kim, Jeong Min; Kim, So Yeon; Kim, Eun Jeong; Cheon, So Yeong; Koo, Bon-Nyeo

    2017-01-01

    The interleukin-1 receptor antagonist (IL-1RA) is a potential stroke treatment candidate. Intranasal delivery is a novel method thereby a therapeutic protein can be penetrated into the brain parenchyma by bypassing the blood-brain barrier. Thus, this study tested whether intranasal IL-1RA can provide neuroprotection and brain penetration in transient cerebral ischemia. In male Sprague-Dawley rats, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1 h. The rats simultaneously received 50 mg/kg human IL-1RA through the intranasal (IN group) or intraperitoneal route (IP group). The other rats were given 0.5 mL/kg normal saline (EC group). Neurobehavioral function, infarct size, and the concentration of the administered human IL-1RA in the brain tissue were assessed. In addition, the cellular distribution of intranasal IL-1RA in the brain and its effect on proinflammatory cytokines expression were evaluated. Intranasal IL-1RA improved neurological deficit and reduced infarct size until 7 days after MCAO (p<0.05). The concentrations of the human IL-1RA in the brain tissue 24 h after MCAO were significantly greater in the IN group than in the IP group (p<0.05). The human IL-1RA was confirmed to be co-localized with neuron and microglia. Furthermore, the IN group had lower expression of interleukin-1β and tumor necrosis factor-α at 6 h after MCAO than the EC group (p<0.05). These results suggest that intranasal IL-1RA can reach the brain parenchyma more efficiently and provide superior neuroprotection in the transient focal cerebral ischemia. PMID:27530114

  13. 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

  14. Effects of AMP-activated protein kinase in cerebral ischemia.

    PubMed

    Li, Jun; McCullough, Louise D

    2010-03-01

    AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to 'cell stress', including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed.

  15. Effects of AMP-activated protein kinase in cerebral ischemia

    PubMed Central

    Li, Jun; McCullough, Louise D

    2010-01-01

    AMP-activated protein kinase (AMPK) is a serine threonine kinase that is highly conserved through evolution. AMPK is found in most mammalian tissues including the brain. As a key metabolic and stress sensor/effector, AMPK is activated under conditions of nutrient deprivation, vigorous exercise, or heat shock. However, it is becoming increasingly recognized that changes in AMPK activation not only signal unmet metabolic needs, but also are involved in sensing and responding to ‘cell stress', including ischemia. The downstream effect of AMPK activation is dependent on many factors, including the severity of the stressor as well as the tissue examined. This review discusses recent in vitro and in vivo studies performed in the brain/neuronal cells and vasculature that have contributed to our understanding of AMPK in stroke. Recent data on the potential role of AMPK in angiogenesis and neurogenesis and the interaction of AMPK with 3-hydroxy-3-methy-glutaryl-CoA reductase inhibitors (statins) agents are highlighted. The interaction between AMPK and nitric oxide signaling is also discussed. PMID:20010958

  16. Sequential assessment of regional cerebral blood flow, regional cerebral blood volume, and blood-brain barrier in focal cerebral ischemia: a case report

    SciTech Connect

    Di Piero, V.; Perani, D.; Savi, A.; Gerundini, P.; Lenzi, G.L.; Fazio, F.

    1986-06-01

    Regional CBF (rCBF) and regional cerebral blood volume (rCBV) were evaluated by N,N,N'-trimethyl-N'-(2)-hydroxy-3-methyl-5-(123I)iodobenzyl-1, 3-propanediamine-2 HCl- and /sup 99m/TC-labeled red blood cells, respectively, and single-photon emission computerized tomography (SPECT) in a patient with focal cerebral ischemia. Sequential transmission computerized tomography (TCT) and SPECT functional data were compared with clinical findings to monitor the pathophysiological events occurring in stroke. A lack of correlation between rCBF-rCBV distributions and blood-brain barrier (BBB) breakdown was found in the acute phase. In the face of more prolonged alteration of BBB, as seen by TCT enhancement, a rapid evolution of transient phenomena such as luxury perfusion was shown by SPECT studies. Follow-up of the patient demonstrated a correlation between the neurological recovery and a parallel relative improvement of the cerebral perfusion.

  17. 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

  18. Factors Secreted by Endothelial Progenitor Cells Enhance Neurorepair Responses after Cerebral Ischemia in Mice

    PubMed Central

    Rosell, Anna; Morancho, Anna; Navarro-Sobrino, Miriam; Martínez-Saez, Elena; Hernández-Guillamon, Mar; Lope-Piedrafita, Silvia; Barceló, Verónica; Borrás, Francesc; Penalba, Anna; García-Bonilla, Lidia; Montaner, Joan

    2013-01-01

    Cell therapy with endothelial progenitor cells (EPCs) has emerged as a promising strategy to regenerate the brain after stroke. Here, we aimed to investigate if treatment with EPCs or their secreted factors could potentiate angiogenesis and neurogenesis after permanent focal cerebral ischemia in a mouse model of ischemic stroke. BALB/C male mice were subjected to distal occlusion of the middle cerebral artery, and EPCs, cell-free conditioned media (CM) obtained from EPCs, or vehicle media were administered one day after ischemia. Magnetic resonance imaging (MRI) was performed at baseline to confirm that the lesions were similar between groups. Immunohistochemical and histological evaluation of the brain was performed to evaluate angio-neurogenesis and neurological outcome at two weeks. CM contained growth factors, such as VEGF, FGF-b and PDGF-bb. A significant increase in capillary density was noted in the peri-infarct areas of EPC- and CM-treated animals. Bielschowsky’s staining revealed a significant increase in axonal rewiring in EPC-treated animals compared with shams, but not in CM-treated mice, in close proximity with DCX-positive migrating neuroblasts. At the functional level, post-ischemia forelimb strength was significantly improved in animals receiving EPCs or CM, but not in those receiving vehicle media. In conclusion, we demonstrate for the first time that the administration of EPC-secreted factors could become a safe and effective cell-free option to be considered in future therapeutic strategies for stroke. PMID:24023842

  19. Complexity of the cell-cell interactions in the innate immune response after cerebral ischemia.

    PubMed

    Cuartero, María I; Ballesteros, Iván; Lizasoain, Ignacio; Moro, María A

    2015-10-14

    In response to brain ischemia a cascade of signals leads to the activation of the brain innate immune system and to the recruitment of blood borne derived cells to the ischemic tissue. These processes have been increasingly shown to play a role on stroke pathogenesis. Here, we discuss the key features of resident microglia and different leukocyte subsets implicated in cerebral ischemia with special emphasis of neutrophils, monocytes and microglia. We focus on how leukocytes are recruited to injured brain through a complex interplay between endothelial cells, platelets and leukocytes and describe different strategies used to inhibit their recruitment. Finally, we discuss the possible existence of different leukocyte subsets in the ischemic tissue and the repercussion of different myeloid phenotypes on stroke outcome. The knowledge of the nature of these heterogeneous cell-cell interactions may open new lines of investigation on new therapies to promote protective immune responses and tissue repair after cerebral ischemia or to block harmful responses. This article is part of a Special Issue entitled SI: Cell Interactions In Stroke.

  20. 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.

  1. Neuroprotective activity of lavender oil on transient focal cerebral ischemia in mice.

    PubMed

    Wang, Dong; Yuan, Xuan; Liu, Ting; Liu, Liangliang; Hu, Yanli; Wang, Zhenhua; Zheng, Qiusheng

    2012-08-15

    The air-dried aerial parts of Lavandula angustifolia Mill, a traditional Uygur herbal drug, is used as resuscitation-inducing therapy to treat neurodisfunctions, such as stroke. This study was designed to assess the neuroprotective effects of lavender oil against ischemia/reperfusion (IR) injury in mice. Focal cerebral ischemia was induced by the intraluminal occlusion method with a nylon string. The neurodysfuntion was evaluated by neurological deficit and the infarct area was showed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The histopathological changes were observed by hematoxylin and eosin staining. The levels of mitochondria-generated reactive oxygen species (ROS), malondialdehyde (MDA) and carbonyl, the ratio of reduced glutathione (GSH)/glutathione disulfide (GSSG), the activities of superoxide dismutase (SOD), catalase (CAT) and glutathion peroxidase (GSH-Px) in brain tissue were measured to estimate the oxidative stress state. Neurological deficit, infarct size, histopathology changes and oxidative stress markers were evaluated after 22 h of reperfusion. In comparison with the model group, treatment with lavender oil significantly decreased neurological deficit scores, infarct size, the levels of MDA, carbonyl and ROS, and attenuated neuronal damage, upregulated SOD, CAT, GSH-Px activities and GSH/GSSG ratio. These results suggested that the neuroprotective effects of lavender oil against cerebral ischemia/reperfusion injury may be attributed to its antioxidant effects.

  2. Nanoparticles for targeted delivery of antioxidant enzymes to the brain after cerebral ischemia and reperfusion injury

    PubMed Central

    Yun, Xiang; Maximov, Victor D; Yu, Jin; Zhu, Hong; Vertegel, Alexey A; Kindy, Mark S

    2013-01-01

    Stroke is one of the major causes of death and disability in the United States. After cerebral ischemia and reperfusion injury, the generation of reactive oxygen species (ROS) and reactive nitrogen species may contribute to the disease process through alterations in the structure of DNA, RNA, proteins, and lipids. We generated various nanoparticles (liposomes, polybutylcyanoacrylate (PBCA), or poly(lactide-co-glycolide) (PLGA)) that contained active superoxide dismutase (SOD) enzyme (4,000 to 20,000 U/kg) in the mouse model of cerebral ischemia and reperfusion injury to determine the impact of these molecules. In addition, the nanoparticles were untagged or tagged with nonselective antibodies or antibodies directed against the N-methyl-𝒟-aspartate (NMDA) receptor 1. The nanoparticles containing SOD protected primary neurons in vitro from oxygen-glucose deprivation (OGD) and limited the extent of apoptosis. The nanoparticles showed protection against ischemia and reperfusion injury when applied after injury with a 50% to 60% reduction in infarct volume, reduced inflammatory markers, and improved behavior in vivo. The targeted nanoparticles not only showed enhanced protection but also showed localization to the CA regions of the hippocampus. Nanoparticles alone were not effective in reducing infarct volume. These studies show that targeted nanoparticles containing protective factors may be viable candidates for the treatment of stroke. PMID:23385198

  3. Postcarotid endarterectomy cerebral hyperperfusion can be prevented by minimizing intraoperative cerebral ischemia and strict postoperative blood pressure control under continuous sedation.

    PubMed

    Kawamata, Takakazu; Okada, Yoshikazu; Kawashima, Akitsugu; Yoneyama, Taku; Yamaguchi, Kohji; Ono, Yuko; Hori, Tomokatsu

    2009-03-01

    Cerebral hyperperfusion syndrome is a major complication after carotid endarterectomy (CEA). We investigated whether our strategy of minimizing intraoperative cerebral ischemia and strict postoperative blood pressure control under continuous sedation prevented postoperative hyperperfusion. Eighty consecutive patients undergoing CEA were studied. A shunt was used in all patients during CEA. All patients were managed postoperatively under continuous sedation for as long as 48 hours on the basis of the regional cerebral blood flow (rCBF) measured immediately after CEA. Postoperative hyperperfusion was assessed, on the basis of the cerebral blood flow study under sedation (propofol) after CEA, either as a greater than 30% increase in rCBF compared with the contralateral side, or a greater than 100% increase in the corrected rCBF (calculated from percentage reduction of the contralateral rCBF induced by propofol) compared with preoperative values. No patient developed cerebral hyperperfusion syndrome. Postoperative hyperperfusion was found at very low rates (2.5% in the middle cerebral artery territory and 1.3% in the anterior cerebral artery territory by definition 1, and 0% in both territories by definition 2). Ratios of regional oxygen saturation after internal carotid artery clamping to preclamp baseline values were greater than 0.9 in 78 of 80 patients, indicating very mild intraoperative cerebral ischemia. Parameters related to cerebral ischemia during CEA, such as regional oxygen saturation, internal carotid artery cross-clamping duration, and stump pressure (index), did not affect the incidence of postoperative hyperperfusion. The present study suggests that minimizing intraoperative cerebral ischemia using a shunt, followed by strict postoperative blood pressure control under continuous sedation, can prevent post-CEA hyperperfusion.

  4. Hemodynamic variability and cerebrovascular control after transient cerebral ischemia

    PubMed Central

    Allan, Philip D; Faulkner, James; O’Donnell, Terrence; Lanford, Jeremy; Wong, Lai-kin; Saleem, Saqib; Woolley, Brandon; Lambrick, Danielle; Stoner, Lee; Tzeng, Yu-Chieh

    2015-01-01

    We investigated if hemodynamic variability, cerebral blood flow (CBF) regulation, and their interrelationships differ between patients with transient ischemic attack (TIA) and controls. We recorded blood pressure (BP) and bilateral middle cerebral artery flow velocity (MCAv) in a cohort of TIA patients (n = 17), and age-matched controls (n = 15). Spontaneous fluctuations in BP and MCAv were characterized by spectral power analysis, and CBF regulation was assessed by wavelet phase synchronization analysis in the very low- (0.02–0.07 Hz), low- (0.07–0.20 Hz), and high-frequency (0.20–0.40 Hz) ranges. Furthermore, cerebrovascular CO2 reactivity was assessed as a second metric of CBF regulation by inducing hypercapnia with 8% CO2 inhalation followed by hyperventilation driven hypocapnia. We found that TIA was associated with higher BP power (group effect, P < 0.05), but not MCAv power (P = 0.11). CBF regulation (assessed by wavelet phase synchronization and CO2 reactivity) was intact in patients (all P ≥ 0.075) across both hemispheres (all P ≥ 0.51). Pooled data (controls and affected hemisphere of patients) showed that BP and MCAv power were positively correlated at all frequency ranges (R2 = 0.20–0.80, all P < 0.01). Furthermore, LF phase synchronization index was a significant determinant of MCAv power (P < 0.05), while VLF and HF phase synchronization index, and TIA were not (all P ≥ 0.50). These results indicate that CBF stability and control is maintained in TIA patients, but BPV is markedly elevated. BPV attenuation may be an important therapeutic strategy for enhancing secondary stroke prevention in patients who suffer a TIA. PMID:26537345

  5. Prevention and repair of cerebral ischemia-reperfusion injury by Chinese herbal medicine, shengmai san, in rats.

    PubMed

    Xuejiang, W; Magara, T; Konishi, T

    1999-11-01

    The protective activity of Shengmai San, a traditional Chinese herbal medicine, was studied in cerebral ischemia-reperfusion injury in rats. Shengmai San consists of three herbal components, Panax Ginseng, Ophiopogon Japonicus and Schisandra Chinensis and is routinely being used for treating coronary heart disease. When Shengmai San was injected directly into rat duodenum 2h before cerebral ischemia by bilateral carotid artery occlusion, thiobarbituric acid reactive substance (TBARS) formation during reperfusion following ischemia was almost completely suppressed in the brain. The loss of glutathione peroxidase activity after the ischemia-reperfusion was also effectively prevented by the Shengmai San pre-administration whereas the activity was considerably decreased in the damaged brain. It was found that Shengmai San also effectively suppressed the TBARS formation even when it was administered after 45 min reperfusion following ischemia, indicating that Shengmai San improves the oxidative damage already established in the brain. Likewise, the decrease of glutathione peroxidase activity was minimized in the damaged brain by the post-administration of Shengmai San. On the other hand, none of the Shengmai San components were active in protecting the ischemia-reperfusion brain damage when they were independently administered. These experiments suggest the potential of Shengmai San in both preventive and therapeutic usages for cerebral ischemia-reperfusion injury.

  6. 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

  7. ARRB1/β-arrestin-1 mediates neuroprotection through coordination of BECN1-dependent autophagy in cerebral ischemia

    PubMed Central

    Wang, Pei; Xu, Tian-Ying; Wei, Kai; Guan, Yun-Feng; Wang, Xia; Xu, Hui; Su, Ding-Feng; Pei, Gang; Miao, Chao-Yu

    2014-01-01

    Autophagy, a highly conserved process conferring cytoprotection against stress, contributes to the progression of cerebral ischemia. β-arrestins are multifunctional proteins that mediate receptor desensitization and serve as important signaling scaffolds involved in numerous physiopathological processes. Here, we show that both ARRB1 (arrestin, β 1) and ARRB2 (arrestin, β 2) were upregulated by cerebral ischemic stress. Knockout of Arrb1, but not Arrb2, aggravated the mortality, brain infarction, and neurological deficit in a mouse model of cerebral ischemia. Accordingly, Arrb1-deficient neurons exhibited enhanced cell injury upon oxygen-glucose deprivation (OGD), an in vitro model of ischemia. Deletion of Arrb1 did not affect the cerebral ischemia-induced inflammation, oxidative stress, and nicotinamide phosphoribosyltransferase upregulation, but markedly suppressed autophagy and induced neuronal apoptosis/necrosis in vivo and in vitro. Additionally, we found that ARRB1 interacted with BECN1/Beclin 1 and PIK3C3/Vps34, 2 major components of the BECN1 autophagic core complex, under the OGD condition but not normal conditions in neurons. Finally, deletion of Arrb1 impaired the interaction between BECN1 and PIK3C3, which is a critical event for autophagosome formation upon ischemic stress, and markedly reduced the kinase activity of PIK3C3. These findings reveal a neuroprotective role for ARRB1, in the context of cerebral ischemia, centered on the regulation of BECN1-dependent autophagosome formation. PMID:24988431

  8. 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.

  9. Current evidence for AMPK activation involvement on resveratrol-induced neuroprotection in cerebral ischemia.

    PubMed

    Pineda-Ramírez, Narayana; Gutiérrez Aguilar, Germán Fernando; Espinoza-Rojo, Mónica; Aguilera, Penélope

    2017-02-14

    Cerebral ischemia is a neurological condition in which energetics and oxidative stress are dysregulated. Resveratrol is a stilbene with potent pharmacological effects associated with its antioxidant properties. In the brain, resveratrol produces protective responses against ischemia, decreases infarct volume and improves neurological function. Adenosine monophosphate-activated protein kinase (AMPK) is a cellular sensor that acts as a switch to initiate adaptive changes in response to fluctuations in energy metabolism. In ischemia, AMPK is activated, nevertheless conflicting results about its contribution to protection have become apparent, and this matter continues without resolution. Interestingly, AMPK activation by resveratrol has been implicated in regulating cell survival in different experimental models. Although resveratrol's ability to regulate AMPK directly or after signaling is only beginning to be understood, targeting this enzyme by resveratrol in brain suggest that it could contribute to the amelioration of some pathologic features induced after an energetic deficit. The present review discusses the potential role of resveratrol in regulating AMPK activity on brain before, during, or after ischemia and offer suggestions for feasible future studies.

  10. 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

  11. Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy.

    PubMed

    Vasquez-Vivar, Jeannette; Shi, Zhongjie; Luo, Kehuan; Thirugnanam, Karthikeyan; Tan, Sidhartha

    2017-10-01

    Antenatal brain hypoxia-ischemia, which occurs in cerebral palsy, is considered a significant cause of motor impairments in children. The mechanisms by which antenatal hypoxia-ischemia causes brain injury and motor deficits still need to be elucidated. Tetrahydrobiopterin is an important enzyme cofactor that is necessary to produce neurotransmitters and to maintain the redox status of the brain. A genetic deficiency of this cofactor from mutations of biosynthetic or recycling enzymes is a well-recognized factor in the development of childhood neurological disorders characterized by motor impairments, developmental delay, and encephalopathy. Experimental hypoxia-ischemia causes a decline in the availability of tetrahydrobiopterin in the immature brain. This decline coincides with the loss of brain function, suggesting this occurrence contributes to neuronal dysfunction and motor impairments. One possible mechanism linking tetrahydrobiopterin deficiency, hypoxia-ischemia, and neuronal injury is oxidative injury. Evidence of the central role of the developmental biology of tetrahydrobiopterin in response to hypoxic ischemic brain injury, especially the development of motor deficits, is discussed. Copyright © 2017. Published by Elsevier B.V.

  12. 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. © 2016 The Authors. Developmental Medicine & Child Neurology © 2016 Mac Keith Press.

  13. Online electrochemical monitoring of dynamic change of hippocampal ascorbate: toward a platform for in vivo evaluation of antioxidant neuroprotective efficiency against cerebral ischemia injury.

    PubMed

    Liu, Kun; Yu, Ping; Lin, Yuqing; Wang, Yuexiang; Ohsaka, Takeo; Mao, Lanqun

    2013-10-15

    Effective monitoring of cerebral ascorbate following intravenous antioxidant treatment is of great importance in evaluating the antioxidant efficiency for neuroprotection because ascorbate is closely related to a series of ischemia-induced neuropathological processes. This study demonstrates the validity of an online electrochemical system (OECS) for ascorbate detection as a platform for in vivo evaluation of neuroprotective efficiency of antioxidants by studying the dynamic change of hippocampal ascorbate during the acute period of cerebral ischemia and its responses to intravenous administration of antioxidants including ascorbate and glutathione (GSH). The OECS consists of a selective electrochemical detector made of a thin-layer electrochemical flow cell integrated with in vivo microdialysis. With such a system, the basal level of hippocampal ascorbate is determined to be 5.18 ± 0.60 μM (n = 20). This level is increased by 10 min of two-vessel occlusion (2-VO) ischemia treatment and reaches 11.51 ± 3.43 μM (n = 5) at the time point of 60 min after the ischemia. The 2-VO ischemia-induced hippocampal ascorbate increase is obviously attenuated by immediate intravenous administration of ascorbate (2.94 g/kg) or glutathione (5.12 g/kg) within 10 min after ischemia and the ascorbate level remains to be 3.75 ± 1.66 μM (n = 4) and 5.30 ± 0.79 μM (n = 5), respectively, at the time point of 60 min after ischemia. To confirm if the attenuated hippocampal ascorbate increase is attributed to the antioxidant-induced oxidative stress alleviation, we further study the immunoreactivity of 8-hydroxy-2-deoxyguanosine (8-OHdG) in the ischemic hippocampus and find that the 8-OHdG immunoreactivity is decreased by the administration of ascorbate or GSH as compared to the ischemic brain without antioxidant treatment. These results substantially demonstrate that the OECS for ascorbate detection could be potentially used as a platform for evaluating the efficiency of antioxidant

  14. PI3K/Akt Pathway Contributes to Neurovascular Unit Protection of Xiao-Xu-Ming Decoction against Focal Cerebral Ischemia and Reperfusion Injury in Rats

    PubMed Central

    Xiang, Jun; Zhang, Yong; Wang, Guo-Hua; Bao, Jie; Li, Wen-Wei; Zhang, Wen; Xu, Li-Li; Cai, Ding-Fang

    2013-01-01

    In the present study, we used a focal cerebral ischemia and reperfusion rat model to investigate the protective effects of Xiao-Xu-Ming decoction (XXMD) on neurovascular unit and to examine the role of PI3K (phosphatidylinositol 3-kinase)/Akt pathway in this protection. The cerebral ischemia was induced by 90 min of middle cerebral artery occlusion. Cerebral infarct area was measured by tetrazolium staining, and neurological function was observed at 24 h after reperfusion. DNA fragmentation assay, combined with immunofluorescence, was performed to evaluate apoptosis of neuron, astrocyte, and vascular endothelial cell which constitute neurovascular unit. The expression levels of proteins involved in PI3K/Akt pathway were detected by Western blot. The results showed that XXMD improved neurological function, decreased cerebral infarct area and neuronal damage, and attenuated cellular apoptosis in neurovascular unit, while these effects were abolished by inhibition of PI3K/Akt with LY294002. We also found that XXMD upregulated p-PDKl, p-Akt, and p-GSK3β expression levels, which were partly reversed by LY294002. In addition, the increases of p-PTEN and p-c-Raf expression levels on which LY294002 had no effect were also observed in response to XXMD treatment. The data indicated the protective effects of XXMD on neurovascular unit partly through the activation of PI3K/Akt pathway. PMID:23781261

  15. 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

  16. Protective effects of natrii sulfas on cerebral focal ischemia induced by MCAO in rats.

    PubMed

    Sohn, Youngjoo; Kang, Ho Chang; Kim, Kon Sik; Park, Sun-Min; Sohn, Nak-Won; Jung, Hyuk-Sang; Kim, Sung-Hoon

    2009-01-01

    This study examined the effect of Natrii sulfas, a treatment for stroke patients suffering constipation in Oriental medicine, on the physiological indices and brain edema of rats. Brain edema was induced by a middle cerebral artery occlusion (MCAO), Natrii sulfas was administered after the MCAO. At 3, 6, 15, 24, and 48 hours after reperfusion, the physiological indices such as the fecal weight, urine volume and water content in the stools were assessed. The edema index was measured 48 hours after reperfusion. At 48 hours, the expressions of iNOS, MMP9, VEGF, GFAP, Bax, Bcl-2, c-Fos, and HSP72 positive astrocytes were observed on the brain tissues by immunohistochemistry. Natrii sulfas significantly improved the decrease in fecal weight, urine volume and water content in the stool caused by the ischemic insult (p < 0.05) and attenuated the brain edema caused by the ischemia insult (p < 0.05). Natrii sulfas significantly down-regulated iNOS and MMP9 expressions and attenuated the astrocyte swelling due to brain edema in the penumbra of the cerebral cortex of MCAO rats. Natrii sulfas reduced the excess Bax and HSP72 expressions in ischemic brain, which was statistically significant in the penumbra of the cerebral cortex but not in the caudate putamen. These results suggest Natrii sulfas has a protective effect on ischemia-induced brain edema and improves the physiological symptoms.

  17. Can Gender Differences Be Evaluated in a Rhesus Macaque (Macaca mulatta) Model of Focal Cerebral Ischemia?

    PubMed Central

    Murphy, Stephanie J; Kirsch, Jeffrey R; Zhang, Wenri; Grafe, Marjorie R; West, G Alex; del Zoppo, Gregory J; Traystman, Richard J; Hurn, Patricia D

    2008-01-01

    Gender differences, sex steroid effects, and sex-specific candidate therapeutics in ischemic stroke have been studied in rodents but not in nonhuman primates. In this feasibility study (n = 3 per group), we developed a model of transient focal cerebral ischemia in adult male and female rhesus macaques that consistently includes white matter injury. The animals also were used to determine whether gender-linked differences in histopathologic outcomes could be evaluated in this model in future, larger preclinical trials. Histologic brain pathology was evaluated at 4 d after 90 min of reversible occlusion of the middle cerebral artery (MCA). MCA occlusion was accomplished by using a transorbital approach and temporary placement of an aneurysm clip. Male and female rhesus macaques 7 to 11 y of age were studied. Baseline and intraischemic blood glucose, systolic blood pressure, heart rate, oxygen saturation, end-tidal CO2, and rectal temperatures were not different among groups. The variability in injury volume was comparable to that observed in human focal cerebrovascular ischemia and in other nonhuman primate models using proximal MCA occlusion. In this small sample, the volume of injury was not different between male and female subjects, but observed variability was higher in female caudate nucleus, putamen, and hemisphere. This report is the first to compare cerebral ischemic outcomes in female and male rhesus macaques. The female rhesus macaque ischemic stroke model could be used after rodent studies to provide preclinical data for clinical trials in women. PMID:19149416

  18. 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.

  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. Regulation of body temperature and neuroprotection by endogenous interleukin-6 in cerebral ischemia.

    PubMed

    Herrmann, Oliver; Tarabin, Victoria; Suzuki, Shigeaki; Attigah, Nicolas; Coserea, Irinel; Schneider, Armin; Vogel, Johannes; Prinz, Simone; Schwab, Stefan; Monyer, Hannah; Brombacher, Frank; Schwaninger, Markus

    2003-04-01

    Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6-deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6-deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.

  1. Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats.

    PubMed

    Ma, Shuwei; Yin, Huafeng; Chen, Lvyi; Liu, Hongxia; Zhao, Ming; Zhang, Xiantao

    2012-01-01

    Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats.

  2. 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

  3. Inhibition of cerebral ischemia/reperfusion injury-induced apoptosis: nicotiflorin and JAK2/STAT3 pathway

    PubMed Central

    Hu, Guang-qiang; Du, Xi; Li, Yong-jie; Gao, Xiao-qing; Chen, Bi-qiong; Yu, Lu

    2017-01-01

    Nicotiflorin is a flavonoid extracted from Carthamus tinctorius. Previous studies have shown its cerebral protective effect, but the mechanism is undefined. In this study, we aimed to determine whether nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis through the JAK2/STAT3 pathway. The cerebral ischemia/reperfusion injury model was established by middle cerebral artery occlusion/reperfusion. Nicotiflorin (10 mg/kg) was administered by tail vein injection. Cell apoptosis in the ischemic cerebral cortex was examined by hematoxylin-eosin staining and terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Bcl-2 and Bax expression levels in ischemic cerebral cortex were examined by immunohistochemial staining. Additionally, p-JAK2, p-STAT3, Bcl-2, Bax, and caspase-3 levels in ischemic cerebral cortex were examined by western blot assay. Nicotiflorin altered the shape and structure of injured neurons, decreased the number of apoptotic cells, down-regulates expression of p-JAK2, p-STAT3, caspase-3, and Bax, decreased Bax immunoredactivity, and increased Bcl-2 protein expression and immunoreactivity. These results suggest that nicotiflorin protects against cerebral ischemia/reperfusion injury-induced apoptosis via the JAK2/STAT3 pathway. PMID:28250754

  4. Expression Pattern of Peroxisome Proliferator-Activated Receptors in Rat Hippocampus following Cerebral Ischemia and Reperfusion Injury

    PubMed Central

    Wang, Hong; Jiang, Rong; He, Qin; Zhang, Yunmei; Zhang, Yanli; Li, Yong; Zhuang, Ruichun; Luo, Ying; Li, Yu; Wan, Jinyuan; Tang, Yong; Yu, Huarong; Jiang, Qingsong; Yang, Junqing

    2012-01-01

    The present study was designed to investigate the pattern of time-dependent expression of peroxisome proliferator-activated receptors (PPARα, β, and γ) after global cerebral ischemia and reperfusion (I/R) damage in the rat hippocampus. Male Sprague Dawley (SD) rats were subjected to global cerebral I/R. The rat hippocampi were isolated to detect the expression of PPARs mRNA and protein levels at 30 min–30 d after I/R by RT-PCR and Western blot analysis, respectively. The expression levels of PPARs mRNA and protein in the rat hippocampus significantly increased and peaked at 24 h for PPARα and γ (at 48 h for PPARβ) after I/R, then gradually decreased, and finally approached control levels on d 30. The present results suggest that global cerebral I/R can cause obvious increases of hippocampal PPARs mRNA and protein expression within 15 d after I/R. These findings may help to guide the experimental and clinical therapeutic use of PPARs agonists against brain injury. PMID:23304113

  5. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia.

    PubMed

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-09-05

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance.

  6. Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

    PubMed Central

    Shu, Xiaoliang; Zhang, Yongsheng; Xu, Han; Kang, Kai; Cai, Donglian

    2013-01-01

    Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex. Intrahypothalamic administration of brain-derived neurotrophic factor (40 ng) suppressed the decrease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance. PMID:25206547

  7. Geranylgeranylacetone protects against cerebral ischemia and reperfusion injury: HSP90 and eNOS phosphorylation involved.

    PubMed

    He, Dake; Song, Xiaoqing; Li, Ling

    2015-03-02

    Cerebral ischemia and reperfusion (I/R) can trigger a cytotoxic cascade with overflow of reactive oxygen species, paradoxically causing neurological dysfunction, redox imbalance, inflammation and apoptosis. The present study aims to investigate the effect of geranylgeranylacetone(GGA) on cerebral I/R injury and the underlying mechanism. The results demonstrated that cerebral I/R increased the neurological function abnormality, brain edema, inflammation and oxidative injury in rats as well as the cognitive impairment, which was significantly reversed by GGA in a dose-dependent manner. GGA also suppressed the cell injury and apoptosis caused by cerebral I/R. Moreover, the protective effect of GGA was found to involve heat shock protein 90 (HSP90) and phosphorylated endothelial nitric oxide synthase (eNOS) expression and activity. Both the HSP90 and eNOS inhibitor abolished the effect of GGA. The data showed that GGA could protect rats against cerebral I/R injury, which may be related to the induction of HSP90 and activation of eNOS. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. E2-25K SUMOylation inhibits proteasome for cell death during cerebral ischemia/reperfusion

    PubMed Central

    Jeong, Eun Il; Chung, Hae Won; Lee, Won Jea; Kim, Seo-Hyun; Kim, Hyunjoo; Choi, Seon-Guk; Jung, Yong-Keun

    2016-01-01

    Cerebral ischemia/reperfusion (I/R) causes brain damage accompanied by ubiquitin accumulation and impairment of proteasome activity. In this study, we report that E2-25K, an E2-conjugating enzyme, is SUMOylated during oxidative stress and regulates cerebral I/R-induced damage. Knockdown of E2-25K expression protects against oxygen/glucose deprivation and reoxygenation (OGD/R)-induced neuronal cell death, whereas ectopic expression of E2-25K stimulates it. Compared with the control mice, cerebral infarction lesions and behavioral/neurological disorders are ameliorated in E2-25K knockout mice during middle cerebral artery occlusion and reperfusion. In particular, E2-25K is SUMOylated at Lys14 under oxidative stress, OGD/R and I/R to prompt cell death. Further, E2-25K downregulates the proteasome subunit S5a to impair proteasome complex and thus restrain proteasome activity under oxidative stress. This proteasome inhibitory activity of E2-25K is dependent on its SUMOylation. These results suggest that E2-25K has a crucial role in oxidative stress and cerebral I/R-induced damage through inhibiting proteasome via its SUMOylation. PMID:28032866

  9. 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.

  10. Rifampicin Attenuated Global Cerebral Ischemia Injury via Activating the Nuclear Factor Erythroid 2-Related Factor Pathway

    PubMed Central

    Chen, Beibei; Cao, Huimin; Chen, Lili; Yang, Xuemei; Tian, Xiaoyan; Li, Rong; Cheng, Oumei

    2016-01-01

    Background: Recent studies have found that rifampicin has neuroprotective properties in neurodegenerative diseases. However, the exact mechanisms of action remain unclear. The nuclear factor erythroid 2-related factor 2 (Nrf2) has been considered a potential target for neuroprotection. In this study, we examined whether rifampicin exhibits beneficial effects mediated by the Nrf2 pathway after global cerebral ischemia (GCI). Methods: Rats were randomly assigned to four groups that included a sham group and three treatment groups with global ischemia-reperfusion [control, rifampicin, and rifampicin plus brusatol (an inhibitor of Nrf2)]. Rats were subjected to transient GCI induced by bilateral common carotid artery occlusion for 20 min with systemic hypotension by blood withdrawal. The Morris water maze test was performed for neurobehavioral testing, whereas the pathological changes were investigated using HE and TUNEL staining. The protein expression of Nrf2, hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) in the hippocampus were analyzed by Western blotting. The immunofluorescence staining was used to determine the distribution of Nrf2. Results: Rifampicin treatment significantly improved spatial learning ability compared with the control group, which was consistent with the pathological changes. In addition, rifampicin significantly elevated the nuclear expression of Nrf2, Nrf2 downstream anti-oxidant protein, HO-1 compared with the control group, and it simultaneously downregulated the expression of COX-2 in the hippocampus on day 3 after ischemia-reperfusion. Interestingly, the forenamed effects of rifampicin were abolished by pretreatment with brusatol, a specific inhibitor of Nrf2 activation. Conclusions: Rifampicin exerts neuroprotective effects against global cerebral ischemia, which may be attributed to activation of the Nrf2 pathway. PMID:27965540

  11. Early sleep apnea screening on a stroke unit is feasible in patients with acute cerebral ischemia

    PubMed Central

    Kepplinger, Jessica; Barlinn, Kristian; Albright, Karen C.; Schrempf, Wiebke; Boehme, Amelia K.; Pallesen, Lars-Peder; Schwanebeck, Uta; Graehlert, Xina; Storch, Alexander; Reichmann, Heinz; Alexandrov, Andrei V.; Bodechtel, Ulf

    2017-01-01

    Early screening for sleep apnea (SA) is rarely considered in patients with acute cerebral ischemia. We aimed to evaluate the feasibility of early SA screening on a stroke unit, its impact on post-discharge SA care and the relation of SA to clinical features. Patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA) prospectively underwent overnight cardiorespiratory polygraphy within 3 ± 2 days of symptom-onset. Feasibility was defined as analyzable polygraphy in 90 % of studied patients. We enrolled 61 patients (84 % AIS, 16 % TIA): mean age 66 ± 8 years, 44 % men, median NIHSS 1 (0–15), median ESS 5 (0–13). Analyzability was given in 56/61 (91.8 %; one-sided 95 % CI, lower-bound 86.0 %) patients indicating excellent feasibility of early SA screening with no significant differences in stroke severity (100 % in TIA, 91 % minor stroke, 83 % major stroke, p = 0.474). Ninety-one percent (51/56) had an apnea–hypopnea index ≥5/h (median: 20/h [0–79]); 32 % (18/ 56) mild, 30 % (17/56) moderate, and 29 % (16/56) severe SA. When comparing sleep-related ischemic stroke (SIS) and non-SIS patients, no differences were found regarding the presence (95 vs. 89 %, p = 0.49) or severity (e.g., severe SA: 32 vs. 27 %, p = 0.69) of SA. After 12 months, 27/38 (71 %) patients given specific recommendations completed in-laboratory sleep work-up and 7/27 (25 %) were prescribed for non-invasive ventilatory correction. In conclusion, early SA screening is feasible in patients with acute cerebral ischemia and may have a positive impact on post-discharge SA care. Given the high frequency and atypical presentation of SA, early screening for SA should be considered in all acute cerebral ischemia patients. PMID:23263538

  12. In Vivo Theranostics at the Peri-Infarct Region in Cerebral Ischemia

    PubMed Central

    Agulla, Jesús; Brea, David; Campos, Francisco; Sobrino, Tomás; Argibay, Bárbara; Al-Soufi, Wajih; Blanco, Miguel; Castillo, José; Ramos-Cabrer, Pedro

    2014-01-01

    The use of theranostics in neurosciences has been rare to date because of the limitations imposed on the free delivery of substances to the brain by the blood-brain barrier. Here we report the development of a theranostic system for the treatment of stroke, a leading cause of death and disability in developed countries. We first performed a series of proteomic, immunoblotting and immunohistological studies to characterize the expression of molecular biomarkers for the so-called peri-infarct tissue, a key region of the brain for stroke treatment. We confirmed that the HSP72 protein is a suitable biomarker for the peri-infarct region, as it is selectively expressed by at-risk tissue for up to 7 days following cerebral ischemia. We also describe the development of anti-HSP72 vectorized stealth immunoliposomes containing imaging probes to make them traceable by conventional imaging techniques (fluorescence and MRI) that were used to encapsulate a therapeutic agent (citicoline) for the treatment of cerebral ischemia. We tested the molecular recognition capabilities of these nano-platforms in vitro together with their diagnostic and therapeutic properties in vivo, in an animal model of cerebral ischemia. Using MRI, we found that 80% of vectorized liposomes were located on the periphery of the ischemic lesion, and animals treated with citicoline encapsulated on these liposomes presented lesion volumes up to 30% smaller than animals treated with free (non-encapsulated) drugs. Our results show the potential of nanotechnology for the development of effective tools for the treatment of neurological diseases. PMID:24396517

  13. Treatment of acute cerebral ischemia using animal models: a meta-analysis

    PubMed Central

    Wang, Peng-Fei; Zhou, Yu; Fang, Huang; Lin, Sen; Wang, Yan-Chun; Liu, Yong; Xia, Jun; Eslick, Guy D.; Yang, Qing-Wu

    2015-01-01

    Background There are numerous potential treatments assessed for acute cerebral ischemia using animal models. This study aimed to assess the effect of these treatments in terms of infarct size and neurobehavioral change. This meta-analysis was conducted to determine if any of these treatments provide a superior benefit so that they might be used on humans. Methods A systematic search was conducted using several electronic databases for controlled animal studies using only nonsurgical interventions for acute cerebral ischemia. A random-effects model was used. Results After an extensive literature search, 145 studies were included in the analysis. These studies included 1408 treated animals and 1362 control animals. Treatments that had the most significant effect on neurobehavioral scales included insulin, various antagonists, including N-methyl-D-aspartate (NMDA) receptor antagonist ACEA1021, calmodulin antagonist DY-9760e, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist YM872, and antiviral agents. Treatments providing the greatest effect on infarct size included statins, sphingosine-1-phosphate agonist (fingolimod), alcohol, angiotensin, and leukotrienes. Treatments offering the greatest reduction in brain water content included various agonists, including sphingosine-1-phosphate agonist fingolimod, statins, and peroxisome proliferator-activated receptor gamma (PPAR-γ). Treatment groups with more than one study all had high heterogeneity (I2 > 80%), however, using meta-regression we determined several sources of heterogeneity including sample size of the treatment and control groups, the occlusion time, but not the year when the study was conducted. Conclusions Some treatments stand out when compared to others for acute cerebral ischemia in animals. Greater replication of treatment studies is required before any treatments are selected for future human trials. PMID:28123790

  14. Early sleep apnea screening on a stroke unit is feasible in patients with acute cerebral ischemia.

    PubMed

    Kepplinger, Jessica; Barlinn, Kristian; Albright, Karen C; Schrempf, Wiebke; Boehme, Amelia K; Pallesen, Lars-Peder; Schwanebeck, Uta; Graehlert, Xina; Storch, Alexander; Reichmann, Heinz; Alexandrov, Andrei V; Bodechtel, Ulf

    2013-05-01

    Early screening for sleep apnea (SA) is rarely considered in patients with acute cerebral ischemia. We aimed to evaluate the feasibility of early SA screening on a stroke unit, its impact on post-discharge SA care and the relation of SA to clinical features. Patients with acute ischemic stroke (AIS) and transient ischemic attack (TIA) prospectively underwent overnight cardiorespiratory polygraphy within 3 ± 2 days of symptom-onset. Feasibility was defined as analyzable polygraphy in 90 % of studied patients. We enrolled 61 patients (84 % AIS, 16 % TIA): mean age 66 ± 8 years, 44 % men, median NIHSS 1 (0-15), median ESS 5 (0-13). Analyzability was given in 56/61 (91.8 %; one-sided 95 % CI, lower-bound 86.0 %) patients indicating excellent feasibility of early SA screening with no significant differences in stroke severity (100 % in TIA, 91 % minor stroke, 83 % major stroke, p = 0.474). Ninety-one percent (51/56) had an apnea-hypopnea index ≥ 5/h (median: 20/h [0-79]); 32 % (18/56) mild, 30 % (17/56) moderate, and 29 % (16/56) severe SA. When comparing sleep-related ischemic stroke (SIS) and non-SIS patients, no differences were found regarding the presence (95 vs. 89 %, p = 0.49) or severity (e.g., severe SA: 32 vs. 27 %, p = 0.69) of SA. After 12 months, 27/38 (71 %) patients given specific recommendations completed in-laboratory sleep work-up and 7/27 (25 %) were prescribed for non-invasive ventilatory correction. In conclusion, early SA screening is feasible in patients with acute cerebral ischemia and may have a positive impact on post-discharge SA care. Given the high frequency and atypical presentation of SA, early screening for SA should be considered in all acute cerebral ischemia patients.

  15. Pro-GLP-1, a Pro-drug of GLP-1, is neuroprotective in cerebral ischemia.

    PubMed

    Zhang, Huinan; Meng, Jingru; Li, Xubo; Zhou, Shimeng; Qu, Di; Wang, Ning; Jia, Min; Ma, Xue; Luo, Xiaoxing

    2015-04-05

    Pro-Glucagon-like peptide-1 (Pro-GLP-1), a long-lasting GLP-1 receptor (GLP-1R) agonist, was developed using a polymeric pro-drug strategy and its neuroprotective effects on ischemic stroke were investigated in C57BL/6 mice. Pro-GLP-1 was injected into the intraperitoneal cavity of C57BL/6 mice once a day for 7days before middle cerebral artery occlusion (MCAO) surgery. The neurological deficit score and TTC staining were determined 24h after ischemia. The results demonstrated that Pro-GLP-1 was slowly degraded in the plasma and brain of the mice, and GLP-1 could be detected even 12h after administration. Pro-GLP-1 was significantly neuroprotective in C57BL/6 mice subjected to MCAO. In cultured cortical neurons, treatment with Pro-GLP-1 attenuated apoptosis induced by oxygen-glucose deprivation (OGD). The neuroprotective effects of Pro-GLP-1 were blocked by a selective GLP-1 receptor antagonist and knockdown of GLP-1 receptor with shRNA. However, Pro-GLP-1 had no effect on blood glucose and insulin levels which indicated that neuroprotection was mediated by the activation of GLP-1 receptor in the brain. Pro-GLP-1 repaired the balance of pro- and anti-apoptotic proteins and decreased the expression of caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. Our research provides evidence that pre-treatment of MCAO mice with Pro-GLP-1 exerts a neuroprotective effect mediated by a blockade of apoptosis and that Pro-GLP-1 might be a potential neuroprotective agent candidate against ischemic stroke. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. 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

  17. Effects of long‑term post‑ischemic treadmill exercise on gliosis in the aged gerbil hippocampus induced by transient cerebral ischemia.

    PubMed

    Ahn, Ji Hyeon; Shin, Myoung Cheol; Park, Joon Ha; Kim, In Hye; Cho, Jeong-Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Chen, Bai Hui; Shin, Bich Na; Tae, Hyun-Jin; Park, Jinseu; Choi, Soo Young; Lee, Yun Lyul; Kim, Dae Won; Kim, Yang Hee; Won, Moo-Ho; Cho, Jun Hwi

    2017-06-01

    Therapeutic exercise is an integral component of the rehabilitation of patients who have suffered a stroke. The objective of the present study was to use immunohistochemistry to investigate the effects of post‑ischemic exercise on neuronal damage or death and gliosis in the aged gerbil hippocampus following transient cerebral ischemia. Aged gerbils (male; age, 22‑24 months) underwent ischemia and were subjected to treadmill exercise for 1 or 4 weeks. Neuronal death was detected in the stratum pyramidale of the hippocampal CA1 region and in the polymorphic layer of the dentate gyrus using cresyl violet and Fluoro‑Jade B histofluorescence staining. No significant difference in neuronal death was identified following 1 or 4 weeks of post‑ischemic treadmill exercise. However, post‑ischemic treadmill exercise affected gliosis (the activation of astrocytes and microglia). Glial fibrillary acidic protein‑immunoreactive astrocytes and ionized calcium binding adaptor molecule 1‑immunoreactive microglia were activated in the CA1 and polymorphic layer of the dentate gyrus of the group without treadmill exercise. Conversely, 4 weeks of treadmill exercise significantly alleviated ischemia‑induced astrocyte and microglial activation; however, 1 week of treadmill exercise did not alleviate gliosis. These findings suggest that long‑term post‑ischemic treadmill exercise following transient cerebral ischemia does not influence neuronal protection; however, it may effectively alleviate transient cerebral ischemia‑induced astrocyte and microglial activation in the aged hippocampus.

  18. Long-lasting neuronal loss following experimental focal cerebral ischemia is not affected by combined administration of tissue plasminogen activator and hyperbaric oxygen.

    PubMed

    Hobohm, Carsten; Laignel, Félix; Kacza, Johannes; Küppers-Tiedt, Lea; Heindl, Marita; Schneider, Dietmar; Grosche, Jens; Härtig, Wolfgang; Michalski, Dominik

    2011-10-12

    Acute focal cerebral ischemia and consecutive energy failure are accompanied by neuronal death in regions with impaired cerebral blood flow. Several translational attempts of potential neuroprotective agents have failed, hence extended perspectives are required regarding the regional differences of neuronal impairment and glial involvement by using clinically relevant stroke models. This study aimed on neuronal loss following experimental focal cerebral ischemia, considering tissue plasminogen activator (tPA) as established treatment in stroke and hyperbaric oxygenation (HBO) as potential neuroprotective co-treatment. Wistar rats were subjected to embolic middle cerebral artery occlusion and underwent either treatment with tPA only, combined tPA+HBO, or no treatment. Neuronal impairment was assessed by Neuronal Nuclei (NeuN) staining in 4 ischemia-related areas and at 4 different time points after stroke induction (24hours, 7, 14 and 28 days). Additionally, spatial relationships between neuronal loss and gliosis were revealed by triple fluorescence staining of neurons, astrocytes and microglia, comparing the ipsi- and contra-lesional hemisphere. Analyzing the ischemic injury in general, a shell-like distribution of neuronal damage was observed, starting in the ischemic core and diminishing over the general ischemic area to the ischemic border zone and the primary non-affected area. This pattern remained detectable up to 4weeks after ischemia induction. Surprisingly, tPA and tPA+HBO did not markedly affect the post-ischemic course of neuronal impairment. Further studies are needed to investigate the effects of treatment with tPA or potential neuroprotective agents on neuronal integrity, with emphasis on the separation of intact neurons from those undergoing apoptosis or necrosis. Copyright © 2011 Elsevier B.V. All rights reserved.

  19. Alterations in Purkinje cell GABAA receptor pharmacology following oxygen and glucose deprivation and cerebral ischemia reveal novel contribution of β1-subunit-containing receptors

    PubMed Central

    Kelley, Melissa H.; Ortiz, Justin; Shimizu, Kaori; Grewal, Himmat; Quillinan, Nidia; Herson, Paco S.

    2013-01-01

    Cerebellar Purkinje cells (PCs) are particularly sensitive to cerebral ischemia, and decreased GABAA receptor function following injury is thought to contribute to PC sensitivity to ischemia-induced excitotoxicity. Here we examined the functional properties of the GABAA receptors that are spared following ischemia in cultured Purkinje cells from rat and in vivo ischemia in mouse. Using subunit-specific positive modulators of GABAA receptors, we observed that oxygen and glucose deprivation (OGD) and cardiac arrest-induced cerebral ischemia cause a decrease in sensitivity to the β2/3-subunit-preferring compound, etomidate. However, sensitivity to propofol, a β-subunit-acting compound that modulates β1–3-subunits, was not affected by OGD. The α/γ-subunit-act-ing compounds, diazepam and zolpidem, were also unaffected by OGD. We performed single-cell reverse transcription–polymerase chain reaction on isolated PCs from acutely dissociated cerebellar tissue and observed that PCs expressed the β1-subunit, contrary to previous reports examining GABAA receptor subunit expression in PCs. GABAA receptor β1-subunit protein was also detected in cultured PCs by western blot and by immunohistochemistry in the adult mouse cerebellum and levels remained unaffected by ischemia. High concentrations of loreclezole (30 µm) inhibited PC GABA-mediated currents, as previously demonstrated with β1-subunit-containing GABAA receptors expressed in heterologous systems. From our data we conclude that PCs express the β1-subunit and that there is a greater contribution of β1-subunit-containing GABAA receptors following OGD. PMID:23176253

  20. Antioxidant and anti-excitotoxicity effect of Gualou Guizhi decoction on cerebral ischemia/reperfusion injury in rats

    PubMed Central

    ZHANG, SHENGNSAN; ZHANG, YUQIN; LI, HUANG; XU, WEI; CHU, KEDAN; CHEN, LIDIAN; CHEN, XIANWEN

    2015-01-01

    Stroke is the leading cause of disability in adults and the second most common cause of mortality worldwide. There is currently intense interest in the use of natural products in the treatment of the condition. The aim of this study was to investigate the effect of Gualou Guizhi decoction (GLGZD) on rats subjected to cerebral ischemia/reperfusion injury and the possible mechanisms involved. Cerebral ischemia/reperfusion injury was induced by the middle cerebral artery occlusion method. Ischemic injury was assessed by estimating neurological function and measuring brain infarct volume, and the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling method was employed to examine ischemia-induced apoptosis. The levels of the antioxidative enzyme superoxide dismutase (SOD) and the concentrations of the non-enzymatic scavenger glutathione (GSH) and malondialdehyde (MDA) were measured to investigate the antioxidant mechanisms. In addition, the levels of excitatory amino acids (EAAs) and glutamate receptor 1 (GluR1) were examined using an automatic amino acid analyzer and immunohistochemical analysis. The administration of GLGZD attenuated the cerebral ischemia/reperfusion injury-induced neural deficits and cerebral infarct volume, reduced the levels of MDA and EAAs (glutamate and aspartate), significantly increased the activity of the antioxidant GSH and notably elevated the activity of SOD. Consistently, GLGZD inhibited ischemia-induced apoptosis and downregulated the expression of GluR1. In conclusion, this study suggested that GLGZD exerts a neuroprotective effect on focal cerebral ischemia/reperfusion injury through the modulation of multiple antioxidant and anti-excitotoxicity pathways. PMID:26136945

  1. 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

  2. Effect of Hyperglycemia on Brain Penetrating Arterioles and Cerebral Blood Flow Before and After Ischemia/Reperfusion

    PubMed Central

    Godfrey, Julie A.

    2010-01-01

    The effect of preexisiting hyperglycemia on cerebral blood flow (CBF) and brain penetrating arterioles before and after 2 h of ischemia and 30 min of reperfusion was determined. Male Wistar rats that were either hyperglycemic (50 mg/kg streptozotocin; n=24) or normoglycemic (n=24) were subjected to transient ischemia by filament occlusion or nonischemic. CBF was measured prior to ischemia using microspheres and during transient ischemia using laser Doppler. Edema was compared by wet/dry weights. Constriction to apamin, TRAM-34, and L-NNA, inhibitors of small- and intermediate-conductance calcium-activated potassium channels (SK and IK) and nitric oxide, were compared in penetrating arterioles from the ischemic hemisphere to investigate changes in basal tone and endothelium-dependent vasodilator responses. Preexisiting hyperglycemia did not affect CBF in non-ischemic animals or after transient ischemia; however, edema was significantly greater. Ischemia and reperfusion caused decreased basal tone in penetrating arterioles similarly in normoglycemic and hyperglycemic animals that was restored by apamin, and further increased by TRAM-34 and L-NNA. The restoration of tone in penetrating arterioles by apamin and TRAM-34 suggests that transient ischemia activates SK and IK channels in penetrating arterioles. This effect of ischemia was not different between normoglycemic and hyperglycemic animals, suggesting that it was related to ischemia and reperfusion rather than hyperglycemia. PMID:20563316

  3. Effect of hyperglycemia on brain penetrating arterioles and cerebral blood flow before and after ischemia/reperfusion.

    PubMed

    Cipolla, Marilyn J; Godfrey, Julie A

    2010-06-01

    The effect of preexisiting hyperglycemia on cerebral blood flow (CBF) and brain penetrating arterioles before and after 2 h of ischemia and 30 min of reperfusion was determined. Male Wistar rats that were either hyperglycemic (50 mg/kg streptozotocin; n=24) or normoglycemic (n=24) were subjected to transient ischemia by filament occlusion or nonischemic. CBF was measured prior to ischemia using microspheres and during transient ischemia using laser Doppler. Edema was compared by wet/dry weights. Constriction to apamin, TRAM-34, and L-NNA, inhibitors of small- and intermediate-conductance calcium-activated potassium channels (SK and IK) and nitric oxide, were compared in penetrating arterioles from the ischemic hemisphere to investigate changes in basal tone and endothelium-dependent vasodilator responses. Preexisiting hyperglycemia did not affect CBF in non-ischemic animals or after transient ischemia; however, edema was significantly greater. Ischemia and reperfusion caused decreased basal tone in penetrating arterioles similarly in normoglycemic and hyperglycemic animals that was restored by apamin, and further increased by TRAM-34 and L-NNA. The restoration of tone in penetrating arterioles by apamin and TRAM-34 suggests that transient ischemia activates SK and IK channels in penetrating arterioles. This effect of ischemia was not different between normoglycemic and hyperglycemic animals, suggesting that it was related to ischemia and reperfusion rather than hyperglycemia.

  4. Lettuce glycoside B ameliorates cerebral ischemia reperfusion injury by increasing nerve growth factor and neurotrophin-3 expression of cerebral cortex in rats

    PubMed Central

    Zhan, Heqin; Li, Shengying; Sun, Juan; Liu, Ruili; Yan, Fulin; Niu, Bingxuan; Zhang, Haifang; Wang, Xinyao

    2014-01-01

    Aims: The aim of the study was to investigate the effects of LGB on cerebral ischemia-reperfusion (I/R) injury in rats and the mechanisms of action of LGB. Materials and Methods: The study involved extracting LGB from P. laciniata, exploring affects of LGB on brain ischemia and action mechanism at the molecular level. The cerebral ischemia reperfusion injury of middle cerebral artery occlusion was established. We measured brain histopathology and brain infarct rate to evaluate the effects of LGB on brain ischemia injury. The expressions of nerve growth factor (NGF) and neurotrophin-3 (NT-3) were also measured to investigate the mechanisms of action by the real-time polymerase chain reaction and immunohistochemistry. Statistical analysis: All results were mentioned as mean ± standard deviation. One-way analysis of variance was used to determine statistically significant differences among the groups. Values of P < 0.05 were considered to be statistically significant. Results: Intraperitoneal injection of LGB at the dose of 12, 24, and 48 mg/kg after brain ischemia injury remarkably ameliorated the morphology of neurons and brain infarct rate (P < 0.05, P < 0.01). LGB significantly increased NGF and NT-3 mRNA (messenger RNA) and both protein expression in cerebral cortex at the 24 and 72 h after drug administration (P < 0.05, P < 0.01). Conclusions: LGB has a neuroprotective effect in cerebral I/R injury and this effect might be attributed to its upregulation of NGF and NT-3 expression ability in the brain cortex during the latter phase of brain ischemia. PMID:24550587

  5. FK506 protects against various immune responses and secondary degeneration following cerebral ischemia.

    PubMed

    Brecht, Stephan; Waetzig, Vicki; Hidding, Ute; Hanisch, Uwe-Karsten; Walther, Michael; Herdegen, Thomas; Neiss, Wolfram F

    2009-12-01

    The immunosuppressant FK506 (1 mg/kg, i.p.) reduces the infarct size following 90 min occlusion of the middle cerebral artery (MCAo) in adult rat brain. Here we have investigated the effect of FK506 on cerebral immune cells that are considered to contribute to neurodegeneration. FK506 substantially attenuated the response of resident and peripheral immune cells following transient ischemia. Between 24 hr and 5 days after MCAo, FK506 reduced the T-cell infiltration in the infarct area as well as the presence of activated and/or phagocytic OX-18, OX-42, GSA-IB4, Iba1, and ED1 positive microglia/macrophages. FK506 also lowered the protein levels of TNFalpha and IL-2 in ischemic brain areas. Repetitive application of FK506 over 20 days attenuated the activation of microglia in the substantia nigra (SN), an area of secondary degeneration. Importantly, FK506 conferred also lasting protection of the neurons of SN; these neurons degenerate by withdrawal of neurotrophic factors from the striatum that undergoes necrotic death as part of the ischemic core. To understand the molecular basis of FK506 effects in cerebral immune cells, we determined in primary postnatal day 0/1 (P0/P1) microglia (i) the expression of the FK506 binding proteins FKBP12, FKBP52, and FKPB65 and (ii) that FK506 (1-100 ng/mL) lowered the number of resting or lipopolysaccharide stimulated microglia as well as we induced the lipopolysaccharide release of TNFalpha in a dose-dependent manner. In summary, FK506 confers rescue of brain tissue following cerebral ischemia not only by neuronal protection, but also by suppression of microglial activation and peripheral immune responses.

  6. Endothelial Nitric Oxide Synthase Polymorphism Is Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage.

    PubMed

    Hendrix, Philipp; Foreman, Paul M; Harrigan, Mark R; Fisher, Winfield S; Vyas, Nilesh A; Lipsky, Robert H; Lin, Minkuan; Walters, Beverly C; Tubbs, R Shane; Shoja, Mohammadali M; Pittet, Jean-Francois; Mathru, Mali; Griessenauer, Christoph J

    2017-05-01

    Nitric oxide is critical in the regulation of cerebral blood flow and smooth muscle proliferation. It is synthesized by 3 nitric oxide synthase (NOS) isoforms: neuronal, inducible, and endothelial NOS (eNOS). Aneurysmal subarachnoid hemorrhage (aSAH) causes endothelial dysfunction that, in turn, contributes to pathophysiologic processes surrounding aSAH. Previous studies reported an association of an eNOS single nucleotide polymorphism (SNP) with the clinical sequelae of aSAH. Here, we further elucidate the impact of this eNOS SNP on the clinical course after aSAH. The Cerebral Aneurysm Renin Angiotensin System study prospectively enrolled aSAH patients at 2 academic institutions in the United States from 2012-2015. Blood samples from all patients enrolled in the study were used for genetic evaluation using 5'exonuclease (Taqman) genotyping assays. Associations between the eNOS SNP rs2070744 (786 T->C) and clinical course after aSAH were analyzed. Samples from 149 aSAH patients were available for analysis. The C allele of the eNOS SNP independently predicted an increased risk for delayed cerebral ischemia (OR = 2.936, 95% CI 1.048-8.226, P = 0.040). The eNOS SNP rs2070744 was not associated with functional outcome or size of aneurysm at the time of rupture. The present study is the first to demonstrate that the C allele of the eNOS SNP 786 T->C rs2070744 is independently associated with an increased risk for delayed cerebral ischemia following aSAH. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Neuroprotective effect of Momordica charantia in global cerebral ischemia and reperfusion induced neuronal damage in diabetic mice.

    PubMed

    Malik, Zafar Ahmad; Singh, Manjeet; Sharma, P L

    2011-01-27

    Momordica charantia L. (Cucurbitaceae) fruits have been used traditionally for centuries, especially for treating diabetes and associated complications. The present study was performed to evaluate neuroprotective effect of lyophilized M. charantia fruit juice against global cerebral ischemia and reperfusion induced neuronal injury in diabetic mice. Global cerebral ischemia induced by occluding both common carotid arteries for 10 min followed by 24 h reperfusion was used to induce neuronal injury. Ischemia-reperfusion induced neuronal injury was evaluated in terms of cerebral infarct size, generation of free radicals measured as thiobarbaturic acid reactive substances (TBARS), and neurological functions measured as short term memory and motor activity. The cerebral oxidative stress and damage, and neurological deficits were dose dependently attenuated by pre-treatment with the lyophilized M. charantia juice (200-800 mg/kg, p.o., o.d.). Moreover, M. charantia also exhibited dose dependent antihyperglycemic activity in diabetic mice. These results suggest that M. charantia has potent neuroprotective activity against global cerebral ischemia-reperfusion induced neuronal injury and consequent neurological deficits in diabetic mice. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Neuroprotective activity of gossypin from Hibiscus vitifolius against global cerebral ischemia model in rats

    PubMed Central

    Chandrashekhar, V. M.; Ganapaty, S.; Ramkishan, A.; Narsu, M. Laxmi

    2013-01-01

    Objectives: The objective of this study is to evaluate the neuroprotective effect of gossypin (isolated from Hibiscus vitifolius) against global cerebral ischemia/reperfusion (I/R) injury-induced oxidative stress in rats. Materials and Methods: Sprague Dawlet rats of wither gender were used in the study. Evaluation of cerbroprotective activity of bioflavonoid gossypin (in 5, 10 and 20 mg/kg oral doses) isolated from H. vitifolius was carried out by using the global cerebral I/R model by bilateral carotid artery occlusion for 30 min, followed by 24 h reperfusion. The antioxidant enzymatic and non-enzymatic levels were estimated along with histopathological studies. Result: Gossypin showed dose-dependent neuroprotective activity by significant decrease in lipid peroxidation (P < 0.001) and increase in the superoxide dismutase, catalase, glutathione and total thiol levels in gossypin treated groups when compared to control group. Cerebral infarction area was markedly reduced in gossypin treated groups when compared to control group. Conclusion: Gossypin showed potent neuroprotective activity against global cerebral I/R injury-induced oxidative stress in rats. PMID:24347764

  9. PPARα Agonist Fenofibrate Ameliorates Learning and Memory Deficits in Rats Following Global Cerebral Ischemia.

    PubMed

    Xuan, Ai-Guo; Chen, Yan; Long, Da-Hong; Zhang, Meng; Ji, Wei-Dong; Zhang, Wen-Juan; Liu, Ji-Hong; Hong, Le-Peng; He, Xiao-Song; Chen, Wen-Liang

    2015-08-01

    Increasing evidence demonstrates that local inflammation contributes to neuronal death following cerebral ischemia. Peroxisome proliferator-activated receptor α (PPARα) activation has been reported to exhibit many pharmacological effects including anti-inflammatory functions. The aim of this study was to investigate the neuroprotective effects of PPARα agonist fenofibrate on the behavioral dysfunction induced by global cerebral ischemia/reperfusion (GCI/R) injury in rats. The present study showed that fenofibrate treatment significantly reduced hippocampal neuronal death, and improved memory impairment and hippocampal neurogenesis after GCI/R. Fenofibrate administration also inhibited GCI/R-induced over-activation of microglia but not astrocytes and prevented up-regulations of pro-inflammatory mediators in hippocampus. Further study demonstrated that treatment with fenofibrate suppressed GCI/R-induced activations of P65 NF-κB and P38 MAPK. Our data suggest that the PPARα agonist fenofibrate can exert functional recovery of memory deficits and neuroprotective effect against GCI/R in rats via triggering of neurogenesis and anti-inflammatory effect mediated by inhibiting activation of P65 NF-κB and P38 MAPK in the hippocampus, which can contribute to improvement in neurological deficits.

  10. Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats.

    PubMed

    Popa-Wagner, Aurel; Badan, Irina; Walker, Lary; Groppa, Sergiu; Patrana, Nicoleta; Kessler, Christof

    2007-03-01

    Old age is associated with a deficient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the first few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the first time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.

  11. Astragaloside IV for Experimental Focal Cerebral Ischemia: Preclinical Evidence and Possible Mechanisms

    PubMed Central

    Wang, Hui-Lin; Zhou, Qi-Hui; Xu, Meng-Bei; Zhou, Xiao-Li

    2017-01-01

    Astragaloside IV (AST-IV) is a principal component of Radix Astragali seu Hedysari (Huangqi) and exerts potential neuroprotection in experimental ischemic stroke. Here, we systematically assessed the effectiveness and possible mechanisms of AST-IV for experimental acute ischemic stroke. An electronic search in eight databases was conducted from inception to March 2016. The study quality score was evaluated using the CAMARADES. Rev Man 5.0 software was used for data analyses. Thirteen studies with 244 animals were identified. The study quality score of included studies ranged from 3/10 to 8/10. Eleven studies showed significant effects of AST-IV for ameliorating the neurological function score (P < 0.05); seven studies for reducing the infarct volume (P < 0.05); and three or two studies for reducing the brain water content and Evans blue leakage (P < 0.05), respectively, compared with the control. The mechanisms of AST-IV for ischemic stroke are multiple such as antioxidative/nitration stress reaction, anti-inflammatory, and antiapoptosis. In conclusion, the findings of present study indicated that AST-IV could improve neurological deficits and infarct volume and reduce the blood-brain barrier permeability in experimental cerebral ischemia despite some methodological flaws. Thus, AST-IV exerted a possible neuroprotective effect during the cerebral ischemia/reperfusion injury largely through its antioxidant, anti-inflammatory, and antiapoptosis properties. PMID:28303172

  12. Does inhibiting Sur1 complement rt-PA in cerebral ischemia?

    PubMed Central

    Simard, J. Marc; Geng, Zhihua; Silver, Frank L.; Sheth, Kevin N.; Kimberly, W. Taylor; Stern, Barney J.; Colucci, Mario; Gerzanich, Volodymyr

    2012-01-01

    Hemorrhagic transformation (HT) associated with recombinant tissue plasminogen activator (rt-PA) complicates and limits its use in stroke. Here, we provide a focused review on the involvement of matrix metalloproteinase 9 (MMP-9) in rt-PA–associated HT in cerebral ischemia, and we review emerging evidence that the selective inhibitor of the sulfonylurea receptor 1 (Sur1), glibenclamide (U.S. adopted name, glyburide), may provide protection against rt-PA–associated HT in cerebral ischemia. Glyburide inhibits activation of MMP-9, ameliorates edema formation, swelling, and symptomatic hemorrhagic transformation, and improves preclinical outcomes in several clinically relevant models of stroke, both without and with rt-PA treatment. A retrospective clinical study comparing outcomes in diabetic patients with stroke treated with rt-PA showed that those who were previously on and were maintained on a sulfonylurea fared significantly better than those whose diabetes was managed without sulfonylureas. Inhibition of Sur1 with injectable glyburide holds promise for ameliorating rt-PA–associated HT in stroke. PMID:22994227

  13. Neuroprotection and reduced gliosis by atomoxetine pretreatment in a gerbil model of transient cerebral ischemia.

    PubMed

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

    2015-12-15

    Atomoxetine (ATX) is a non-stimulant selective norepinephrine reuptake inhibitor that is widely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). In this study, we firstly examined neuroprotective effects of pre- or post-treatment with 15 and 30 mg/kg ATX against ischemic damage in the gerbil hippocampal cornus ammonis 1 (CA1) region subjected to 5 min of transient cerebral ischemia using cresyl violet staining, neuronal nuclei immunohistochemistry and Fluoro-J B histofluorescence staining. We found that only pre-treatment with 30 mg/kg ATX protected CA1 pyramidal neurons from ischemic insult. In addition, pre-treatment with 30 mg/kg ATX, which had neuroprotective effect against ischemic damage, distinctly attenuated the activation of astrocytes and microglia in the ischemic CA1 region compared with the vehicle-treated ischemia group by glial fibrillary acidic protein (for astrocytes) and ionized calcium-binding adapter molecule 1 (for microglia) immunohistochemistry. In brief, our present results indicate that ATX has neuroprotective effect against transient cerebral ischemic insult and that the neuroprotective effect of ATX may be closely associated with attenuated glial activation.

  14. Intranasal Delivery of Exendin-4 Confers Neuroprotective Effect Against Cerebral Ischemia in Mice.

    PubMed

    Zhang, Huinan; Meng, Jingru; Zhou, Shimeng; Liu, Yunhan; Qu, Di; Wang, Ling; Li, Xubo; Wang, Ning; Luo, Xiaoxing; Ma, Xue

    2016-03-01

    Exendin-4 is now considered as a promising drug for the treatment of cerebral ischemia. To determine the neuroprotective effects of intranasal exendin-4, C57BL/6J mice were intranasally administered with exendin-4 daily for 7 days before middle cerebral artery occlusion (MCAO) surgery. Intranasally administered exendin-4 produced higher brain concentrations and lower plasma concentrations when compared to identical doses administered interperitoneally. Neurological deficits and volume of infarcted lesions were analyzed 24 h after ischemia. Intranasal administration of exendin-4 exhibited significant neuroprotection in C57BL/6 mice subjected to MCAO by reducing neurological deficit scores and infarct volume. The neuroprotective effects of exendin-4 were blocked by the knockdown of GLP-1R with shRNA. However, exendin-4 has no impact on glucose and insulin levels which indicated that the neuroprotective effect was mediated by the activation of GLP-1R in the brain. Exendin-4 intranasal administration restored the balance between pro- and anti-apoptotic proteins and decreased the expression of Caspase-3. The anti-apoptotic effect was mediated by the cAMP/PKA and PI3K/Akt pathway. These findings provided evidence that exendin-4 intranasal administration exerted a neuroprotective effect mediated by an anti-apoptotic mechanism in MCAO mice and protected neurons against ischemic injury through the GLP-1R pathway in the brain. Intranasal delivery of exendin-4 might be a promising strategy for the treatment of ischemic stroke.

  15. TRPM7 in cerebral ischemia and potential target for drug development in stroke

    PubMed Central

    Bae, Christine You-jin; Sun, Hong-shuo

    2011-01-01

    Searching for effective pharmacological agents for stroke treatment has largely been unsuccessful. Despite initial excitement, antagonists for glutamate receptors, the most studied receptor channels in ischemic stroke, have shown insufficient neuroprotective effects in clinical trials. Outside the traditional glutamate-mediated excitotoxicity, recent evidence suggests few non-glutamate mechanisms, which may also cause ionic imbalance and cell death in cerebral ischemia. Transient receptor potential melastatin 7 (TRPM7) is a Ca2+ permeable, non-selective cation channel that has recently gained attention as a potential cation influx pathway involved in ischemic events. Compelling new evidence from an in vivo study demonstrated that suppression of TRPM7 channels in adult rat brain in vivo using virally mediated gene silencing approach reduced delayed neuronal cell death and preserved neuronal functions in global cerebral ischemia. In this review, we will discuss the current understanding of the role of TRPM7 channels in physiology and pathophysiology as well as its therapeutic potential in stroke. PMID:21552293

  16. LLDT-8 protects against cerebral ischemia/reperfusion injury by suppressing post-stroke inflammation.

    PubMed

    Chen, Yanke; Zhang, Li; Ni, Jingshu; Wang, Xiaoyu; Cheng, Jian; Li, Yuanchao; Zhen, Xuechu; Cao, Ting; Jia, Jia

    2016-06-01

    (5R)-5-Hydroxytriptolide (LLDT-8), an analogue of triptolide, displays lower toxicity compared to triptolide and has comparable immunosuppressive effects. We investigated the anti-inflammatory and neuroprotective effects of LLDT-8 on cerebral ischemia/reperfusion injury. Nitric oxide production from microglia was assessed by measuring the nitrite concentration in the culture medium with Griess reagent. Microglial cells and ischemic brain tissues were examined for the expression of proinflammatory mediators by qPCR and western blot. Infarct volumes were assessed with TTC histology. The TLR4/NF-κB signaling pathway was analyzed with western blot and immunocytochemistry. LLDT-8 significantly reduced infarct sizes and expression of pro-inflammatory cytokines in the ischemic cortex. LLDT-8 inhibited NO release and expression of TNF-α, IL-1β and iNOS in BV-2 microglia and primary microglia treated with LPS. In addition, LLDT-8 suppressed expression of TLR4, degradation of IκBα and nuclear translocation of NF-κB. LLDT-8 exerted anti-inflammatory effects and protected against acute cerebral ischemia/reperfusion injury possibly by acting through the IκB/NF-κB cascade to suppress microglia-mediated neuroinflammation. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. Damaged Neocortical Perineuronal Nets Due to Experimental Focal Cerebral Ischemia in Mice, Rats and Sheep.

    PubMed

    Härtig, Wolfgang; Mages, Bianca; Aleithe, Susanne; Nitzsche, Björn; Altmann, Stephan; Barthel, Henryk; Krueger, Martin; Michalski, Dominik

    2017-01-01

    As part of the extracellular matrix (ECM), perineuronal nets (PNs) are polyanionic, chondroitin sulfate proteoglycan (CSPG)-rich coatings of certain neurons, known to be affected in various neural diseases. Although these structures are considered as important parts of the neurovascular unit (NVU), their role during evolution of acute ischemic stroke and subsequent tissue damage is poorly understood and only a few preclinical studies analyzed PNs after acute ischemic stroke. By employing three models of experimental focal cerebral ischemia, this study was focused on histopathological alterations of PNs and concomitant vascular, glial and neuronal changes according to the NVU concept. We analyzed brain tissues obtained 1 day after ischemia onset from: (a) mice after filament-based permanent middle cerebral artery occlusion (pMCAO); (b) rats subjected to thromboembolic MACO; and (c) sheep at 14 days after electrosurgically induced focal cerebral ischemia. Multiple fluorescence labeling was applied to explore simultaneous alterations of NVU and ECM. Serial mouse sections labeled with the net marker Wisteria floribunda agglutinin (WFA) displayed largely decomposed and nearly erased PNs in infarcted neocortical areas that were demarcated by up-regulated immunoreactivity for vascular collagen IV (Coll IV). Subsequent semi-quantitative analyses in mice confirmed significantly decreased WFA-staining along the ischemic border zone and a relative decrease in the directly ischemia-affected neocortex. Triple fluorescence labeling throughout the three animal models revealed up-regulated Coll IV and decomposed PNs accompanied by activated astroglia and altered immunoreactivity for parvalbumin, a calcium-binding protein in fast-firing GABAergic neurons which are predominantly surrounded by neocortical PNs. Furthermore, ischemic neocortical areas in rodents simultaneously displayed less intense staining of WFA, aggrecan, the net components neurocan, versican and the cartilage link

  18. Soluble cpg15 from Astrocytes Ameliorates Neurite Outgrowth Recovery of Hippocampal Neurons after Mouse Cerebral Ischemia.

    PubMed

    Zhao, Jing-Jing; Hu, Jie-Xian; Lu, De-Xin; Ji, Chun-Xia; Qi, Yao; Liu, Xiao-Yan; Sun, Feng-Yan; Huang, Fang; Xu, Ping; Chen, Xian-Hua

    2017-02-08

    The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation.SIGNIFICANCE STATEMENT Neuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in

  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. Carvacrol, a Food-Additive, Provides Neuroprotection on Focal Cerebral Ischemia/Reperfusion Injury in Mice

    PubMed Central

    Chen, Jing; Pei, Aijie; Hua, Fang; Qian, Xuanchen; He, Jinjiang; Liu, Chun-Feng; Xu, Xingshun

    2012-01-01

    Carvacrol (CAR), a naturally occurring monoterpenic phenol and food additive, has been shown to have antimicrobials, antitumor, and antidepressant-like activities. A previous study demonstrated that CAR has the ability to protect liver against ischemia/reperfusion injury in rats. In this study, we investigated the protective effects of CAR on cerebral ischemia/reperfusion injury in a middle cerebral artery occlusion mouse model. We found that CAR (50 mg/kg) significantly reduced infarct volume and improved neurological deficits after 75 min of ischemia and 24 h of reperfusion. This neuroprotection was in a dose-dependent manner. Post-treatment with CAR still provided protection on infarct volume when it was administered intraperitoneally at 2 h after reperfusion; however, intracerebroventricular post-treatment reduced infarct volume even when the mice were treated with CAR at 6 h after reperfusion. These findings indicated that CAR has an extended therapeutic window, but delivery strategies may affect the protective effects of CAR. Further, we found that CAR significantly decreased the level of cleaved caspase-3, a marker of apoptosis, suggesting the anti-apoptotic activity of CAR. Finally, our data indicated that CAR treatment increased the level of phosphorylated Akt and the neuroprotection of CAR was reversed by a PI3K inhibitor LY-294002, demonstrating the involvement of the PI3K/Akt pathway in the anti-apoptotic mechanisms of CAR. Due to its safety and wide use in the food industry, CAR is a promising agent to be translated into clinical trials. PMID:22438954

  1. 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

  2. Low ankle-brachial index predicts early risk of recurrent stroke in patients with acute cerebral ischemia.

    PubMed

    Tsivgoulis, Georgios; Bogiatzi, Chrysi; Heliopoulos, Ioannis; Vadikolias, Konstantinos; Boutati, Eleni; Tsakaldimi, Soultana; Al-Attas, Omar S; Charalampidis, Paris; Piperidou, Charitomeni; Maltezos, Efstratios; Papanas, Nikolaos

    2012-02-01

    Low ankle-brachial blood pressure index (ABI) identifies patients with symptomatic and asymptomatic peripheral arterial disease (PAD). We sought to investigate the association of low ABI with early risk of stroke recurrence in patients with acute cerebral ischemia (ACI) and without history of symptomatic PAD. Consecutive patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and no previous history of PAD were prospectively evaluated with ABI measurements. Demographic characteristics, vascular risk factors and secondary prevention therapies were documented. An ABI ≤0.90 in either leg was considered as evidence of asymptomatic PAD, and an ABI >0.90 was considered as normal. Patients with elevated ABI (>1.30) were excluded. The outcome of interest was recurrent stroke during 30-day follow-up. A total of 176 patients with acute cerebral ischemia (mean age 64±14 years, 59.1% men, 76.7% AIS) were evaluated. Asymptomatic PAD was detected in 14.8% (95%CI: 10.2-20.8%) of the studied population. The following factors were independently associated with low ABI on multivariate logistic regression models, after adjustment for potential confounders: coronary artery disease (p=0.008), diabetes mellitus (p=0.017) and increasing age (p=0.042). The cumulative 30-day recurrence rate was higher in patients with low ABI (19.2%; 95%CI: 4.1-34.3) compared to the rest (3.3%; 95%CI: 0.4-6.2%; p=0.001). Atherothrombotic stroke (ASCO grade I; p<0.001), increasing age (p=0.002) and low ABI (p=0.004) were independent predictors of stroke recurrence on multivariate Cox regression models adjusting for confounders. Low ABI appears to be associated with a higher risk of early recurrent stroke in patients with ACI and no history of symptomatic PAD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  3. 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.

  4. [Research on the changes of IL-1 receptor and TNF-alpha receptor in rats with cerebral ischemia reperfusion and the chronergy of acupuncture intervention].

    PubMed

    Wang, Zhan-Kui; Ni, Guang-Xia; Liu, Kun; Xiao, Zhen-Xin; Yang, Bao-Wang; Wang, Jing; Wang, Shu

    2012-11-01

    To explore the intervention timing of acupuncture in treatment of cerebral infarction and the relationship of cerebral ischemia reperfusion injury with inflammatory cytokine receptor. One hundred and ten male healthy Wistar rats were randomly divided into a normal group (n=10), a sham operation group (n=10), a model group (n=10), an acupuncture at non-acupoint group (non-acupoint group, n=40), an acupuncture with regaining consciousness method group (regaining consciousness group, n=40). Four subgroups were set up 1 h ischemia reperfusion in 1 h group, 3 h group, 6 h group, 12 h group in the two acupuncture groups, 10 rats in each subgroup. Two acupuncture groups were treated with acupuncture at four time points (1 h, 3 h, 6 h and 12 h after ischemia reperfusion), and "Shuigou" (GV 26) and "Neiguan" (PC 6) were selected in regaining consciousness group, and the non-acupoints below the bilateral costal region were selected in non-acupoint group. At the corresponding time point, the tissues of the brain were removed and interleukin1 receptor (IL-1RI) and tumor necrosis factor receptor (TNFR-I) mRNA and protein changes were detected by using real-time quantitative polymerase chain reaction and immunoblot assay. The expression of IL-1RI and TNFR-I mRNA and protein in the model group were significantly higher than that in normal group, sham operation group, regaining consciousness group and non-acupoint group (P<0.01, P<0.05). The expression of IL-1RI and TNFR-I mRNA and protein in regaining consciousness group was weakest at 3 h after reperfusion followed successively by 6 h, 1 h, 12 h, and there was no significantly change of IL-1RI and TNFR-I mRNA and protein expression in non-acupoint group among different timing points, but which was decreased as compared with those in the model group at the same time point (all P<0.05). Acupuncture can reduce the expression of IL-1RI and TNFR-I mRNA and protein in rats with cerebral ischemia reperfusion, inhibit the excessive

  5. Protective effects of propofol against whole cerebral ischemia/reperfusion injury in rats through the inhibition of the apoptosis-inducing factor pathway.

    PubMed

    Tao, Tao; Li, Chun-Lei; Yang, Wan-Chao; Zeng, Xian-Zhang; Song, Chun-Yu; Yue, Zi-Yong; Dong, Hong; Qian, Hua

    2016-08-01

    Cerebral ischemia/reperfusion (I/R) injury could cause neural apoptosis that involved the signaling cascades. Cytochrome c release from the mitochondria and the followed activation of caspase 9 and caspase 3 are the important steps. Now, a new mitochondrial protein, apoptosis-inducing factor (AIF), has been shown to have relationship with the caspase-independent apoptotic pathway. In this study, we investigated the protective effects of propofol through inhibiting AIF-mediated apoptosis induced by whole cerebral I/R injury in rats. 120 Wistar rats that obtained the permission of the animal care committee of Harbin Medical University were randomly divided into three groups: sham group (S group), cerebral ischemia/reperfusion injury group (I/R group), and propofol treatment group (P group). Propofol (1.0mg/kg/min) was administered intravenously for 1h before the induction of ischemia in P group. The apoptotic rate in three groups was detected by flow cytometry after 24h of reperfusion. The mitochondrial membrane potential (MMP) changes were detected via microplate reader. The expressions of B-cell leukemia-2 (Bcl-2), Bcl-2 associated X protein (Bax) and AIF were evaluated using Western blot after 6h, 24h and 48h of reperfusion. The results of our study showed that apoptotic level was lower in P group compared with I/R group and propofol could protect MMP. The ratio of Bcl-2/Bax was significantly higher in P group compared with I/R group. The translocation of AIF from mitochondrial to nucleus was lower in P group than that in I/R group. Our findings suggested that the protective effects of propofol on cerebral I/R injury might be associated with inhibiting translocation of AIF from mitochondrial to the nucleus in hippocampal neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Analysis of serum metabolites for the discovery of amino acid biomarkers and the effect of galangin on cerebral ischemia.

    PubMed

    Gao, Jian; Yang, Hongjun; Chen, Jianxin; Fang, Jiansong; Chen, Chang; Liang, Rixin; Yang, Gengliang; Wu, Hongwei; Wu, Chuanhong; Li, Shaojing

    2013-09-01

    Ischemic stroke, a devastating disease with a complex pathophysiology, is a leading cause of death and disability worldwide. In our previous study, we reported that galangin provided direct protection against ischemic injury and acted as a potential neuroprotective agent. However, its associated neuroprotective mechanism has not yet been clarified. In this paper, we explored the potential AA biomarkers in the acute phase of cerebral ischemia and the effect of galangin on those potential biomarkers. In our study, 12 AAs were quantified in rat serum and found to be impaired by middle cerebral artery occlusion (MCAO)-induced focal cerebral ischemia. Using partial least squares discriminate analysis (PLS-DA), we identified the following amino acids as potential biomarkers of cerebral ischemia: glutamic acid (Glu), homocysteine (Hcy), methionine (Met), tryptophan (Trp), aspartic acid (Asp), alanine (Ala) and tyrosine (Tyr). Moreover, four amino acids (Hcy, Met, Glu and Trp) showed significant change in galangin-treated (100 and 50 mg kg(-1)) groups compared to vehicle groups. Furthermore, we identified three pathway-related enzymes tyrosine aminotransferase (TAT), glutamine synthetase (GLUL) and monocarboxylate transporter (SLC16A10) by multiplex interactions with Glu and Hcy, which have been previously reported to be closely related to cerebral ischemia. Through an analysis of the metabolite-protein network analysis, we identified 16 proteins that were associated with two amino acids by multiple interactions with three enzymes; five of them may become potential biomarkers of galangin for acute ischemic stroke as the result of molecule docking. Our results may help develop novel strategies to explore the mechanism of cerebral ischemia, discover potential targets for drug candidates and elucidate the related regulatory signal network.

  7. Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia.

    PubMed Central

    Botchkina, G. I.; Meistrell, M. E.; Botchkina, I. L.; Tracey, K. J.

    1997-01-01

    Cerebral ischemia induces a rapid and dramatic up-regulation of tumor necrosis factor (TNF) protein and mRNA, but the cellular sources of TNF in the ischemic brain have not been defined. The diverse activities of TNF are mediated via ligand interaction with two distinct receptors, p55 and p75, which activate separate intracellular signal transduction pathways, leading to distinct biological effects. Since the effects of cerebral ischemia on TNF receptor (TNFR) expression are unknown, we examined the cellular localization and protein expression of TNF and its two receptors in the rat cerebral cortex in response to permanent middle cerebral artery (MCA) occlusion. The results indicate that focal. cerebral ischemia up-regulates expression of TNF and both TNFRs within the ischemic cortex. The most abundant type of TNF immunoreactivity (IR) was a punctate and filamentous pattern of transected cellular processes; however, cell bodies of neurons, astrocytes, and microglia, as well as infiltrating polymorphonuclear (PMN) leukocytes also showed TNF IR. Brain vasculature displayed TNF IR not only within endothelial cells but also in the perivascular space. MCA occlusion induced significant up-regulation of TNF receptors, with p55 IR appearing within 6 hr, significantly before the appearance of p75 IR at 24 hr after the onset of ischemia. Since p55 has been implicated in transducing cytotoxic signalling of TNF, these results support the proposed injurious role of excessive TNF produced during the acute response to cerebral ischemia. Images FIG. 7 FIG. 3 FIG. 1 FIG. 2 FIG. 4 FIG. 5 FIG. 6 FIG. 8 FIG. 9 PMID:9407552

  8. Tetrahydrocurcumin ameliorates homocysteinylated cytochrome-c mediated autophagy in hyperhomocysteinemia mice after cerebral ischemia.

    PubMed

    Tyagi, Neetu; Qipshidze, Natia; Munjal, Charu; Vacek, Jonathan C; Metreveli, Naira; Givvimani, Srikanth; Tyagi, Suresh C

    2012-05-01

    reduced in I/R + THC-treated groups as compared to sham-operated groups along with reduced brain infarct size. THC also decreased oxidative damage and ameliorated the homocysteinylation of cyto-c in-part by MMP-9 activation which leads to autophagy in I/R groups as compared to sham-operated groups. This study suggests a potential therapeutic role of dietary THC in cerebral ischemia.

  9. Neuroprotection of taurine through inhibition of 12/15 lipoxygenase pathway in cerebral ischemia of rats.

    PubMed

    Zhang, Zhe; Yu, Rongbo; Cao, Lei

    2017-05-01

    Cerebral ischemia exhibits a multiplicity of pathophysiological mechanisms. Taurine (Tau), an endogenous substance, possesses a number of cytoprotective properties. The aim of the present study was to examine the neuroprotective effect of Tau, through affecting 12/15 lipoxygenase (12/15-LOX) signal pathway in an acute permanent middle cerebral artery occlusion (MCAO) model of rats. Sprague-Dawley rats were randomly divided into 3 groups (n = 10), namely the sham-operated group, MCAO group and Tau group. Tau was intraperitoneally administrated immediately after cerebral ischemia. At 24 h after MCAO, neurological function score, brain water content and infarct volume were assessed. The expression of 12/15-lipoxygenase (12/15-LOX), p38 mitogen-activated protein kinase (p38 MAPK), and cytosolic phospholipase A2 (cPLA2) was measured by Western blot. Enzyme-linked immunosorbent assay was used to evaluate the inflammatory factors TNF-α, IL-1β and IL-6 in serum. Compared with MCAO group, taurine significantly improved neurological function and significantly reduced brain water content (p < 0.05) and infarct volume (p < 0.05). Consistent with these indices, the overexpressions of 12/15-LOX, p38 MAPK, cPLA2, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly decreased in Tau group (p < 0.05). Taurine protected the brain from damage caused by MCAO; this effect may be through down-regulation of 12/15-LOX, p38 MAPK, and cPLA2.

  10. Scutellarin attenuates microglia-mediated neuroinflammation and promotes astrogliosis in cerebral ischemia - a therapeutic consideration

    PubMed

    Wu, Chun-Yun; Fang, Ming; Karthikeyan, Aparna; Yuan, Yun; Ling, Eng-Ang

    2016-11-18

    Neuroinflammation plays an important role in different brain diseases including acute brain injuries such as cerebral ischemic stroke and chronic neurodegenerative diseases e.g. Alzheimer's disease etc. The central player in this is the activated microglia which produce substantial amounts of proinflammatory mediators that may exacerbate the disease. Associated with microglia activation is astrogliosis characterized by hypertrophic astrocytes with increased expression of proinflammatory cytokines, neurotrophic factors, stem cell, neuronal and proliferation markers, all these are crucial for reconstruction of damaged tissue and ultimate restoration of neurological functions. Here, we review the roles of activated microglia and reactive astrocytes in brain diseases with special reference to cerebral ischemia, and the effects of scutellarin, a Chinese herbal extract on both glial cells. We first reviewed the close spatial relation between activated microglia and reactive astrocytes as it suggests that both glial cells work in concert for tissue reconstruction and repair. Secondly, we have identified scutellarin as a putative therapeutic agent as it has been found to not only suppress microglial activation thus ameliorating neuroinflammation, but also enhance astrocytic reaction. In the latter, scutellarin amplified the astrocytic reaction by upregulating the expression of neurotrophic factors among others thus indicating its neuroprotective role. Remarkably, the effects of scutellarin on reactive astrocytes were mediated by activated microglia supporting a functional "cross-talk" between the two glial types. This review highlights some of our recent findings taking into consideration of others demonstrating the beneficial effects of scutellarin on both glial cell types in cerebral ischemia as manifested by improvement of neurological functions.

  11. Dietary phytoestrogens improve stroke outcome after transient focal cerebral ischemia in rats.

    PubMed

    Burguete, María C; Torregrosa, Germán; Pérez-Asensio, Fernando J; Castelló-Ruiz, María; Salom, Juan B; Gil, José V; Alborch, Enrique

    2006-02-01

    As phytoestrogens are postulated as being neuroprotectants, we assessed the hypothesis that dietary isoflavone-type phytoestrogens are neuroprotective against ischemic stroke. Transient focal cerebral ischemia (90 min) was induced by middle cerebral artery occlusion (MCAO) following the intraluminal thread technique, both in rats fed with soy-based diet and in rats fed with isoflavone-free diet. Cerebro-cortical laser-Doppler flow (cortical perfusion, CP), arterial blood pressure, core temperature, PaO2, PaCO2, pH and glycemia were measured before, during and after MCAO. Neurological examination and infarct volume measurements were carried out 3 days after the ischemic insult. Dietary isoflavones (both glycosides and aglycones) were measured by high-performance liquid chromatography. Neither pre-ischemic, intra-ischemic nor post-ischemic CP values were significantly different between the soy-based diet and the isoflavone-free diet groups. Animals fed with the soy-based diet showed an infarct volume of 122 +/- 20.2 mm3 (19 +/- 3.3% of the whole ipsilateral hemisphere volume). In animals fed with the isoflavone-free diet the mean infarct volume was significantly higher, 191 +/- 26.7 mm3 (28 +/- 4.1%, P < 0.05). Neurological examination revealed significantly higher impairment in the isoflavone-free diet group compared with the soy-based diet group (3.3 +/- 0.5 vs. 1.9 +/- 0.5, P < 0.05). These results demonstrate that dietary isoflavones improve stroke outcome after transient focal cerebral ischemia in such a way that a higher dietary isoflavone content results in a lower infarct volume and a better neurological status.

  12. 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.

  13. Post-ischemic administration of progesterone reduces caspase-3 activation and DNA fragmentation in the hippocampus following global cerebral ischemia.

    PubMed

    Espinosa-García, Claudia; Vigueras-Villaseñor, Rosa María; Rojas-Castañeda, Julio César; Aguilar-Hernández, Alejandra; Monfil, Tomas; Cervantes, Miguel; Moralí, Gabriela

    2013-08-29

    Delayed death of hippocampal CA1 pyramidal neurons following global cerebral ischemia/reperfusion may be mediated, in part, by caspase-3 activation resulting in DNA fragmentation. Progesterone (P4) is known to exert neuroprotective effects in several models of brain injury. This study was designed to assess the effect of P4 on caspase-3 levels and activation, and DNA fragmentation in the hippocampus following global cerebral ischemia/reperfusion. Adult male Sprague-Dawley rats were subjected to global ischemia by the four-vessel occlusion model. P4 (8 mg/kg), or its vehicle were administered i.v. at 15 min, 2, 6, 24, 48 and 70 h of reperfusion. Remaining pyramidal neurons were assesed by the Nissl staining technique, caspase-3 levels and activation by immunohistochemistry and an in situ activity assay, and DNA fragmentation by the TUNEL method. Post-ischemic progesterone treatment significantly reduced the ischemia/reperfusion-induced increase in caspase-3 levels and activation at 72 h, and DNA fragmentation and CA1 neuronal loss at 7 days. Present results suggest the reduction of caspase-3 levels/activation, and DNA fragmentation, as a part of the neuroprotective effects of progesterone against global cerebral ischemia/reperfusion injury. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. Ischemia

    NASA Astrophysics Data System (ADS)

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

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

  15. Calcitonin gene-related peptide protects rats from cerebral ischemia/reperfusion injury via a mechanism of action in the MAPK pathway

    PubMed Central

    YANG, SI; YUAN, YONGJIE; JIAO, SHAN; LUO, QI; YU, JINLU

    2016-01-01

    The aim of the present study was to investigate the protective function and underlying mechanism of calcitonin gene-related peptide (CGRP) on cerebral ischemia/reperfusion damage in rats. Adult male Wistar rats were selected for the establishment of an ischemia/reperfusion injury model through the application of a middle cerebral artery occlusion. Animals were randomly divided into 6 groups of 24 animals. Drugs were administered according to the design of each group; animals were administered CGRP, CGRP8–37, PD98059 and SB20358. The neurobehavioral scores of the rat cerebral ischemia model in each group were calculated. The infarction range of the rat brain tissues was observed by 2,3,5-triphenyltetrazolium chloride staining. The expression levels of three proteins, phosphorylated c-Jun N-terminal kinase (JNK)/JNK, phosphorylated extracellular signal-regulated protein kinase (ERK)/ERK and p-p38/p38, in the mitogen-activated protein kinase (MAPK) pathway in the brain tissues was detected by western blotting. The results showed that CGRP could improve the neurobehavioral function of the ischemic rats and reduce the infarction range. Western blotting results confirmed that the function of the CGRP was mediated mainly through the reduction of the JNK and p38 phosphorylation and the promotion of ERK phosphorylation. Therefore, the present study confirmed that an increase in the exogenous CRGP could effectively improve ischemia/reperfusion injury of the brain tissue. The mechanisms of action were achieved through a reduction in JNK and p38 phosphorylation and an increase in ERL phosphorylation in the MAPK pathway. These mechanisms were interdependent. PMID:27284409

  16. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy.

    PubMed

    Wang, Jue; Cao, Bin; Han, Dong; Sun, Miao; Feng, Juan

    2017-02-01

    Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke.

  17. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy

    PubMed Central

    Wang, Jue; Cao, Bin; Han, Dong; Sun, Miao; Feng, Juan

    2017-01-01

    Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke. PMID:28203482

  18. Ultra-early angiographic vasospasm associated with delayed cerebral ischemia and infarction following aneurysmal subarachnoid hemorrhage.

    PubMed

    Al-Mufti, Fawaz; Roh, David; Lahiri, Shouri; Meyers, Emma; Witsch, Jens; Frey, Hans-Peter; Dangayach, Neha; Falo, Cristina; Mayer, Stephan A; Agarwal, Sachin; Park, Soojin; Meyers, Philip M; Sander Connolly, E; Claassen, Jan; Michael Schmidt, J

    2016-05-27

    OBJECTIVE The clinical significance of cerebral ultra-early angiographic vasospasm (UEAV), defined as cerebral arterial narrowing within the first 48 hours of aneurysmal subarachnoid hemorrhage (aSAH), remains poorly characterized. The authors sought to determine its frequency, predictors, and impact on functional outcome. METHODS The authors prospectively studied UEAV in a cohort of 1286 consecutively admitted patients with aSAH between August 1996 and June 2013. Admission clinical, radiographic, and acute clinical course information was documented during patient hospitalization. Functional outcome was assessed at 3 months using the modified Rankin Scale. Logistic regression and Cox proportional hazards models were generated to assess predictors of UEAV and its relationship to delayed cerebral ischemia (DCI) and outcome. Multiple imputation methods were used to address data lost to follow-up. RESULTS The cohort incidence rate of UEAV was 4.6%. Multivariable logistic regression analysis revealed that younger age, sentinel bleed, and poor admission clinical grade were significantly associated with UEAV. Patients with UEAV had a 2-fold increased risk of DCI (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.4-3.9, p = 0.002) and cerebral infarction (OR 2.0, 95% CI 1.0-3.9, p = 0.04), after adjusting for known predictors. Excluding patients who experienced sentinel bleeding did not change this effect. Patients with UEAV also had a significantly higher hazard for DCI in a multivariable model. UEAV was not found to be significantly associated with poor functional outcome (OR 0.8, 95% CI 0.4-1.6, p = 0.5). CONCLUSIONS UEAV may be less frequent than has been reported previously. Patients who exhibit UEAV are at higher risk for refractory DCI that results in cerebral infarction. These patients may benefit from earlier monitoring for signs of DCI and more aggressive treatment. Further study is needed to determine the long-term functional significance of UEAV.

  19. Protective Role of Fucoidan in Cerebral Ischemia-Reperfusion Injury through Inhibition of MAPK Signaling Pathway.

    PubMed

    Che, Nan; Ma, Yijie; Xin, Yinhu

    2016-11-25

    Fucoidan has been reported to exhibit various beneficial activities ranging from to antivirus and anticancer properties. However, little information is available about the effects of fucoidan on cerebral ischemia-reperfusion injury (IRI). Our study aimed to explore the effects of fucoidan on cerebral IRI, as well as the underlying mechanisms. Sprague-Dawley (SD) rats were randomly subjected to four groups: Sham, IRI+saline (IRI+S), IRI+80 mg/kg fucoidan (IRI+F80), and IRI+160 mg/kg fucoidan (IRI+F160). Fucoidan (80 mg/kg or 160 mg/kg) was intraperitoneally injected from 7 days before the rats were induced to cerebral IRI model with middle cerebral artery occlusion (MCAO) method. At 24 h after reperfusion, neurological deficits and the total infarct volume were determined. The levels of inflammation-associated cytokines (interleukin (IL)-1β, IL-6, myeloperoxidase (MPO), and tumor necrosis factor (TNF)-α), oxidative stress-related proteins (malondialdehyde (MDA) and superoxide dismutase (SOD)) in the ischemic brain were measured by enzyme-linked immunosorbent assay (ELISA). Besides, the levels of apoptosis-related proteins (p-53, Bax, and B-cell lymphoma (Bcl)-2) and mitogen-activated protein kinase (MAPK) pathway (phosphorylation-extracellular signalregulated kinase (p-ERK), p-c-Jun N-terminal kinase (JNK), and p-p38) were measured. Results showed that administration of fucoidan significantly reduced the neurological deficits and infarct volume compared to the IRI+S group in a dose-dependent manner. Also, fucoidan statistically decreased the levels of inflammation-associated cytokines, and oxidative stress-related proteins, inhibited apoptosis, and suppressed the MAPK pathway. So, Fucoidan plays a protective role in cerebral IRI might be by inhibition of MAPK pathway.

  20. 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.

  1. [The use of extra-intracranial microanastomosis in the treatment of cerebral ischemia in patients with nontraumatic subarachnoid hemorrhage].

    PubMed

    Krylov, V V; Dash'yan, V G; Luk'yanchikov, V A; Tokarev, A S; Polunina, N A; Sytnik, A V; Solodov, A A; Grigor'eva, E V; Kudryashova, N E; Guseinova, G K

    2016-01-01

    to evaluate the use of extra-intracranial microanastomosis (EICMA) in the treatment of brain ischemia in patients with nontraumatic subarachnoid hemorrhage (SAH). In the period from 01.01.14 to 01.07.15, there were 229 surgeries for ruptured intracranial aneurysms performed in the urgent surgery unit. Nine patients with marked and widespread angiospasm, subcompensated and decompensated cerebral ischemia underwent the simultaneous clipping of ruptured intracranial aneurysms and EICMA. The age of patients varied from 32 to 52 years (mean 36 years). The severity of patient's state was assessed as III-IV grades on the Hunt and Hess scale before operation. The surgery was performed 1-2 days after admission to the hospital, 1-8 days after the development of SAH. Excellent and good outcome was recorded in 4 patients, severe disability in 3 patients, fatal outcome in 2 patients. The fatal outcome was due to decompensated cerebral ischemia and progressive angiospasm with the high linear blood flow rate and the following reduction in perfusion in the affected hemisphere. The simultaneous clipping of ruptured intracranial aneurysms and EICMA in the acute stage of SAH of patients with subcompensated cerebral ischemia allow to improve treatment This technique is most applicable for patients with proximal angiospasm of M1- and M2-segments of the middle cerebral artery in the first 24 h of the development of a focal neurological deficit supported by the reduction in perfusion in the corresponding vascular area.

  2. RTN1-C mediates cerebral ischemia/reperfusion injury via ER stress and mitochondria-associated apoptosis pathways.

    PubMed

    Gong, Lingli; Tang, Yuewen; An, Ran; Lin, Muya; Chen, Lijian; Du, Jian

    2017-10-05

    The reticulon family has been found to induce apoptosis, inhibit axon regeneration and regulate protein trafficking. However, little is known about the mechanisms of how reticulon proteins are involved in neuronal death-promoting processes during ischemia. Here, we report that the expression of Reticulon Protein 1-C (RTN1-C) was associated with the progression of cerebral ischemia/reperfusion (I/R) injury. Using a combination of rat middle cerebral artery occlusion (MCAO) stroke and oxygen-glucose deprivation followed by reoxygenation (OGD/R) models, we determined that the expression of RTN1-C was significantly increased during cerebral ischemic/reperfusion. RTN1-C overexpression induced apoptosis and increased the cell vulnerability to ischemic injury, whereas RTN1-C knockdown reversed ischemia-induced apoptosis and attenuated the vulnerability of OGD/R-treated neural cells. Mechanistically, we demonstrated that RTN1-C mediated OGD/R-induced apoptosis through ER stress and mitochondria-associated pathways. RTN1-C interacted with Bcl-xL and increased its localization in the ER, thus reducing the anti-apoptotic activity of Bcl-xL. Most importantly, knockdown of Rtn1-c expression in vivo attenuated apoptosis in MCAO rats and reduced the extent of I/R-induced brain injury, as assessed by infarct volume and neurological score. Collectively, these data support for the first time that RTN1-C may represent a novel candidate for therapies against cerebral ischemia/reperfusion injury.

  3. 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

  4. β-Caryophyllene Pretreatment Alleviates Focal Cerebral Ischemia-Reperfusion Injury by Activating PI3K/Akt Signaling Pathway.

    PubMed

    Zhang, Qian; An, Ruidi; Tian, Xiaocui; Yang, Mei; Li, Minghang; Lou, Jie; Xu, Lu; Dong, Zhi

    2017-02-24

    β-Caryophyllene (BCP) has been reported to be protective against focal cerebral ischemia-reperfusion (I/R) injury by its anti-oxidative and anti-inflammatory features. Recent study demonstrates that the BCP exhibits potential neuroprotection against I/R injury induced apoptosis, however, the mechanism remains unknown. Therefore, we investigate the underlying anti-apoptotic mechanism of BCP pretreatment in I/R injury. Sprague-Dawley rats (pretreated with BCP suspensions or solvent orally for 7 days) were subjected to transient Middle Cerebral Artery Occlusion (MCAO) for 90 min, followed by 24 h reperfusion. Results showed that BCP pretreatment improved the neurologic deficit score, lowered the infarct volume and decreased number of apoptotic cells in the hippocampus. Moreover, in western blot and RT-qPCR detections, BCP pretreatment down-regulated the expressions of Bax and p53, up-regulated the expression of Bcl-2, and enhanced the phosphorylation of Akt on Ser473. Blockage of PI3K activity by wortmannin not only abolished the BCP-induced decreases in infarct volume and neurologic deficit score, but also dramatically abrogated the enhancement of AKt phosphorylation. Our results suggested that BCP pre-treatment protects against I/R injury partly by suppressing apoptosis via PI3K/AKt signaling pathway activation.

  5. Retracted: IL-37 reduces inflammatory response after cerebral ischemia and reperfusion injury through down-regulation of pro-inflammatory cytokines.

    PubMed

    Patel, Faye J; Volkmann, Domenico T; Taylor, Gary W; Hansson, Michael A; Anderson, Jerzy F; Zhou, Yuko; Scoazec, Leonardo M; Hartford, Christina V; Hainz, Douglas L

    2014-10-01

    The purpose of the present study was to determine the effects of interleukin-37 (IL-37) on brain inflammation induced by ischemia/reperfusion (I/R). A transgenic mouse strain was generated to express human IL-37 (hIL-37tg), and these mice were subjected to cerebral I/R. We made middle cerebral artery ischemia-reperfusion model in mice. Compared with wild type, scores of cerebral infarct size and neurologic impairment in hIL-37tg mice were obviously lower after 24h ischemia and 72 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in hIL-37tg mice was less serious than that in WT mice. The results showed that IL-37 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of pro-inflammatory cytokines; TNF-alpha, IL-6, IL-1β, MCP-1 and MIP-1. Our study suggests that IL-37 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity and IL-37 may become a new target for prevention of cerebral ischemia-reperfusion injury. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Cerebral ischemia or intrauterine inflammation promotes differentiation of oligodendroglial precursors in preterm ovine fetuses: possible cellular basis for white matter injury.

    PubMed

    Kitanishi, Ryuta; Matsuda, Tadashi; Watanabe, Shinpei; Saito, Masatoshi; Hanita, Takushi; Watanabe, Tatsuya; Kobayashi, Yoshiyasu

    2014-01-01

    White matter injury in premature infants is known to be major cause of long-term neurocognitive disability, but the pathogenic mechanism remains unclear, hampering our ability to develop preventions. Periventricular leukomalacia is a severe form of white matter injury. In the present study, we explored the effects of cerebral ischemia and/or intrauterine inflammation on the development of oligodendroglia in the cerebral white matter using chronically instrumented fetal sheep. Each fetus received one of three insults: hemorrhage, inflammation and their combination. In the hemorrhage group, 40% of the fetoplacental blood volume was acutely withdrawn, and 24 hours after removal, the blood was returned to the fetus. The inflammation group received intravenous granulocyte-colony stimulating factor and intra-amniotic endotoxin and thus suffered from necrotizing funisitis and chorioamnionitis. The inflammatory hemorrhage group underwent acute hemorrhage under the inflammatory state. The sham group received no insults. Importantly, periventricular leukomalacia was not detected in the sham and the inflammation groups. Differentiating oligodendroglia at various developmental stages were identified by immunohistochemical analysis with specific antibodies. No difference in the density of oligodendroglial progenitors was detected among the four groups, whereas oligodendroglial precursors were significantly reduced in the three insult groups, compared to sham control. Moreover, the density of immature oligodendroglia was higher in the inflammation group and the inflammatory hemorrhage group, while the density of mature oligodendroglia was highest in the hemorrhage group. We propose that cerebral ischemia or intrauterine inflammation induces the differentiation of oligodendroglial precursors in preterm fetuses, eventually resulting in their exhaustion.

  7. Mesoglycan in treatment of patients with cerebral ischemia: effects on hemorheologic and hematochemical parameters.

    PubMed

    Vecchio, F; Zanchin, G; Maggioni, F; Santambrogio, C; De Zanche, L

    1993-12-01

    The present study evaluates the hematochemical and hemorheologic effects of mesoglycan, a preparation of natural glycosaminoglycans, administered by the intramuscular route to patients with a recent episode of cerebral ischemia. A total of twenty patients (13 males and 7 females), between the ages of 45 and 75, under observation for a cerebral ischemic episode occurring at least 2 months prior to enrollment, were treated with intramuscular mesoglycan (30 mg, twice daily), for 15 days. Blood samples were taken prior to and at the end of treatment to measure the investigated parameters. Following mesoglycan treatment we observed a statistically significant decrease in fibrinogen plasma concentration, total cholesterol and triglycerides, while HDL cholesterol was found to increase. In addition, erythrocytes filterability improved at the end of treatment. No changes were observed in coagulation parameters such as prothrombin time, partial thromboplastin time, or antithrombin III. The results of the present study demonstrate that a 15-days treatment of intramuscular mesoglycan in patients recovering from a cerebral ischemic episode produces significant changes in fibrinogen and lipid plasma levels with no apparent anticoagulant effect.

  8. 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.

  9. Gingko biloba extract (EGb 761) prevents increase of Bad-Bcl-XL interaction following cerebral ischemia.

    PubMed

    Koh, Phil-Ok

    2009-01-01

    A standardized extract of Gingko biloba, EGb 761, has been shown to exert a neuroprotective effect against permanent and transient focal cerebral ischemia. This study investigated whether EGb 761 modulates Bcl-2 family proteins in ischemic brain injury. Male adult rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO), brain tissues were collected 24 hours after MCAO. EGb761 administration significantly decreased the number of TUNEL-positive cells in the cerebral cortex. Ischemic brain injury induced decrease of Bcl-2 and Bcl-X(L) levels. EGb 761 prevented not only the injury-induced decrease of Bcl-2 and Bcl-X(L) levels, but also the injury-induced increase of Bax. Moreover, in the presence of EGb 761, the interaction of Bad and Bcl-X(L) decreased compared to that of vehicle-treated animals. In addition, EGb 761 prevented the injury-induced increase of cleaved PARP. The finding suggests that EGb 761 prevents cell death against ischemic brain injury and EGb 761 neuroprotection is affected by preventing the injury-induced increase of Bad and Bcl-X(L) interaction.

  10. Postnatal Erythropoietin Mitigates Impaired Cerebral Cortical Development Following Subplate Loss from Prenatal Hypoxia–Ischemia

    PubMed Central

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

    2015-01-01

    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. PMID:24722771

  11. 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.

  12. 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.

  13. Kir6.1 knockdown aggravates cerebral ischemia/reperfusion-induced neural injury in mice.

    PubMed

    Dong, Yin-Feng; Wang, Lin-Xiao; Huang, Xu; Cao, Wen-Jing; Lu, Ming; Ding, Jian-Hua; Sun, Xiu-Lan; Hu, Gang

    2013-08-01

    ATP-sensitive potassium (K-ATP) channels couple energy metabolism with electric activity, which play important roles in brain diseases including stroke. However, the impacts of Kir6.1-containing K-ATP channels that mainly expressed on glia in stroke remain unclear. In this study, we found that expression of Kir6.1 was significantly decreased in the ischemic brain area of C57BL/6J mice after 1-h middle cerebral artery occlusion (MCAO) and 24-h reperfusion. Then, we subjected Kir6.1 heterozygote knockout (Kir6.1(+/-) ) mice to cerebral ischemia/reperfusion (I/R) injury and found that Kir6.1(+/-) mice exhibited exacerbated neurological disorder and enlarged infarct size, companied by glial over-activation and blood-brain barrier (BBB) damages. Furthermore, we showed that Kir6.1 knockdown aggravated endoplasmic reticulum (ER) stress and thereby increased the levels of proinflammatory factors tumor necrosis factor-α and interleukin-1β (TNF-α and IL-1β) in mouse brain. Our findings reveal that Kir6.1 knockdown exacerbates cerebral I/R-induced brain damages via increasing ER stress and inflammatory response, indicating that Kir6.1-containing K-ATP channels may be a potential therapeutic target for stroke. © 2013 John Wiley & Sons Ltd.

  14. [Influence of hepatocyte growth factor on iNOS, NO and IL-1β in the cerebrum during cerebral ischemia/reperfusion in rats].

    PubMed

    He, Fang; Ye, Bei; Chen, Jianzhen; Sun, Xiaoyan; Li, Chang

    2014-01-01

    To explore the effect of hepatocyte growth factor (HGF) on inducible nitric oxide synthase (iNOS), NO and interleukin-1β (IL-1β) in the cerebrum of rats subjected to cerebral ischemia/reperfusion (I/R). Sprague-Dawley rats were randomly divided into 5 groups: a sham group, an I/R group,an HGF1 group, an HGF2 group, and an HGF3 group. The latter 3 groups were respectively injected 15, 30 and 60 μg/kg HGF. The focal cerebral I/R model was established by sutureoccluded method. After 1.5 h ischemia followed by 24 h reperfusion, the iNOS activity and NO content in the ischemic cerebral tissue were assessed. The expression of iNOS mRNA and IL-1β mRNA was detected. The level of iNOS protein and IL-1β content were determined. In addition, cultured cerebral cortical neurons in vitro were exposed to I/R. Then the expression of iNOS and IL-1β protein in the neurons was detected, and NO content was assessed. The iNOS activity and NO content in the ischemic cerebral tissue were increased. The expression of iNOS mRNA and IL-1β mRNA was upregulated. The level of iNOS protein and IL- 1β content were increased. Administration of HGF decreased the iNOS activity and NO content, and downregulated the expression of iNOS mRNA, IL-1β mRNA, iNOS protein and IL-1β content in the ischemic cerebral tissue. HGF decreased the expression of IL-1β, iNOS protein and NO content in the cortical neurons exposed to I/R in vitro. HGF can inhibit the expression of IL-1β and decrease the expression of iNOS and content of NO, which is probably one of the mechanisms mediating the protection of HGF against cerebral ischemia injury.

  15. L-carnosine inhibits neuronal cell apoptosis through signal transducer and activator of transcription 3 signaling pathway after acute focal cerebral ischemia.

    PubMed

    Wang, Jian-Ping; Yang, Zhi-Tang; Liu, Cong; He, Yuan-Hong; Zhao, Shan-Shan

    2013-04-24

    Considerable studies have showed that L-carnosine provides anti-oxidative and anti-apoptotic roles in the animal models of global or focal cerebral ischemia. However, the anti-apoptotic mechanisms of L-carnosine in the focal cerebral ischemia model have yet to be elucidated. To investigate the molecular mechanisms, rat models of permanent middle cerebral artery occlusion (pMCAO) and sham operation were first established and then pMCAO and sham-operated rats were treated with L-carnosine or vehicle alone. After this treatment, neurological deficits were evaluated at 12, 24 and 72 h after operation and the infarct volume was measured at 72 h after treatment. In addition, we also detected the mRNA expression of signal transducer and activator of transcription 3 (STAT3) and Pim-1 and the protein expression of phosphorylated STAT3, Pim-1, bcl-2 and cleaved caspase-3 at 12, 24 and 72 h post-pMCAO. Our results showed that the L-carnosine-treated rats had milder neurological deficits and smaller infarct volume and showed up-regulated expression in mRNA levels of STAT3 and Pim-1 than vehicle-treated rats at 72 h after treatment. Meanwhile, compared with vehicle-treated rats, the L-carnosine-treated rats exhibited higher protein expressions of pSTAT3, Pim-1 and bcl-2 but lower expression of cleaved caspase-3 protein at 72 h following operation. These results indicate that L-carnosine plays an important role in inhibiting neuronal cell apoptosis through STAT3 signaling pathway after acute cerebral ischemia.

  16. Detection of inflammation following renal ischemia by magnetic resonance imaging.

    PubMed

    Jo, Sang-Kyung; Hu, Xuzhen; Kobayashi, Hisataka; Lizak, Martin; Miyaji, Takehiko; Koretsky, Alan; Star, Robert A

    2003-07-01

    Determining the disease culprits in human acute renal failure (ARF) has been difficult because of the paucity of renal biopsies and the lack of noninvasive methods to determine the location or cause of renal injury. Recently, ultrasmall superparamagnetic iron oxide (USPIO) particles have been used to detect inflammation in animal models. Therefore, we tested if USPIO enhanced magnetic resonance imaging (MRI) could detect inflammation in ischemic ARF in rats. Rats were subjected to 40 or 60 minutes of bilateral ischemia or injected with mercuric chloride. MR images were obtained before and 24 hours after USPIO injection, and the signal intensity decrease in the outer medulla was measured. Cells containing iron particles were identified by iron staining and transmission electron microscopy (TEM). Leukocytes were identified by ED-1 and chloracetate esterase staining. Injection of USPIO particles caused a black band to appear in the outer medulla at 48, 72, and 120 hours after ischemia. This band was not detected in normal animals, 24 hours after ischemia, or 48 hours after mercuric chloride injection. The signal intensity change in the outer medulla correlated with serum creatinine and the number of iron particle containing cells. Most infiltrating cells were macrophages, and iron particles were present inside lysosomes of macrophages. USPIO injection did not alter renal function in normal or ischemic animals. USPIO-enhanced MRI could detect inflammation noninvasively from 48 hours after 40 or 60 minutes of renal ischemia in rats. This method might be useful to understand the pathogenesis of human ARF and to evaluate the effectiveness of anti-inflammatory agents.

  17. Ischemic postconditioning may not influence early brain injury induced by focal cerebral ischemia/reperfusion in rats

    PubMed Central

    Kim, Yoo Kyung; Shin, Jin Woo; Joung, Kyoung Woon

    2010-01-01

    Background Experimental studies have shown that ischemic postconditioning can reduce neuronal injury in the setting of cerebral ischemia, but the mechanisms are not yet clearly elucidated. This study was conducted to determine whether ischemic postconditioning can alter expression of heat shock protein 70 and reduce acute phase neuronal injury in rats subjected to transient focal cerebral ischemia/reperfusion. Methods Focal cerebral ischemia was induced by intraluminal middle cerebral artery occlusion for 60 min in twenty male Sprague-Dawley rats (250-300 g). Rats were randomized into control group and an ischemic postconditioning group (10 rats per group). The animals of control group had no intervention either before or after MCA occlusion. Ischemic postconditioning was elicited by 3 cycles of 30 s reperfusion interspersed by 10 s ischemia immediately after onset of reperfusion. The infarct ratios, brain edema ratios and motor behavior deficits were analyzed 24 hrs after ischemic insult. Caspase-3 reactive cells and cells showing heat shock protein 70 activity were counted in the caudoputamen and frontoparietal cortex. Results Ischemic postconditiong did not reduce infarct size and brain edema ratios compared to control group. Neurologic scores were not significantly different between groups. The number of caspase-3 reactive cells in the ischemic postconditioning group was not significantly different than the value of the control group in the caudoputamen and frontoparietal cortex. The number of cells showing heat shock protein 70 activity was not significantly different than the control group, as well. Conclusions These results suggest that ischemic postconditioning may not influence the early brain damage induced by focal cerebral ischemia in rats. PMID:20498797

  18. Quantitative analysis of iron concentration and expression of ferroportin 1 in the cortex and hippocampus of rats induced by cerebral ischemia.

    PubMed

    Li, Lin; Li, Yan-wei; Zhao, Jin-ying; Liu, Yue-Ze; Holscher, Christian

    2009-11-01

    Iron overload induced by brain ischemia has been shown to be involved in neurodegenerative disease. Little is known about the relationship between brain ischemia and ferroportin 1 (FP1). The aims of this study are: (i) to determine whether iron accumulation in the brain is induced by cerebral hypoperfusion; and (ii) to test whether expression of FP1 is influenced by cerebral ischemia. The common carotid arteries (CCA) of rats were ligated bilaterally to induce cerebral ischemia, and the iron concentration of the cortex and hippocampus was measured by graphite furnace atomic absorption spectrometry. Iron was stained by Perl's method. The expression of FP1 mRNA and protein was shown by the reverse transcriptase polymerase chain reaction and immunohistochemical methods. The iron concentration in the cortex and hippocampus of ischemic rats had increased on day 7 (CCA7) and significantly on day 28 (CCA28) compared to control rats. More iron granules had been deposited in the cerebral cortex and hippocampus in rats with bilaterally ligated CCA on CCA7 and CCA28. In ischemic rats, FP1 expression in the cerebral cortex and hippocampus was decreased by CCA7 and this was more marked by CCA28 compared to control rats. We therefore concluded that iron deposition in the cerebral cortex and hippocampus of rats is induced by cerebral ischemia. Iron deposition may be attributed to the decrease in FP1 expression, and this inhibition of FP1 expression could be a major contributor to the formation of iron deposits in cerebral ischemia.

  19. 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

  20. Increased risk of delayed cerebral ischemia in subarachnoid hemorrhage patients with additional intracerebral hematoma.

    PubMed

    Platz, Johannes; Güresir, Erdem; Wagner, Marlies; Seifert, Volker; Konczalla, Juergen

    2017-02-01

    OBJECTIVE Delayed cerebral ischemia (DCI) has a major impact on the outcome of patients suffering from aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to assess the influence of an additional intracerebral hematoma (ICH) on the occurrence of DCI. METHODS The authors conducted a single-center retrospective analysis of cases of SAH involving patients treated between 2006 and 2011. Patients who died or were transferred to another institution within 10 days after SAH without the occurrence of DCI were excluded from the analysis. RESULTS Additional ICH was present in 123 (24.4%) of 504 included patients (66.7% female). ICH was classified as frontal in 72 patients, temporal in 24, and perisylvian in 27. DCI occurred in 183 patients (36.3%). A total of 59 (32.2%) of these 183 patients presented with additional ICH, compared with 64 (19.9%) of the 321 without DCI (p = 0.002). In addition, DCI was detected significantly more frequently in patients with higher World Federation of Neurosurgical Societies (WFNS) grades. The authors compared the original and modified Fisher Scales with respect to the occurrence of DCI. The modified Fisher Scale (mFS) was superior to the original Fisher Scale (oFS) in predicting DCI. Furthermore, they suggest a new classification based on the mFS, which demonstrates the impact of additional ICH on the occurrence of DCI. After the different scales were corrected for age, sex, WFNS score, and aneurysm site, the oFS no longer was predictive for the occurrence of DCI, while the new scale demonstrated a superior capacity for prediction as compared with the mFS. CONCLUSIONS Additional ICH was associated with an increased risk of DCI in this study. Furthermore, adding the presence or absence of ICH to the mFS improved the identification of patients at the highest risk for the development of DCI. Thus, a simple adjustment of the mFS might help to identify patients at high risk for DCI.

  1. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents

    PubMed Central

    2017-01-01

    Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia. PMID:28634570

  2. Neuroprotective Effects of Bone Marrow Mesenchymal Stem Cells on Bilateral Common Carotid Arteries Occlusion Model of Cerebral Ischemia in Rat

    PubMed Central

    Pourheydar, Bagher; Azimzadeh, Mostafa; Rezaei Moghadam, Adel; Marzban, Asghar

    2016-01-01

    Cell therapy is the most advanced treatment of the cerebral ischemia, nowadays. Herein, we discuss the neuroprotective effects of bone marrow mesenchymal stem cells (BMSCs) on rat hippocampal cells following intravenous injection of these cells in an ischemia-reperfusion model. Adult male Wistar rats were divided into 5 groups: control, sham (surgery without blockage of common carotid arteries), ischemia (common carotid arteries were blocked for 30 min prior to reperfusion), vehicle (7 days after ischemia PBS was injected via the tail vein), and treatment (injections of BMSC into the tail veins 7 days after ischemia). We performed neuromuscular and vestibulomotor function tests to assess behavioral function and, finally, brains were subjected to hematoxylin and eosin (H&E), anti-Brdu immunohistochemistry, and TUNEL staining. The ischemia group had severe apoptosis. The group treated with BMSCs had a lower mortality rate and also had significant improvement in functional recovery (P < 0.001). Ischemia-reperfusion for 30 min causes damage and extensive neuronal death in the hippocampus, especially in CA1 and CA3 regions, leading to several functional and neurological deficits. In conclusion, intravenous injection of BMSCs can significantly decrease the number of apoptotic neurons and significantly improve functional recovery, which may be a beneficial treatment method for ischemic injuries. PMID:27847404

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

    PubMed

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

    2014-01-28

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

  4. Chronic Cerebral Ischemia Induces Downregulation of A1 Adenosine Receptors During White Matter Damage in Adult Mice.

    PubMed

    Cheng, Pengfei; Ren, Yifei; Bai, Shunjie; Wu, Yu; Xu, Yi; Pan, Junxi; Chen, Jin; Zhu, Xiaofeng; Qi, Zhiguo; Shao, Weihua; Tang, Weiju; Liu, Meiling; Xie, Peng; Huang, Wen

    2015-11-01

    The role of A1 adenosine receptors (A1ARs) in the white matter under chronic cerebral ischemic conditions remains unclear. Here, we used right unilateral common carotid artery occlusion (rUCCAO) to construct a chronic cerebral ischemic mouse model. A1AR expression and proteolipid protein (PLP, a marker of white matter myelination) in the corpus callosum were observed by immunoreaction and immunohistochemistry, respectively. Pro-inflammatory interleukin-1β (IL-1β) and anti-inflammatory interleukin-10 (IL-10) levels were determined by ELISA. The Morris water maze test was employed to detect cognitive impairment. A1AR expression significantly decreased in the rUCCAO group as compared with the sham control group on weeks 2, 4, and 6, respectively. IL-10 levels in the rUCCAO group significantly declined on week 6, while there was no significant change in IL-1β expression. PLP expression significantly decreased in the rUCCAO group on weeks 2, 4, and 6. Moreover, latency time for the Morris water maze test significantly increased in the rUCCAO group on weeks 4 and 6, while the number of platform location crossing significantly decreased in the rUCCAO group on weeks 2, 4, and 6. In conclusion, this study provides the first evidence that chronic cerebral ischemia appears to induce A1AR downregulation and inhibition of IL-10 production, which may play key roles in the neuropathological mechanisms of ischemic white matter lesions. These data will facilitate future studies in formulating effective therapeutic strategies for ischemic white matter lesions.

  5. Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents.

    PubMed

    Bhattacharya, Pallab; Pandey, Anand Kumar; Paul, Sudip; Patnaik, Ranjana; Yavagal, Dileep R

    2013-01-01

    Aquaporin-4(AQP4) is an abundant water channel protein in brain that regulates water transport to maintain homeostasis. Cerebral edema resulting from AQP4 over expression is considered to be one of the major determinants for progressive neuronal insult during cerebral ischemia. Although, both upregulation and downregulation of AQP4 expression is associated with brain pathology, over expression of AQP4 is one of the chief contributors of water imbalance in brain during ischemic pathology. We have found that Piroxicam binds to AQP4 with optimal binding energy value. Thus, we hypothesized that Piroxicam is neuroprotective in the rodent cerebral ischemic model by mitigating cerebral edema via AQP4 regulation. Rats were treated with Piroxicam OR placebo at 30 min prior, 2 h post and 4 h post 60 minutes of MCAO followed by 24 hour reperfusion. Rats were evaluated for neurological deficits and motor function just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, RT-PCR and western blot experiments. Piroxicam pretreatment thirty minutes prior to ischemia and four hour post reperfusion afforded neuroprotection as evident through significant reduction in cerebral infarct volume, improvement in motor behavior, neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde were also found to be significantly reduced in ischemic brain regions in treated animals. This neuroprotection was found to be associated with inhibition of acid mediated rise in intracellular calcium levels and also downregulated AQP4 expression. Findings of the present study provide significant evidence that Piroxicam acts as a potent AQP4 regulator and renders neuroprotection in focal cerebral ischemia. Piroxicam could be clinically exploited for the treatment of brain stroke along with other anti-stroke therapeutics in future.

  6. Beneficial effects of sulindac in focal cerebral ischemia: a positive role in Wnt/β-catenin pathway.

    PubMed

    Xing, Yinxue; Zhang, Xiangjian; Zhao, Kang; Cui, Lili; Wang, Lina; Dong, Lipeng; Li, Yanhua; Liu, Zongjie; Wang, Chaohui; Zhang, Xiaolin; Zhu, Chunhua; Qiao, Huimin; Ji, Ye; Cao, Xiaoyun

    2012-10-30

    Accumulated evidences have established that inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a target for treatment. Sulindac is well known as a nonsteroidal anti-inflammatory drug. However, little is known regarding the effect of sulindac in acute cerebral ischemia. Here, we designed this study to investigate the potential protective effects of sulindac in focal cerebral ischemia and the mechanisms underlying in vivo. Focal cerebral ischemia was induced in male Sprague-Dawley rats by permanent middle cerebral artery occlusion (pMCAO). Sulindac was administrated at dose of 4, 10, or 20mg/kg at 30 min before the operation. Neurological deficit scores, brain water content and infarct volumes were measured at 24h after pMCAO. Immunohistochemistry, western blot and reverse transcription-polymerase chain reaction were used for examining the mediators involved in Wnt/β-catenin signaling pathway, including the positive regulators dishevelled (Dvl) and β-catenin, the negative regulators adenomatous polyposis coli (APC), and P-β-catenin, as well as the downstream targets Bcl-2, Bax and claudin-5. Compared with Vehicle group, 20mg/kg sulindac reduced neurological deficits, brain water content and infarct volumes. The same dose of sulindac upregulated the expression of Dvl, β-catenin, Bcl2 and claudin-5, and downregulated APC, P-β-catenin and Bax compared with Vehicle group. These results showed that sulindac had a significant beneficial effect in cerebral ischemia; this effect may be correlated with the activation of the Wnt/β-catenin signaling. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Neuroprotective efficacy and therapeutic time window of peroxynitrite decomposition catalysts in focal cerebral ischemia in rats#

    PubMed Central

    Thiyagarajan, Meenakshisundaram; Kaul, Chaman Lal; Sharma, Shyam Sundar

    2004-01-01

    Free radicals have been implicated in cerebral ischemia reperfusion (IR) injury. Massive production of nitric oxide and superoxide results in continuous formation of peroxynitrite even several hours after IR insult. This can produce DNA strand nicks, hydroxylation and/or nitration of cytosolic components of neuron, leading to neuronal death. Peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(N-methyl-4′-pyridyl)porphyrinato iron (III) (FeTMPyP) and 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (FeTPPS) have been demonstrated to protect neurons in in vitro cultures; however, their neuroprotective efficacy in cerebral IR injury has not been explored. In the present study, we investigated the efficacy and the therapeutic time window of FeTMPyP and FeTPPS in focal cerebral ischemia (FCI). FCI was induced according to the middle cerebral artery occlusion (MCAO) method. After 2 h of MCAO and 70 h of reperfusion, the extent of neurological deficits, infarct and edema volume were measured in Sprague–Dawley rats. FeTMPyP and FeTPPS were administered at different time points 2, 6, 9 and 12 h post MCAO. FeTMPyP and FeTPPS (3 mg kg−1, i.v.) treatment at 2 and 6 h post MCAO produced significant reduction in infarct volume, edema volume and neurological deficits. However, treatment at latter time points did not produce significant neuroprotection. Significant reduction of peroxynitrite in blood and nitrotyrosine in brain sections was observed on FeTMPyP and FeTPPS treatment. As delayed treatment of FeTMPyP and FeTPPS produced neuroprotection, we tested whether treatment had any influence over the apoptotic neuronal death. DNA fragmentation and in situ nick end-labeling assays showed that FeTMPyP and FeTPPS treatment reduced IR injury-induced DNA fragmentation. In conclusion, peroxynitrite decomposition catalysts (FeTMPyP and FeTPPS) produced prominent neuroprotection even if administered 6 h post MCAO and the neuroprotective effect is at least in

  8. 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

  9. Neuroprotective effect of tyrosol on transient focal cerebral ischemia in rats.

    PubMed

    Bu, Youngmin; Rho, Seongjoo; Kim, Jinmo; Kim, Mi Yeon; Lee, Dae Hee; Kim, Sun Yeou; Choi, Hoyoung; Kim, Hocheol

    2007-03-13

    Tyrosol (2-(4-hydroxyphenyl)ethanol) is a well-known phenolic compound with antioxidant properties that is present in wine, olive oil, and other plant-derived products. The purpose of this study was to determine the neuroprotective effect of tyrosol in a stroke animal model. By using the transient middle cerebral artery occlusion rat model (2 h of occlusion, 22 h of reperfusion), we investigated the effects of tyrosol on infarct volume and sensory motor function deficit by performing 2,3,5-triphenyltetrazolium chloride staining and behavior tests after ischemia. Tyrosol showed a dose-dependent neuroprotective effect that peaked at 64.9% in rats treated with 30 mg/kg of tyrosol. In rotarod, beam balance, and foot fault tests, tyrosol exhibited protective effects against the sensory motor dysfunction. In conclusion, our results suggest that tyrosol is an appropriate candidate to be used in stroke therapy.

  10. [Research progress of acupuncture for cerebral ischemia reperfusion injury in recent 10 years].

    PubMed

    Yang, Yang; Sun, Hua

    2015-07-01

    By searching relevant data from the PubMed database, Chinese National Knowledge Infrastructure (CNKI) database and Wanfang database, a comprehensive analysis and review regarding acupuncture for cerebral ischemia reperfusion injury (CIRI) in recent 10 years were performed. The results showed that acupuncture could inhibit the inflammatory reaction, reduce oxidative stress injury, restrain brain edema formation, inhibit apoptosis, promote neural and vascular regeneration, etc. Acupuncture methods used included electroacupuncture, scalp acupuncture, eye acupuncture and "consciousness-restoring resuscitation needling", etc. The existing problem was that the intervention action of acupuncture was mainly focused on inhibiting inflammatory reaction and oxidative stress injury, and the study on apoptosis and neural and vascular regeneration was needed. It is suggested that from the aspect of multiple target points, the intervention mechanism of acupuncture for CIRI should be systemically studied in the future, which could provide new idea for clinical diagnosis and treatment on ischemic cerebrovascular diseases.

  11. Bilateral extensive cerebral infarction and mesenteric ischemia associated with segmental arterial mediolysis in two young women.

    PubMed

    Basso, Monique Camila; Flores, Patrícia Carrasco; de Azevedo Marques, Ary; de Souza, Guilherme Leme; D'Elboux Guimarães Brescia, Marília; Campos, Cynthia Resende; de Cleva, Roberto; Saldiva, Paulo Hilario Nascimento; Mauad, Thais

    2005-10-01

    Segmental arterial mediolysis (SAM) is a rare non-atherosclerotic non-inflammatory vascular disease that affects mainly muscular arteries of the splanchnic and cerebral territories. Reported herein are two cases of SAM in young women with fatal outcome. One of the patients had an atypical form of the disease, which primarily affected small intestinal submucosal and subserosal arteries, and resulted in acute mesenteric ischemia. The other had bilateral brain infarction with SAM of internal carotid arteries (ICA). Pathological examination of both cases did not reveal the cause of blood flow disturbance: large mesenteric branches of the former and ICA of the latter were free of either dissection or thrombosis; in addition, small intestinal arteries of the first patient did not show signs of vasculitis. These findings suggest that unusual pathways of arterial occlusion and dissection may occur in the context of SAM.

  12. 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

  13. Verapamil augments the neuroprotectant action of berberine in rat model of transient global cerebral ischemia.

    PubMed

    Singh, Dhirendra Pratap; Chopra, Kanwaljit

    2013-11-15

    Various potential molecules with putative positive role in stroke pathology have failed to confer neuro-protection in animal models due to their insufficient bioavailability in brain. Efflux of these molecules by P-glycoprotein (P-gp), on blood brain barrier (BBB) is one of the reasons of their poor bioavailability. Berberine, have anti-inflammatory, antioxidant, anti-apoptotic properties, but also having low oral bioavailabilty. Verapamil, which increased the central nervous system uptake of few drugs, when concomitantly administered with berberine was evaluated in this animal model. Wistar rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 15 min followed by reperfusion resulting in transient global cerebral ischemia. For 19 days berberine (5, 10, 20mg/kg, p.o.) alone and in similar doses concomitantly with verapamil (2mg/kg, p.o.) was evaluated employing various neuro-behavioral test, biochemical parameters and molecular estimations. The adjunction of berberine with verapamil improved the neurological outcome in a battery of behavioral paradigms, improved spatial memory in Morris water maze task, ameliorated the oxidative-nitrosative stress, increased acetylcholinesterase (AChE) activity, as well as improved mitochondrial complex (I, II, and IV) activity, reducing tumor necrosis factor-alpha, interleukin-1 beta and caspase-3 levels in brain tissues as compared to berberine alone group in ischemic rats. There is a strong possibility of improved brain bioavailabity of berberine when combined with verapamil. The findings suggested that the combination of berberine with verapamil, which could enhance its brain uptake, will surely provide a greater impact in neroprotection drug discovery for search of such combination.

  14. Matrix Metalloproteinase-12 Induces Blood-Brain Barrier Damage After Focal Cerebral Ischemia.

    PubMed

    Chelluboina, Bharath; Klopfenstein, Jeffrey D; Pinson, David M; Wang, David Z; Vemuganti, Raghu; Veeravalli, Krishna Kumar

    2015-12-01

    Matrix metalloproteinases (MMPs) have a central role in compromising the integrity of the blood-brain barrier (BBB). The role of MMP-12 in brain damage after ischemic stroke remains unknown. The main objective of the current study is to investigate the effect of MMP-12 suppression at an early time point before reperfusion on the BBB damage in rats. Sprague-Dawley rats were subjected to middle cerebral artery occlusion and reperfusion. MMP-12 shRNA-expressing plasmids formulated as nanoparticles were administered at a dose of 1 mg/kg body weight. The involvement of MMP-12 on BBB damage was assessed by performing various techniques, including Evans blue dye extravasation, 2,3,5-triphenyltetrazolium chloride staining, immunoblot, gelatin zymography, and immunofluorescence analysis. MMP-12 is upregulated ≈31-, 47-, and 66-fold in rats subjected 1-, 2-, or 4-hour ischemia, respectively, followed by 1-day reperfusion. MMP-12 suppression protected the BBB integrity by inhibiting the degradation of tight-junction proteins. Either intravenous or intra-arterial delivery of MMP-12 shRNA-expressing plasmid significantly reduced the percent Evans blue dye extravasation and infarct size. Furthermore, MMP-12 suppression reduced the endogenous levels of other proteases, such as tissue-type plasminogen activator and MMP-9, which are also known to be the key players involved in BBB damage. These results demonstrate the adverse role of MMP-12 in acute brain damage that occurs after ischemic stroke and, thereby, suggesting that MMP-12 suppression could be a promising therapeutic target for cerebral ischemia. © 2015 American Heart Association, Inc.

  15. Acute Isolated Central Facial Palsy as Manifestation of Middle Cerebral Artery Ischemia.

    PubMed

    Sands, Kara A; Shahripour, Reza Bavarsad; Kumar, Gyanendra; Barlinn, Kristian; Lyerly, Michael J; Haršány, Michal; Cure, Joel; Yakov, Yuri L; Alexandrov, Anne W; Alexandrov, Andrei V

    2016-09-01

    Isolated central facial palsy (I-CFP) is attributed to a lacunar syndrome affecting the corona radiata region or pons. We examined our acute stroke registry for patients presenting with I-CFP and localized their symptoms to a vascular lesion. Our database of consecutive patients with symptoms of acute cerebral ischemia admitted from January 2008 to December 2012 was reviewed for NIH Stroke Scale (NIHSS) scores and subcomponents. All patients with I-CFP ± dysarthria (total NIHSS ≤ 3) had contrast-enhanced MR-angiography and transcranial Doppler as standard of care. All ischemic lesions were localized by MRI within 72 hours from symptom onset. Of 2,202 patients with acute cerebral ischemia, 879 patients (35%) had NIHSS score ≤ 3 points (mean age 63 + 15 years, 46 % women). Nine patients (.4%) presented with I-CFP ± dysarthria. Of these, only 1 had a lesion in the corona radiata and patent MCA, 1 had a pontine lesion without proximal vessel occlusion (2/9, or 22%). Remaining 7 patients (78%) had flow-limiting thromboembolic mid-to-distal M1/proximal M2 MCA disease. Of these, 6 (86%) patients had a prominent early anterior temporal artery on MRA and nonlacunar ischemic lesions on MRI. Contrary to current teaching of lesion localization for an I-CFP, our study revealed the majority of acute patients presenting with this symptom had evidence of flow-limiting thromboembolic MCA disease rather than a lacunar lesion. Our findings underscore the essential role of comprehensive vascular imaging in patients presenting with I-CFP, which is commonly associated with acute flow-limiting thromboembolic MCA disease. Copyright © 2016 by the American Society of Neuroimaging.

  16. Vascular integrin immunoreactivity is selectively lost on capillaries during rat focal cerebral ischemia and reperfusion.

    PubMed

    Burggraf, Dorothe; Trinkl, Andreas; Burk, Jan; Martens, Helge K; Dichgans, Martin; Hamann, Gerhard F

    2008-01-16

    The alpha1-integrin cell adhesion molecules, the principal endothelial receptors for basal lamina (BL) components disappear during transient ischemia. The current study investigated the localization of integrins, the time dependency and vessel size selectivity in the normal rat brain before and after 3 h of cerebral ischemia (I3) and reperfusion (R). Additionally we looked for a correlation to the amount of extravasation and hemorrhage. In the normal brain, there was a clear immunoreactivity for the alpha1, alpha6, and beta1 integrins on the endothelial perivascular cells. After I3 followed by variable reperfusion intervals of 0, 9, and 24 h (R0, R9 and R24; respectively), the number of vessels and staining intensity indicating immunoreactivity in the ischemic area were compared with the contralateral side. The number of the beta1-immunoreactive capillaries was steadily decreasing with the reperfusion time: -12+/-5%, -15+/-7% and -43+/-8% at I3R0, I3R9 and I3R24 (all p<0.05). The beta1-staining intensity decreased homogeneously to -21% at I3R24 (p<0.05). Vascular staining for alpha1 was affected similarly. Interestingly, the alpha6-positive arterioles/venules were also reduced by -21% at I3R24 (p<0.05) in a diameter-selective way on vessels with diameters larger than 15 mum. The correlated break-down of the blood-brain-barrier was demonstrated by the significant rise of the extravasation of BSA from the perfusion solution as well as the increased hemorrhage after MCAO/R (hemoglobin: 103+/-4% versus 330+/-17%; BSA 101+/-3% versus 132+/-9% in I0R0 and I3R24, respectively). The prominent capillary vulnerability contributes significantly to the impairment of the microvascular integrity and after ischemia and reperfusion.

  17. Collateral blood flow in different cerebrovascular hierarchy provides endogenous protection in cerebral ischemia.

    PubMed

    Luo, Chuanming; Liang, Fengyin; Ren, Huixia; Yao, Xiaoli; Liu, Qiang; Li, Mingyue; Qin, Dajiang; Yuan, Ti-Fei; Pei, Zhong; Su, Huanxing

    2016-11-15

    Collateral blood flow as vascular adaptions to focal cerebral ischemia is well recognized. However, few studies directly investigate the dynamics of collateral vessel recruitment in vivo and little is known about the effect of collateral blood flow in different cerebrovascular hierarchy on the neuropathology after focal ischemic stroke. Here, we report that collateral blood flow is critically involved in blood vessel compensations following regional ischemia. We occluded a pial arteriole using femtosecond laser ablating under the intact thinned skull and documented the changes of collateral flow around the surface communication network and between the surface communication network and subsurface microcirculation network using in vivo two photon microscopy imaging. Occlusion of the pial arteriole apparently increased the diameter and collateral blood flow of its leptomeningeal anastomoses, which significantly reduced the cortical infarction size. This result suggests that the collateral flow via surface communicating network connected with leptomeningeal anastomoses could greatly impact on the extent of infarction. We then further occluded the target pial arteriole and all of its leptomeningeal anastomoses. Notably, this type of occlusion led to reversals of blood flow in the penetrating arterioles mainly proximal to the occluded pial arteriole in a direction from the subsurface microcirculation network to surface arterioles. Interesting, the cell death in the area of ischemic penumbra was accelerated when we performed occlusion to cease the reversed blood flow in those penetrating arterioles, suggesting that the collateral blood flow from subsurface microcirculation network exerts protective roles in delaying cell death in the ischemic penumbra. In conclusion, we provide the first experimental evidence that collateral blood vessels at different cerebrovascular hierarchy are endogenously compensatory mechanisms in brain ischemia. This article is protected by

  18. Sodium Mapping in Focal Cerebral Ischemia in the Rat by Quantitative 23Na MRI

    PubMed Central

    Yushmanov, Victor E.; Yanovski, Boris; Kharlamov, Alexander; LaVerde, George; Boada, Fernando E.; Jones, Stephen C.

    2009-01-01

    Purpose To validate 23Na twisted projection magnetic resonance imaging (MRI) as a quantitative technique to assess local brain sodium concentration ([Na+]br) during rat focal ischemia every 5.3 minutes. Materials and Methods The MRI protocol included an ultrashort echo-time (0.4 msec), a correction of radiofrequency (RF) inhomogeneities by B1 mapping, and the use of 0–154 mM NaCl calibration standards. To compare MRI [Na+]br values with those obtained by emission flame photometry in precision-punched brain samples of about 0.5 mm3 size, MR images were aligned with a histological three-dimensional reconstruction of the punched brain and regions of interest (ROIs) were placed precisely over the punch voids. Results The Bland–Altman analysis of [Na+]br in normal and ischemic cortex and caudate putamen of seven rats quantitated by 23Na MRI and flame photometry yielded a mean bias and limits of agreement (at ±1.96 SD) of 2% and 43% of average, respectively. A linear increase in [Na+]br was observed between 1 and 6 hours after middle cerebral artery occlusion. Conclusion 23Na MRI provides accurate and reliable results within the whole range of [Na+]br in ischemia with a temporal resolution of 5.3 minutes and precisely targeted submicroliter ROIs in selected brain structures. PMID:19306443

  19. Therapeutic time window for the neuroprotective effects of NGF when administered after focal cerebral ischemia.

    PubMed

    Yang, Ji-Ping; Liu, Huai-Jun; Yang, Hua; Feng, Ping-Yong

    2011-06-01

    In the present study, we evaluated the neuroprotection time window for nerve growth factor (NGF) after ischemia/reperfusion brain injury in rabbits as related to this anti-apoptosis mechanism. Male New Zealand rabbits were subjected to 2 h of middle cerebral artery occlusion (MCAO), followed by 70 h of reperfusion. NGF was administered after injury to evaluate the time window. Neurological deficits, infarct volume, neural cell apoptosis and expressions of caspase-3 and Bcl-2 were measured. Compared to saline-treated control, NGF treatment at 2, 3 and 5 h after MCAO significantly reduced infarct volume, neural cell apoptosis and expression of caspase-3 (P < 0.01), up-regulated the expression of Bcl-2 and improved functional recovery (P < 0.01). However, treatment at latter time points did not produce significant neuroprotection. Neuroprotection treatment with NGF provides an extended time window of up to 5 h after ischemia/reperfusion brain injury, in part by attenuating the apoptosis.

  20. Anti-inflammatory effects of total isoflavones from Pueraria lobata on cerebral ischemia in rats.

    PubMed

    Lim, Dong Wook; Lee, Changho; Kim, In-Ho; Kim, Yun Tai

    2013-08-28

    Puerariae radix, the dried root of Pueraria lobata Ohwi, is one of earliest and most important edible crude herbs used for various medical purposes in Oriental medicine. The aim of the present study was to determine the anti-inflammatory effects of Total Isoflavones from P. lobata (TIPL), which contains the unique isoflavone puerarin, in ischemia in vivo models. Oral administration of TIPL (100 mg/kg) reduced the brain infarct volume and attenuated ischemia-induced cyclooxygenase-2 (COX-2) up-regulation at 2 days after middle cerebral artery occlusion (MCAo) in rats. Moreover, TIPL reduced activation of glial fibrillary acid protein (GFAP) and CD11b antibody (OX-42) at 7 days after MCAo in hippocampal CA1 region. These results show that TIPL can protect the brain from ischemic damage after MCAo. Regarding the immunohistochemical study, the effects of TIPL may be attributable to its anti-inflammatory properties by the inhibition of COX-2 expression, astrocyte expression, and microglia.

  1. Overexpression of SOD1 in transgenic rats protects vulnerable neurons against ischemic damage after global cerebral ischemia and reperfusion.

    PubMed

    Chan, P H; Kawase, M; Murakami, K; Chen, S F; Li, Y; Calagui, B; Reola, L; Carlson, E; Epstein, C J

    1998-10-15

    Transient global cerebral ischemia resulting from cardiac arrest is known to cause selective death in vulnerable neurons, including hippocampal CA1 pyramidal neurons. It is postulated that oxygen radicals, superoxide in particular, are involved in cell death processes. To test this hypothesis, we first used in situ imaging of superoxide radical distribution by hydroethidine oxidation in vulnerable neurons. We then generated SOD1 transgenic (Tg) rats with a five-fold increase in copper zinc superoxide dismutase activity. The Tg rats and their non-Tg wild-type littermates were subjected to 10 min of global ischemia followed by 1 and 3 d of reperfusion. Neuronal damage, as assessed by cresyl violet staining and DNA fragmentation analysis, was significantly reduced in the hippocampal CA1 region, cortex, striatum, and thalamus in SOD1 Tg rats at 3 d, as compared with the non-Tg littermates. There were no changes in the hippocampal CA3 subregion and dentate gyrus, resistant areas in both SOD1 Tg and non-Tg rats. Quantitative analysis of the damaged CA1 subregion showed marked neuroprotection against transient global cerebral ischemia in SOD1 Tg rats. These results suggest that superoxide radicals play a role in the delayed ischemic death of