Sickle Mice Are Sensitive to Hypoxia/Ischemia-Induced Stroke but Respond to Tissue-Type Plasminogen Activator Treatment.

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Sun, Yu-Yo; Lee, Jolly; Huang, Henry; Wagner, Mary B; Joiner, Clinton H; Archer, David R; Kuan, Chia-Yi

2017-12-01

The effects of lytic stroke therapy in patients with sickle cell anemia are unknown, although a recent study suggested that coexistent sickle cell anemia does not increase the risk of cerebral hemorrhage. This finding calls for systemic analysis of the effects of thrombolytic stroke therapy, first in humanized sickle mice, and then in patients. There is also a need for additional predictive markers of sickle cell anemia-associated vasculopathy. We used Doppler ultrasound to examine the carotid artery of Townes sickle mice tested their responses to repetitive mild hypoxia-ischemia- and transient hypoxia-ischemia-induced stroke at 3 or 6 months of age, respectively. We also examined the effects of tPA (tissue-type plasminogen activator) treatment in transient hypoxia-ischemia-injured sickle mice. Three-month-old sickle cell (SS) mice showed elevated resistive index in the carotid artery and higher sensitivity to repetitive mild hypoxia-ischemia-induced cerebral infarct. Six-month-old SS mice showed greater resistive index and increased flow velocity without obstructive vasculopathy in the carotid artery. Instead, the cerebral vascular wall in SS mice showed ectopic expression of PAI-1 (plasminogen activator inhibitor-1) and P-selectin, suggesting a proadhesive and prothrombotic propensity. Indeed, SS mice showed enhanced leukocyte and platelet adherence to the cerebral vascular wall, broader fibrin deposition, and higher mortality after transient hypoxia-ischemia. Yet, post-transient hypoxia-ischemia treatment with tPA reduced thrombosis and mortality in SS mice. Sickle mice are sensitive to hypoxia/ischemia-induced cerebral infarct but benefit from thrombolytic treatment. An increased resistive index in carotid arteries may be an early marker of sickle cell vasculopathy. © 2017 American Heart Association, Inc.

Brain scan in cerebral ischemia. An experimental model in the rat

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Turner, J.H.

1975-01-01

A rapid embolic method for consistent induction of stroke in the rat is described. Brain scans were performed using a micro-pinhole collimator system, and the value of the model for studies in localization of radiopharmaceuticals in cerebral ischemia is demonstrated

Diagnostic radiology of apoplexy - imaging of cerebral ischemia

International Nuclear Information System (INIS)

Rieber, A.; Tomczak, R.; Brambs, H.J.

1998-01-01

The recent enhancements achieved in CT and MR imaging techniques have launched a debate about the techniques preferrably to be applied for diagnostic evaluation of acute cerebral stroke. At present, CT still is the modality of choice for primary evaluation of cerebral ischemia, due to relative cost-effectiveness, high availability, and the capability to reliably differentiate ischemia from hemorrhage. MRI on the other hand is superior to CT in detecting and imaging the infarction area within the first few hours, especially if the technique of diffusion-weighted sequencing is applied. Current research focuses on determining whether MRI with perfusion and diffusion-weighted sequencing will yield images distinctly showing the penumbra on the one hand, and the damaged brain tissue on the other. It remains to be seen whether improved tomographic imaging will lead to novel approaches for therapy. (orig./CB) [de

Hemodynamic disturbances in cerebral ischemia; Correlation between positron emission tomographic and angiographic findings

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Tenjin, Hiroshi; Ueda, Satoshi; Mizukawa, Norihiko; Imahori, Yoshio; Hino, Akihiko; Ohmori, Yoshio [Kyoto Prefectural Univ. of Medicine (Japan); Nakahashi, Hisamitsu

1993-04-01

Proper treatment of ischemic stroke requires better understanding of cerebral hemodynamic changes. The hemodynamic changes associated with ischemia were measured using positron emission tomography and related to angiographic findings in the subacute and chronic stages of 17 ischemia patients who showed symptoms of main trunk stenosis of the internal carotid artery system. The hemodynamic factors, cerebral blood flow, cerebral blood volume, cerebral metabolic rate for oxygen, oxygen extraction fraction, and flow/volume ratio, were measured in regions of interest determined from the angiographic stenosis (over 50%) and compared in each stage. The cerebral blood flow and flow/volume ratio in the territory downstream of the main trunk stenosis and cerebral metabolic rate for oxygen in the whole cortex were decreased in the subacute stage. In the chronic stage, cerebral blood flow and flow/volume ratio decreased mainly in borderzone areas. (author).

Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia.

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Dong, Beibei; Cai, Min; Fang, Zongping; Wei, Haidong; Zhu, Fangyun; Li, Guochao; Dong, Hailong; Xiong, Lize

2013-06-10

The plasma protein hemopexin (HPX) exhibits the highest binding affinity to free heme. In vitro experiments and gene-knock out technique have suggested that HPX may have a neuroprotective effect. However, the expression of HPX in the brain was not well elucidated and its expression after cerebral ischemia-reperfusion injury was also poorly studied. Furthermore, no in vivo data were available on the effect of HPX given centrally on the prognosis of focal cerebral ischemia. In the present study, we systematically investigated expression of HPX in normal rat brain by immunofluorescent staining. The results showed that HPX was mainly expressed in vascular system and neurons, as well as in a small portion of astrocytes adjacent to the vessels in normal rat brain. Further, we determined the role of HPX in the process of focal cerebral ischemic injury and explored the effects of HPX treatment in a rat model of transient focal cerebral ischemia. After 2 h' middle cerebral artery occlusion (MCAO) followed by 24 h' reperfusion, the expression of HPX was increased in the neurons and astrocytes in the penumbra area, as demonstrated by immunohistochemistry and Western blot techniques. Intracerebroventricular injection of HPX at the onset of reperfusion dose-dependently reduced the infarct volumes and improved measurements of neurological function of the rat subjected to transient focal cerebral ischemia. The neuroprotective effects of HPX sustained for up to 7 days after experiments. Our study provides a new insight into the potential neuroprotective role of HPX as a contributing factor of endogenous protective mechanisms against focal cerebral ischemia injury, and HPX might be developed as a potential agent for treatment of ischemic stroke.

Transesophageal echocardiography in patients with cryptogenic cerebral ischemia

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Dreger Henryk

2009-03-01

Full Text Available Abstract Background In about one third of all patients with cerebral ischemia, no definite cause can be identified (cryptogenic stroke. In many patients with initially suspected cryptogenic stroke, however, a cardiogenic etiology can eventually be determined. Hence, the aim of this study was to describe the prevalence of abnormal echocardiographic findings in a large number of these patients. Method Patients with cryptogenic cerebral ischemia (ischemic stroke, IS, and transient ischemic attack, TIA were included. The initial work-up included a neurological examination, EEG, cCT, cMRT, 12-lead ECG, Holter-ECG, Doppler ultrasound of the extracranial arteries, and transthoracic echocardiography. A multiplane transeophageal echocardiography (TEE, including i.v. contrast medium application [Echovist], Valsalva maneuver was performed in all patients Results 702 consecutive patients (380 male, 383 IS, 319 TIA, age 18–90 years were included. In 52.6% of all patients, TEE examination revealed relevant findings. Overall, the most common findings in all patients were: patent foramen ovale (21.7%, previously undiagnosed valvular disease (15.8%, aortic plaques, aortic valve sclerosis, atrial septal aneurysms, regional myocardial dyskinesia, dilated left atrium and atrial septal defects. Older patients (> 55 years, n = 291 and patients with IS had more relevant echocardiographic findings than younger patients or patients with TIA, respectively (p = 0.002, p = 0.003. The prevalence rates of PFO or ASD were higher in younger patients (PFO: 26.8% vs. 18.0%, p = 0.005, ASD: 9.6% vs. 4.9%, p = 0.014. Conclusion A TEE examination in cryptogenic stroke reveals contributing cardiogenic factors in about half of all patients. Younger patients had a higher prevalence of PFO, whereas older patients had more frequently atherosclerotic findings. Therefore, TEE examinations seem indicated in all patients with cryptogenic stroke – irrespective of age – because of

Nonhuman primate models of focal cerebral ischemia

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Jingjing Fan

2017-01-01

Full Text Available 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.

Diffusion-weighted MRI in acute cerebral stroke

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Takayama, Hideichi; Kobayashi, Masahito; Suga, Sadao; Kawase, Takeshi; Nagasawa, Masakazu; Sadanaga, Humiko; Okamura, Miyuki; Kanai, Yoshihiro; Mihara, Ban [Mihara Memorial Hospital, Isezaki, Gunma (Japan)

1999-03-01

Diffusion-weighted MRI has been demonstrated to be valuable in the assessment of cerebral stroke. Recent advance in MR systems of hardware with larger maximum gradient amplitude and faster imaging strategies, such as EPI, has made it possible to acquire whole brain diffusion-weighted imaging (DWI) in less that one minute. The purposes of this study are to evaluate clinical usefulness of DWI and to clarify pitfalls in the diagnosis of acute cerebral stroke. Seventeen patients with 18 ischemic lesions were studied. DWI were taken with 1.5 Tesla MRI (Magnetom Vision, Siemens, Germany) using EPI sequence. Fifteen lesions out of them (3 in cerebral cortex, 9 in basal ganglia/deep white matter and 3 in cerebellum) were studied serially at various times up to 147 days. Acute cerebral infarction was seen clearly as an area of hyperintensity with DWI and as hypointensity in apparent diffusion coefficient (ADC) maps which are indicative of decreased diffusion. DWI detected areas of hyperintense acute infarcts, as early as 2.5 hours after onset, which were not visualized on T{sub 2}-weighted image (T2WI). The lesion of cerebral infarction became isointense in ADC maps at 14-28 days after onset, whereas with DWI it became isointense at about 2 months. Because ADC changed earlier than DWI, ADC maps were useful for differentiate acute from nonacute lesion in cases of recurrent stroke within a short period. In a patient with transient global amnesia for 7 hours, DWI did not show any lesion at 8 hours. In terms of cerebral hemorrhage, lesions were seen as area of hyperintensity in DWI at 3 days and were not distinguishable from that of infarct. Despite limitations in the diagnosis of transient ischemia and cerebral hemorrhage, DWI is a useful technique for early detection of cerebral infarction, especially within the first 6 hours after stroke onset. (author)

Diffusion-weighted MRI in acute cerebral stroke

International Nuclear Information System (INIS)

Takayama, Hideichi; Kobayashi, Masahito; Suga, Sadao; Kawase, Takeshi; Nagasawa, Masakazu; Sadanaga, Humiko; Okamura, Miyuki; Kanai, Yoshihiro; Mihara, Ban

1999-01-01

Diffusion-weighted MRI has been demonstrated to be valuable in the assessment of cerebral stroke. Recent advance in MR systems of hardware with larger maximum gradient amplitude and faster imaging strategies, such as EPI, has made it possible to acquire whole brain diffusion-weighted imaging (DWI) in less that one minute. The purposes of this study are to evaluate clinical usefulness of DWI and to clarify pitfalls in the diagnosis of acute cerebral stroke. Seventeen patients with 18 ischemic lesions were studied. DWI were taken with 1.5 Tesla MRI (Magnetom Vision, Siemens, Germany) using EPI sequence. Fifteen lesions out of them (3 in cerebral cortex, 9 in basal ganglia/deep white matter and 3 in cerebellum) were studied serially at various times up to 147 days. Acute cerebral infarction was seen clearly as an area of hyperintensity with DWI and as hypointensity in apparent diffusion coefficient (ADC) maps which are indicative of decreased diffusion. DWI detected areas of hyperintense acute infarcts, as early as 2.5 hours after onset, which were not visualized on T 2 -weighted image (T2WI). The lesion of cerebral infarction became isointense in ADC maps at 14-28 days after onset, whereas with DWI it became isointense at about 2 months. Because ADC changed earlier than DWI, ADC maps were useful for differentiate acute from nonacute lesion in cases of recurrent stroke within a short period. In a patient with transient global amnesia for 7 hours, DWI did not show any lesion at 8 hours. In terms of cerebral hemorrhage, lesions were seen as area of hyperintensity in DWI at 3 days and were not distinguishable from that of infarct. Despite limitations in the diagnosis of transient ischemia and cerebral hemorrhage, DWI is a useful technique for early detection of cerebral infarction, especially within the first 6 hours after stroke onset. (author)

Magnetic resonance spectroscopy and imaging in cerebral ischemia

International Nuclear Information System (INIS)

Rijen, P.C. van.

1991-01-01

In-vivo proton and phosphorus magnetic resonance spectroscopy was used to detect changes in cerebral metabolism during ischemia and other types of metabolic stress. Magnetic resonance imaging was performed in an animal model to observe morphological alterations during focal cerebral ischemia. Spectroscopy was performed in animal models with global ischemia, in volunteers during hyperventilation and pharmaco-logically altered cerebral perfusion, and in patients with acute and prolonged focal cerebral ischemia. (author). 396 refs.; 44 figs.; 14 tabs

Protective Effect Of Bosentan In Experimental Cerebral Ischemia-Reperfusion Injury

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Eser Ataş

2013-02-01

Full Text Available OBJECTIVE: In cerebral ischemia, there are many factors that start the events leading to cell death. These factors contain free radical production, excitotoxicity, sodium and calcium flow disruption, enzymatic changes, stimulation of the inflamatuar process, the activation of platelets and leukocytes, delayed coagulation, endothelial dysfunction and endothelin (ET release. Bosentan is the competitive antagonist of endothelin receptors; ETA and ETB. The aim of this study is to determine whether the protective effects of bosentan in experimental cerebral ischemia reperfusion injury. MATERIAL and METHODS: In this study, after ischemia-reperfusion procedure, bosentan molecule was regularly given to rats for 5 days. The brain tissues of decapitated rats were histopathologically examined. The levels of oxidant and antioxidant were determined in these brain tissues. RESULTS: It was observed that antioxidant levels and histopathological examinations were in rats given bosentan better than control group rats. CONCLUSION: In conclusion, this study has showed that bosentan may be an agent which could reduce negative effects resulting from neuronal death associated with ischemic stroke.

Aquaporin-4 inhibition mediates piroxicam-induced neuroprotection against focal cerebral ischemia/reperfusion injury in rodents.

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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.

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

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Wolfgang Härtig

2017-08-01

Full Text Available 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

Combination therapy of ifenprodil with piroxicam may be an effective therapeutic intervention in cerebral stroke: a hypothesis.

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Bhattacharya, Pallab; Pandey, Anand Kumar; Paul, Sudip; Patnaik, Ranjana

2012-10-01

Owing to the intricate and multifaceted pathology of cerebral stroke, multiple drug therapy had long been suggested for effective stroke treatment. Therefore, the development of a potential new combination of drug is necessitated which can bring about desirable improved neuroprotection targeting different pathways against ischemic stroke. In this context, we hypothesize the combination effect of Piroxicam, a Non steroidal anti inflammatory drug with Ifenprodil, a NR2b selective NMDAR antagonist in animal model of cerebral ischemia. A few past studies have enumerated the neuroprotective roles of Piroxicam and Ifenprodil administered in singlet against cerebral ischemia in animal model, hence we hypothesized that by using Piroxicam and Ifenprodil in combination would provide additive neuroprotection than either of the agents used alone. In this article, we discuss our hypothesis regarding the possibility of Piroxicam and Ifenprodil as a potent combination which may have a positive therapeutic role in treatment of cerebral ischemia through its anti-inflammatory, anti-apoptotic and anti-oxidative characteristics of Piroxicam with Ifenprodil which has been proved to have neuroprotective, anticonvulsant and antinociceptive effects and has potentials for the treatment of several neuropsychiatric disorders, such as Parkinson's disease alcoholism and drug addiction. Copyright © 2012 Elsevier Ltd. All rights reserved.

Reduced PBR/TSPO Expression After Minocycline Treatment in a Rat Model of Focal Cerebral Ischemia: A PET Study Using [18F]DPA-714

International Nuclear Information System (INIS)

Martin, A.; Boisgard, R.; Tavitian, B.; Kassiou, M.; Dolle, F.

2011-01-01

Background: Many new candidate pharmaceuticals designed to improve recovery after stroke have been proposed recently, but there are still too few molecular imaging methods capable to assess their efficacy. A hallmark of the inflammatory reaction that follows focal cerebral ischemia is overexpression of the mitochondrial peripheral benzodiazepine receptor/18 kDa translocator protein (PBR/TSPO) in the monocytic lineage and astrocytes. This overexpression can be imaged with positron emission tomography (PET) using PBR/TSPO-selective radioligands such as [ 18 F]DPA-714. Purpose: Here, we tested whether PET with [ 18 F]DPA-714 would evidence the effect of minocycline, a broad spectrum antibiotic presently tested as neuro-protective agent after stroke, on the inflammatory reaction induced in an experimental model of stroke. Procedures: Ten rats were subjected to a 2-h transient middle cerebral artery occlusion with reperfusion. Minocycline or saline was intravenously administrated 1 h after reperfusion and daily during the following 6 days. PET studies were performed using [ 18 F]DPA-714 at 7 days after cerebral ischemia. Results: In vivo PET imaging showed a significant decrease in [ 18 F]DPA-714 uptake at 7 days after cerebral ischemia in rats treated with minocycline with respect to saline-treated animals. Minocycline treatment had no effect on the size of the infarcted area. Conclusion: Minocycline administered daily during 7 days after ischemia decreases [ 18 F]DPA- 714 binding, suggesting that the drug exerts an anti-inflammatory activity. [ 18 F]DPA-714 PET is a useful bio-marker to study novel anti-inflammatory strategies in experimental cerebral ischemia. (authors)

Memantine mediates neuroprotection via regulating neurovascular unit in a mouse model of focal cerebral ischemia.

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Chen, Zheng-Zhen; Yang, Dan-Dan; Zhao, Zhan; Yan, Hui; Ji, Juan; Sun, Xiu-Lan

2016-04-01

Memantine is a low-moderate affinity and uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist, which is also a potential neuroprotectant in acute ischemic stroke for its particular action profiles. The present study was to reveal the mechanisms involved in the neuroprotection of memantine. We used a mouse model of permanent focal cerebral ischemia via middle cerebral artery occlusion to verify our hypothesis. 2,3,5-Triphenyltetrazolium chloride staining was used to compare infarct size. The amount of astrocytes and the somal volume of the microglia cell body were analyzed by immunohistochemistry and stereological estimates. Western blotting was used to determine the protein expressions. Memantine prevented cerebral ischemia-induced brain infarct and neuronal injury, and reduced oxygen-glucose deprivation-induced cortical neuronal apoptosis. Moreover, memantine reduced the amount of the damaged astrocytes and over activated microglia after 24h of ischemia. In the early phase of ischemia, higher production of MMP-9 was observed, and thereby collagen IV was dramatically disrupted. Meanwhile, the post-synaptic density protein 95(PSD-95) was also severely cleavaged. Memantine decreased MMP-9 secretion, prevented the degradation of collagen IV in mouse brain. PSD-95 cleavage was also inhibited by memantine. These results suggested that memantine exerted neuroprotection effects in acute ischemic brain damage, partially via improving the functions of neurovascular unit. Taking all these findings together, we consider that memantine might be a promising protective agent against ischemic stroke. Copyright © 2016 Elsevier Inc. All rights reserved.

Axon guidance factor netrin-1 and its receptors regulate angiogenesis after cerebral ischemia

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Ding, Qiao; Liao, Song-Jie; Yu, Jian

2014-01-01

Neurogenesis and angiogenesis play important roles in functional recovery after ischemic stroke. When cerebral ischemia occurs, axon regeneration can compensate for the loss of apoptotic neurons in the ischemic area. The formation of new blood vessels ameliorates the local decrease in blood supply, enhancing the supply of oxygen and nutrients to newly-formed neurons. New blood vessels also act as a scaffold for the migration of neuroblasts to the infarct area after ischemic stroke. In light o...

Effect of NMDA Receptor Antagonist on Local Cerebral Glucose Metabolic Rate in Focal Cerebral Ischemia

International Nuclear Information System (INIS)

Kim, Sang Eun; Hong, Seung Bong; Yoon, Byung Woo

1995-01-01

There has recently been increasing interest in the use of NMDA receptor antagonists as potential neuroprotective agents for the treatment of ischemic stroke. To evaluate the neuroprotective effect of the selective non-competitive NMDA receptor antagonist MK-801 in focal cerebral ischemia, local cerebral glucose utilization (1CGU) was examined in 15 neuroanatomically discrete regions of the conscious rat brain using the 2-deoxy-D[14C]glucose quantitative autoradiographic technique 24 hr after left middle cerebral artery occlusion (MCAO). Animals received MK-801 (5 mg/kg i.v.) or saline vehicle before (20-30 min) or after (30 min) MCAO. Both pretreatment and posttreatment of MK-801 increased occluded/non-occluded 1CGU ratio in 7 and 5 of the 15 regions measured, respectively(most notably in cortical structures). Following MK-801 pretreatment, there was evidence of widespread increases in 1CCPU not only in the non-occluded hemisphere (12 of the 15 areas studied) but also in the occluded hemisphere (13 of the 15 areas studied), while MK-801 posttreatment did not significantly increase 1CGU both in the normal and occluded hemispheres. These data indicate that MK-801 has a neuroprotective effect in focal cerebral ischemia and demonstrate that MK-801 provides widespread alterations of glucose utilization in conscious animals.

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

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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 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.

MRI of experimental focal cerebral ischemia in sheep

International Nuclear Information System (INIS)

Foerschler, A.; Waldmin, D.; Gille, U.; Leipzig Univ.; Zimmer, C.

2007-01-01

Purpose: With respect to the specific characteristic of rete mirabile epidurale rostrale in sheep, the aim of this study was to investigate the use of time of flight (TOF) magnetic resonance angiography (MRA) to observe vascular anatomy and to validate MCA occlusion in a new model of experimental focal cerebral ischemia by permanent middle cerebral artery (MCA) occlusion in sheep (designed to study stroke therapy using autologous stem cells from umbilical cord blood). Furthermore, we wanted to assess the extent and natural time course of ischemic focal brain injury in sheep using functional and morphological magnetic resonance imaging (MRI). Materials and Method: 13 Merino sheep were examined. In 4 of the animals all, in 5 sheep 1 or 2 MCA branches were occluded and in 1 one case touched (sham operation). 4 controls did not undergo a surgical procedure. 23 MRI sessions were performed in 10 sheep. These sessions included T1, T2, T2 * sequences, diffusion-weighted imaging (DWI) and TOF MRA before and 2 - 46 days after the onset of stroke using a 1.5T clinical MR scanner. Corrosion casts of the cerebral arteries of 3 sheep were prepared and compared to MRA. Results: The MRA visualized the vessel anatomy or occlusion distal to the rete mirabile. Anatomical variants concerning the variant origin of the MCA and inconstant arteria choroidea rostralis and communicans rostralis were revealed. Sheep with occluded left MCA showed space occupying lesions with a drop in ADC values. Depending on the number of preserved MCA branches (0; 1; 2), highly significant (p < 0.001) differences in lesion size (21 ± 5.7; 13; 1.7 ± 1.3 ml) could be found. No indication of ischemia but minimal contusion damage was observed in the sham operated animal. (orig.)

Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat

DEFF Research Database (Denmark)

Maddahi, Aida; Chen, Qingwen; Edvinsson, Lars

2009-01-01

BACKGROUND: Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression of metallopr......BACKGROUND: Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression...

Protective effects of alkaloid extract from Leonurus heterophyllus on cerebral ischemia reperfusion injury by middle cerebral ischemic injury (MCAO) in rats.

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Liang, Hao; Liu, Ping; Wang, Yunshan; Song, Shuliang; Ji, Aiguo

2011-07-15

The neuronal damage following cerebral ischemia is a serious risk to stroke patients. The aim of this study was to investigate the neuroprotective effects of alkaloid extract from Leonurus heterophyllus (LHAE) on cerebral ischemic injury. After 24 h of reperfusion following ischemia for 2 h induced by middle cerebral artery occlusion (MCAO), some rats were intraperitoneally administered different doses of LHAE (3.6, 7.2, 14.4 mg/kg, respectively). Neurological examination was measured in all animals. Infarct volume, myeloperoxidase (MPO) activity, levels of nitrate/nitrite metabolite (NO) and apoptosis ratio of nerve fiber in brain were determined. The results showed that LHAE at 7.2 mg/kg or 14.4 mg/kg exerted significantly decreasing neurological deficit scores and reducing the infarct volume on rats with focal cerebral ischemic injury (pagent. Further studies are warranted to assess the efficacy and safety of LHAE in patients. Copyright © 2011 Elsevier GmbH. All rights reserved.

Neural Vascular Mechanism for the Cerebral Blood Flow Autoregulation after Hemorrhagic Stroke

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Ming Xiao

2017-01-01

Full Text Available During the initial stages of hemorrhagic stroke, including intracerebral hemorrhage and subarachnoid hemorrhage, the reflex mechanisms are activated to protect cerebral perfusion, but secondary dysfunction of cerebral flow autoregulation will eventually reduce global cerebral blood flow and the delivery of metabolic substrates, leading to generalized cerebral ischemia, hypoxia, and ultimately, neuronal cell death. Cerebral blood flow is controlled by various regulatory mechanisms, including prevailing arterial pressure, intracranial pressure, arterial blood gases, neural activity, and metabolic demand. Evoked by the concept of vascular neural network, the unveiled neural vascular mechanism gains more and more attentions. Astrocyte, neuron, pericyte, endothelium, and so forth are formed as a communicate network to regulate with each other as well as the cerebral blood flow. However, the signaling molecules responsible for this communication between these new players and blood vessels are yet to be definitively confirmed. Recent evidence suggested the pivotal role of transcriptional mechanism, including but not limited to miRNA, lncRNA, exosome, and so forth, for the cerebral blood flow autoregulation. In the present review, we sought to summarize the hemodynamic changes and underline neural vascular mechanism for cerebral blood flow autoregulation in stroke-prone state and after hemorrhagic stroke and hopefully provide more systematic and innovative research interests for the pathophysiology and therapeutic strategies of hemorrhagic stroke.

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

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Hui-Lin Wang

2017-01-01

Full Text Available 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.

Symptomatic Cerebral Vasospasm and Delayed Cerebral Ischemia Following Transsphenoidal Resection of a Craniopharyngioma.

Science.gov (United States)

Ricarte, Irapuá Ferreira; Funchal, Bruno F; Miranda Alves, Maramélia A; Gomes, Daniela L; Valiente, Raul A; Carvalho, Flávio A; Silva, Gisele S

2015-09-01

Vasospasm has been rarely described as a complication associated with craniopharyngioma surgery. Herein we describe a patient who developed symptomatic vasospasm and delayed cerebral ischemia after transsphenoidal surgery for a craniopharyngioma. A 67-year-old woman became drowsy 2 weeks after a transsphenoidal resection of a craniopharyngioma. A head computed tomography (CT) was unremarkable except for postoperative findings. Electroencephalogram and laboratory studies were within the normal limits. A repeated CT scan 48 hours after the initial symptoms showed bilateral infarcts in the territory of the anterior cerebral arteries (ACA). Transcranial Doppler (TCD) showed increased blood flow velocities in both anterior cerebral arteries (169 cm/second in the left ACA and 145 cm/second in the right ACA) and right middle cerebral artery (164 cm/second) compatible with vasospasm. A CT angiography confirmed the findings. She was treated with induced hypertension and her level of consciousness improved. TCD velocities normalized after 2 weeks. Cerebral vasospasm should be considered in the differential diagnosis of patients with altered neurologic status in the postoperative period following a craniopharyngioma resection. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Non-traumatic neurological emergencies: imaging of cerebral ischemia

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Grunwald, Iris; Reith, Wolfgang [Department of Neuroradiology, Saarland University Clinic, Homburg/Saar (Germany)

2002-07-01

Cardiovascular disease is the leading cause of death worldwide with almost one-third of all cardiovascular deaths ascribed to stroke. Imaging modalities, such as CT, MRI, positron emission tomography (PET), and single photon emission CT (SPECT) provide tremendous insight into the pathophysiology of acute stroke. Computed tomography is considered the most important initial diagnostic study in patients with acute stroke, because underlying structural lesions, such as tumor, vascular malformation, or subdural hematoma, can mimic stroke clinically. Diffusion-weighted imaging (DWI) has the ability to visualize changes in diffusion within minutes after the onset of ischemia and has become a powerful tool in the evaluation of patients with stroke syndrome. Territories with diffusion and perfusion mismatch may define tissues at risk, but with potential recovery. An alternative strategy with CT technology uses rapid CT for dynamic perfusion imaging, with similar goals in mind. Angiography can be performed in the hyperacute stage if thrombolytic therapy is being considered. Indications for diagnostic angiography include transient ischemic attacks in a carotid distribution, amaurosis fugax, prior stroke in a carotid distribution, a high-grade stenotic lesion in a carotid artery, acquiring an angiographic correlation of magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) concerning stenotic findings. In 50% of all angiograms performed in the hyperacute stage, occlusion of a vessel is observed; however, the need for angiography has been made less necessary due to the improvements of MRA, duplex ultrasound, and CTA. Numerous etiologies can lead to infarction. In children, pediatric stroke is very uncommon. The most common cause is an embolus from congenital heart disease with right-to-left shunts. Also a dissection of large extracranial vessels may result in cerebral infarction, and although the brain is equipped with numerous venous drainage routes

Non-traumatic neurological emergencies: imaging of cerebral ischemia

International Nuclear Information System (INIS)

Grunwald, Iris; Reith, Wolfgang

2002-01-01

Cardiovascular disease is the leading cause of death worldwide with almost one-third of all cardiovascular deaths ascribed to stroke. Imaging modalities, such as CT, MRI, positron emission tomography (PET), and single photon emission CT (SPECT) provide tremendous insight into the pathophysiology of acute stroke. Computed tomography is considered the most important initial diagnostic study in patients with acute stroke, because underlying structural lesions, such as tumor, vascular malformation, or subdural hematoma, can mimic stroke clinically. Diffusion-weighted imaging (DWI) has the ability to visualize changes in diffusion within minutes after the onset of ischemia and has become a powerful tool in the evaluation of patients with stroke syndrome. Territories with diffusion and perfusion mismatch may define tissues at risk, but with potential recovery. An alternative strategy with CT technology uses rapid CT for dynamic perfusion imaging, with similar goals in mind. Angiography can be performed in the hyperacute stage if thrombolytic therapy is being considered. Indications for diagnostic angiography include transient ischemic attacks in a carotid distribution, amaurosis fugax, prior stroke in a carotid distribution, a high-grade stenotic lesion in a carotid artery, acquiring an angiographic correlation of magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) concerning stenotic findings. In 50% of all angiograms performed in the hyperacute stage, occlusion of a vessel is observed; however, the need for angiography has been made less necessary due to the improvements of MRA, duplex ultrasound, and CTA. Numerous etiologies can lead to infarction. In children, pediatric stroke is very uncommon. The most common cause is an embolus from congenital heart disease with right-to-left shunts. Also a dissection of large extracranial vessels may result in cerebral infarction, and although the brain is equipped with numerous venous drainage routes

Validation of enhanced and dynamic computed tomography for cerebral ischemia

Energy Technology Data Exchange (ETDEWEB)

Ono, Kenichiro; Arimoto, Hirohiko; Wada, Kojiro; Takahara, Takashi; Shirotani, Toshiki; Shimizu, Akira [Japan Self-Defense Forces Central Hospital, Tokyo (Japan); Hatanaka, Kosuke [Japan Self-Defense Forces Medical School, Tokyo (Japan)

2003-03-01

This paper shows the usefulness of enhanced and dynamic CT for ischemic stroke patients. Sixteen patients with disturbance of consciousness or neurological sign who did not have low-density area on plain CT were selected for this study. We performed enhanced CT sequentially. Enhanced CT image, time-density curve and functional image were compared with final infarcted area and occlusion level of cerebral artery. Three patients whose enhanced CT images showed obvious laterality had occlusion of internal carotid (IC) or horizontal portion of middle cerebral artery (M1). Four of five patients whose functional image and time density curve revealed abnormal region had ischemia because of more peripheral vessel occlusion or IC stenosis. Others with no abnormality on all images had lacunar infarction or did not have infarction finally. Occlusion of cerebral artery proximal portion could be diagnosed only with enhanced CT images. If selected slice was fit to the lesion, more distant level of ischemic area could be determined 100% by time-density curve and functional image. This examination takes only about ten minutes without transferring the patient. Enhanced CT and dynamic scan is useful tool to determine the diagnosis and management for ischemic stroke patients. (author)

Validation of enhanced and dynamic computed tomography for cerebral ischemia

International Nuclear Information System (INIS)

Ono, Kenichiro; Arimoto, Hirohiko; Wada, Kojiro; Takahara, Takashi; Shirotani, Toshiki; Shimizu, Akira; Hatanaka, Kosuke

2003-01-01

This paper shows the usefulness of enhanced and dynamic CT for ischemic stroke patients. Sixteen patients with disturbance of consciousness or neurological sign who did not have low-density area on plain CT were selected for this study. We performed enhanced CT sequentially. Enhanced CT image, time-density curve and functional image were compared with final infarcted area and occlusion level of cerebral artery. Three patients whose enhanced CT images showed obvious laterality had occlusion of internal carotid (IC) or horizontal portion of middle cerebral artery (M1). Four of five patients whose functional image and time density curve revealed abnormal region had ischemia because of more peripheral vessel occlusion or IC stenosis. Others with no abnormality on all images had lacunar infarction or did not have infarction finally. Occlusion of cerebral artery proximal portion could be diagnosed only with enhanced CT images. If selected slice was fit to the lesion, more distant level of ischemic area could be determined 100% by time-density curve and functional image. This examination takes only about ten minutes without transferring the patient. Enhanced CT and dynamic scan is useful tool to determine the diagnosis and management for ischemic stroke patients. (author)

The protective effect of dexanabinol (HU-211) on nitric oxide and cysteine protease-mediated neuronal death in focal cerebral ischemia.

Science.gov (United States)

Durmaz, Ramazan; Ozden, Hilmi; Kanbak, Güngör; Aral, Erinç; Arslan, Okan Can; Kartkaya, Kazim; Uzuner, Kubilay

2008-09-01

We hypothesized that dexanabinol can prevent neuronal death by protecting neuronal lysosomes from nitric oxide (NO)-mediated toxicity, and in turn, by suppressing the release of cathepsins during cerebral ischemia. Focal cerebral ischemia was induced in two sets of animals by permanent middle cerebral artery occlusion. The first set was used to monitor NO concentration and cathepsin activity, while the second was used for histological examination with hematoxylin and eosin, and TUNEL staining. In post-ischemic brain tissue, NO content and cathepsin B and L activity increased (p 0.05). The number of eosinophilic and apoptotic neurons increased in the post-ischemic cerebral cortex (p agent for the treatment of stroke patients.

Ligustrazine monomer against cerebral ischemia-reperfusion injury

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Hai-jun Gao

2015-01-01

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

Agmatine attenuates brain edema through reducing the expression of aquaporin-1 after cerebral ischemia

Science.gov (United States)

Kim, Jae Hwan; Lee, Yong Woo; Park, Kyung Ah; Lee, Won Taek; Lee, Jong Eun

2010-01-01

Brain edema is frequently shown after cerebral ischemia. It is an expansion of brain volume because of increasing water content in brain. It causes to increase mortality after stroke. Agmatine, formed by the decarboxylation of -arginine by arginine decarboxylase, has been shown to be neuroprotective in trauma and ischemia models. The purpose of this study was to investigate the effect of agmatine for brain edema in ischemic brain damage and to evaluate the expression of aquaporins (AQPs). Results showed that agmatine significantly reduced brain swelling volume 22 h after 2 h middle cerebral artery occlusion in mice. Water content in brain tissue was clearly decreased 24 h after ischemic injury by agmatine treatment. Blood–brain barrier (BBB) disruption was diminished with agmatine than without. The expressions of AQPs-1 and -9 were well correlated with brain edema as water channels, were significantly decreased by agmatine treatment. It can thus be suggested that agmatine could attenuate brain edema by limitting BBB disruption and blocking the accumulation of brain water content through lessening the expression of AQP-1 after cerebral ischemia. PMID:20029450

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

DEFF Research Database (Denmark)

Madsen, Pernille M; Clausen, Bettina H; Degn, Matilda

2016-01-01

Microglia respond to focal cerebral ischemia by increasing their production of the neuromodulatory cytokine tumor necrosis factor, which exists both as membrane-anchored tumor necrosis factor and as cleaved soluble tumor necrosis factor forms. We previously demonstrated that tumor necrosis factor...... reduced infarct volumes at one and five days after stroke. This was associated with improved functional outcome after experimental stroke. No changes were found in the mRNA levels of tumor necrosis factor and tumor necrosis factor-related genes (TNFR1, TNFR2, TACE), pro-inflammatory cytokines (IL-1β, IL-6...... knockout mice display increased lesion volume after focal cerebral ischemia, suggesting that tumor necrosis factor is neuroprotective in experimental stroke. Here, we extend our studies to show that mice with intact membrane-anchored tumor necrosis factor, but no soluble tumor necrosis factor, display...

Detection of vascular cell adhesion molecule-1 expression with USPIO-enhanced molecular MRI in a mouse model of cerebral ischemia

International Nuclear Information System (INIS)

Frechou, M.; Beray-Berthat, V.; Plotkine, M.; Marchand-Leroux, C.; Margaill, I.; Raynaud, J.S.; Gombert, F.; Lancelot, E.; Ballet, S.; Robert, P.; Louin, G.; Meriaux, S.

2013-01-01

Vascular damage plays a critical role after stroke, leading notably to edema, hemorrhages and stroke recurrence. Tools to characterize the vascular lesion are thus a real medical need. In this context, the specific nano-particular contrast agent P03011, an USPIO (ultra-small superparamagnetic iron oxide) conjugated to a peptide that targets VCAM-1 (vascular cell adhesion molecule-1), was developed to detect this major component of the vascular inflammatory response. This study aimed to make the proof of concept of the capacity of this targeted USPIO to detect VCAM-1 with MRI after cerebral ischemia in mouse. The time course of VCAM-1 expression was first examined by immunohistochemistry in our model of cerebral ischemia-reperfusion. Secondly, P03011 or non-targeted USPIO P03007 were injected 5 h after ischemia (100 mmol iron kg -1 ; i.v.) and in vivo and ex vivo MRI were performed 24 h after ischemia onset. Double labeling immunofluorescence was then performed on brain slices in order to detect both USPIO and VCAM-1. VCAM-1 expression was significantly up-regulated 24 h after ischemia in our model. In animals receiving P03011, both in vivo and ex vivo MRI performed 24 h after ischemia onset showed hypointense foci which could correspond to iron particles. Histological analysis showed a co-localization of the targeted USPIO and VCAM-1. This study demonstrates that VCAM-1 detection is possible with the USPIO P03011 in a model of cerebral ischemia. This kind of contrast agent could be an interesting clinical tool to characterize ischemic lesions in terms of vascular damage. (authors)

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

Science.gov (United States)

Liu, Xiaobai; Wang, Zhenhua; Wang, Ping; Yu, Bo; Liu, Yunhui; Xue, Yixue

2013-07-21

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

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

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Dong-shu Zhang

2015-01-01

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

Alleviation of glutamate mediated neuronal insult by piroxicam in rodent model of focal cerebral ischemia: a possible mechanism of GABA agonism.

Science.gov (United States)

Bhattacharya, Pallab; Pandey, Anand Kumar; Paul, Sudip; Patnaik, Ranjana

2014-12-01

Neurotransmitter imbalance is an inevitable outcome in cerebral ischemia that leads to neuronal death. In the present study, we evaluated the effects of piroxicam, a nonsteroidal anti-inflammatory drug (NSAID), on extracellular brain glutamate and γ-aminobutyric acid (GABA) release, survival time, and neuronal cell death. Transient focal cerebral ischemia in male Charles Foster rat led to neuronal infarction and compromised intrinsic antioxidant status. Thirty-minute preadministration of piroxicam (10 mg/kg b.w.) showed a significant (P piroxicam administration in stroke rat significantly reduced (P piroxicam attenuates extracellular glutamate release and also reduces neuronal cell death due to reduction in oxidative stress in cerebral ischemia. Our results also indicate a consequent increase of extracellular GABA in brain regions administered with piroxicam, which hints that piroxicam alleviates glutamate excitotoxicity possibly by GABA agonism.

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

International Nuclear Information System (INIS)

Cao Canxiang; Yang Qingwu; Lv Fenglin; Cui Jie; Fu Huabin; Wang Jingzhou

2007-01-01

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-α 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

Contribution of positron emission tomography to physiopathological study of cerebral ischemia in man

Energy Technology Data Exchange (ETDEWEB)

Baron, J C; Bousser, M G; Comar, D; Rougemont, D; Lebrun-Grandie, P [Commissariat a l' Energie Atomique, Centre Hospitalier Frederic Joliot, 91 - Orsay (France); Castaigne, P [Hopital de la Salpetriere, 75 - Paris (France)

1983-12-29

The development of positron emission tomography now allows the local study of cerebral blood flow, oxygen consumption and glucose utilization in ischemic stroke patients. In recent cerebral infarction, a disruption of the normal couple between flow and metabolism is almost constantly observed: in the first few days cerebral blood flow is either inadequate (persistant ischemia) or over-abundant (''luxury perfusion''), whereas a late ''luxury perfusion'' is almost constant within the necrotic area between the 10th and the 40th day. Threshold values for cerebral blood flow and oxygen consumption that are ultimately associated with necrosis or tissue integrity have been determined. A metabolic depression without C.T. Scan counterpart has been observed in various brain structures remote from the infarcted area per se. Lastly, the hemodynamic and metabolic effects of superficial-temporal-middle-cerebral-artery anastomosis have been studied.

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

Directory of Open Access Journals (Sweden)

Le Li

2016-01-01

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

Diabetic microangiopathy: impact of impaired cerebral vasoreactivity and delayed angiogenesis after permanent middle cerebral artery occlusion on stroke damage and cerebral repair in mice.

Science.gov (United States)

Poittevin, Marine; Bonnin, Philippe; Pimpie, Cynthia; Rivière, Léa; Sebrié, Catherine; Dohan, Anthony; Pocard, Marc; Charriaut-Marlangue, Christiane; Kubis, Nathalie

2015-03-01

Diabetes increases the risk of stroke by three, increases related mortality, and delays recovery. We aimed to characterize functional and structural alterations in cerebral microvasculature before and after experimental cerebral ischemia in a mouse model of type 1 diabetes. We hypothesized that preexisting brain microvascular disease in patients with diabetes might partly explain increased stroke severity and impact on outcome. Diabetes was induced in 4-week-old C57Bl/6J mice by intraperitoneal injections of streptozotocin (60 mg/kg). After 8 weeks of diabetes, the vasoreactivity of the neurovascular network to CO2 was abolished and was not reversed by nitric oxide (NO) donor administration; endothelial NO synthase (eNOS) and neuronal NO synthase (nNOS) mRNA, phospho-eNOS protein, nNOS, and phospho-nNOS protein were significantly decreased; angiogenic and vessel maturation factors (vascular endothelial growth factor a [VEGFa], angiopoietin 1 (Ang1), Ang2, transforming growth factor-β [TGF-β], and platelet-derived growth factor-β [PDGF-β]) and blood-brain barrier (BBB) occludin and zona occludens 1 (ZO-1) expression were significantly decreased; and microvessel density was increased without changes in ultrastructural imaging. After permanent focal cerebral ischemia induction, infarct volume and neurological deficit were significantly increased at D1 and D7, and neuronal death (TUNEL+ / NeuN+ cells) and BBB permeability (extravasation of Evans blue) at D1. At D7, CD31+ / Ki67+ double-immunolabeled cells and VEGFa and Ang2 expression were significantly increased, indicating delayed angiogenesis. We show that cerebral microangiopathy thus partly explains stroke severity in diabetes. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Exercise Therapy Augments the Ischemia-Induced Proangiogenic State and Results in Sustained Improvement after Stroke

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Man He

2013-04-01

Full Text Available The induction of angiogenesis will stimulate endogenous recovery mechanisms, which are involved in the long-term repair and restoration process of the brain after an ischemic event. Here, we tested whether exercise influences the pro-angiogenic factors and outcomes after cerebral infarction in rats. Wistar rats were exposed to two hours of middle-cerebral artery occlusion and reperfusion. Different durations of treadmill training were performed on the rats. The expression of matrix metalloproteinase 2 (MMP2 and vascular endothelial growth factor (VEGF-related genes and proteins were higher over time post-ischemia, and exercise enhanced their expression. Sixteen days post-ischemia, the regional cerebral blood flow in the ischemic striatum was significantly increased in the running group over the sedentary. Although no difference was seen in infarct size between the running and sedentary groups, running evidently improved the neurobehavioral score. The effects of running on MMP2 expression, regional cerebral blood flow and outcome were abolished when animals were treated with bevacizumab (BEV, a VEGF-targeting antibody. Exercise therapy improves long-term stroke outcome by MMP2-VEGF-dependent mechanisms related to improved cerebral blood flow.

Relaxation along a fictitious field (RAFF and Z-spectroscopy using alternating-phase irradiation (ZAPI in permanent focal cerebral ischemia in rat.

Directory of Open Access Journals (Sweden)

Kimmo T Jokivarsi

Full Text Available Cerebral ischemia alters the molecular dynamics and content of water in brain tissue, which is reflected in NMR relaxation, diffusion and magnetization transfer (MT parameters. In this study, the behavior of two new MRI contrasts, Relaxation Along a Fictitious Field (RAFF and Z-spectroscopy using Alternating-Phase Irradiation (ZAPI, were quantified together with conventional relaxation parameters (T1, T2 and T1ρ and MT ratios in acute cerebral ischemia in rat. The right middle cerebral artery was permanently occluded and quantitative MRI data was acquired sequentially for the above parameters for up to 6 hours. The following conclusions were drawn: 1 Time-dependent changes in RAFF and T1ρ relaxation are not coupled to those in MT. 2 RAFF relaxation evolves more like transverse, rather than longitudinal relaxation. 3 MT measured with ZAPI is less sensitive to ischemia than conventional MT. 4 ZAPI data suggest alterations in the T2 distribution of macromolecules in acute cerebral ischemia. It was shown that both RAFF and ZAPI provide complementary MRI information from acute ischemic brain tissue. The presented multiparametric MRI data may aid in the assessment of brain tissue status early in ischemic stroke.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Drug-Induced Hypothermia as Beneficial Treatment before and after Cerebral Ischemia

DEFF Research Database (Denmark)

Johansen, Flemming F; Hasseldam, Henrik; Rasmussen, Rune Skovgaard

2014-01-01

Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when...... conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature...... was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced...

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

Institute of Scientific and Technical Information of China (English)

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

2015-01-01

Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral isch-emic 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 th rough 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 ex-ercise signiifcantly 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.

Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection

OpenAIRE

Yu, Yong-Qiang; Liu, Lian-Cheng; Wang, Fa-Cai; Liang, Yan; Cha, Da-Qin; Zhang, Jing-Jing; Shen, Yu-Jun; Wang, Hai-Ping; Fang, Shengyun; Shen, Yu-Xian

2009-01-01

Cerebral ischemia-induced accumulation of unfolded proteins in vulnerable neurons triggers endoplasmic reticulum (ER) stress. Arginine-rich, mutated in early stage tumors (ARMET) is an ER stress-inducible protein and upregulated in the early stage of cerebral ischemia. The purposes of this study were to investigate the characteristics and implications of ARMET expression induced by focal cerebral ischemia. Focal cerebral ischemia in rats was induced by right middle cerebral artery occlusion w...

Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages

Directory of Open Access Journals (Sweden)

Hsiao-Wen Lin

2009-03-01

Full Text Available Hsiao-Wen Lin, E-Jian LeeNeurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, TaiwanAbstract: Melatonin (N-acetyl-5-methoxy-tryptamine, a naturally occurring indole produced mainly by the pineal gland, is a well known antioxidant. Stroke (cerebral ischemia is the second leading cause of death worldwide. To date, however, effective and safe treatment for stroke remains unavailable. Melatonin is both lipid- and water-soluble and readily crosses the blood–brain barrier (BBB. Increasing evidence has shown that, in animal stroke models, administering melatonin significantly reduces infarct volume, edema, and oxidative damage and improves electrophysiological and behavioral performance. Here, we reviewed studies that assess effects of melatonin on cerebral ischemia in acute, sub-acute, and chronic stages. In addition to its potent antioxidant properties, melatonin exerts antiapoptotic, antiexcitotoxic, anti-inflammatory effects and promotes mitochondrial functions in animals with cerebral ischemia. Given that melatonin shows almost no toxicity to humans and possesses multifaceted protective capacity against cerebral ischemia, it is valuable to consider using melatonin in clinical trials on patients suffering from stroke.Keywords: cerebral ischemia, melatonin, stroke, neuroprotection

Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice

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Nietfeld Wilfried

2010-03-01

Full Text Available Abstract Background The complement system is a crucial mediator of inflammation and cell lysis after cerebral ischemia. However, there is little information about the exact contribution of the membrane attack complex (MAC and its inhibitor-protein CD59. Methods Transient focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO in young male and female CD59a knockout and wild-type mice. Two models of MCAO were applied: 60 min MCAO and 48 h reperfusion, as well as 30 min MCAO and 72 h reperfusion. CD59a knockout animals were compared to wild-type animals in terms of infarct size, edema, neurological deficit, and cell death. Results and Discussion CD59a-deficiency in male mice caused significantly increased infarct volumes and brain swelling when compared to wild-type mice at 72 h after 30 min-occlusion time, whereas no significant difference was observed after 1 h-MCAO. Moreover, CD59a-deficient mice had impaired neurological function when compared to wild-type mice after 30 min MCAO. Conclusion We conclude that CD59a protects against ischemic brain damage, but depending on the gender and the stroke model used.

Neuroprotective Activity of Lavender Oil on Transient Focal Cerebral Ischemia in Mice

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Qiusheng Zheng

2012-08-01

Full Text Available 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.

Pharmacologicalmodification of thegabaergicsystem as a potentialvariant of cerebral protection in acute cerebral ischemia

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Олександр Володимирович Тихоновський

2015-10-01

Full Text Available The aim is to study the possible impact of some derivatives of gamma-aminobutyric acid (GABA, piracetam, picamilon and Krebs cycle intermediates - succinate (as sodium salt on the pathobiochemical changes in the central nervous system, that occur under experimental playing of acute ischemic tissue damage of the cerebrum.Research methods: The study was conducted in 96 rats Wistar, who were on a standardized vivarium diet. Cerebral ischemia was caused by bond of the unilateral common carotid artery. All drugs were administered intraperitoneally once daily for 4 days after modeling of an acute cerebral ischemia after which animals were withdrawn from experiment. In the brain tissues concentrations of pyruvic, izocitric, dairy and apple acids were determined. The activity of antioxidant enzymes: catalase and superoxide dysmutaza. In addition, the brain tissues the contents of lipid peroxidation products were evaluated – diene conjugates and malonic dialdehyde. Level of brain energy production was judged by the content of the adenylic nucleotide and also phosphocreatine . The degree of destruction of the brain cells was assessed by activity of the enzyme lactate dehydrogenase in the blood and brain fraction of the creatine phosphokinase.Research results: As a result of studies, on the 4th day of ischemia a significant carbohydrate metabolism is detected, which is reflected in the sharp strengthening of anaerobic glycolysis and reduced activity of the Krebs cycle reactions, as evidenced by a significant increase in quantity of lactate and decrease in quantity of malate, isocitrate and pyruvate.A sharp strengthening of anaerobic glycolysis results in the accumulation of oxidized products and intermediates especially the latter product – lactic acid. Metabolic acidosis develops against the background of energy failure, which leads to activation of lipid peroxidation reactions. Courses appointment of the cyclic derivatives of GABA piracetam

Effectiveness of sugammadex for cerebral ischemia/reperfusion injury.

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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.

Effectiveness of sugammadex for cerebral ischemia/reperfusion injury

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Sule Ozbilgin

2016-06-01

Full Text Available 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.

β2-Adrenergic Receptor-Mediated HIF-1α Upregulation Mediates Blood Brain Barrier Damage in Acute Cerebral Ischemia

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Yanyun Sun

2017-08-01

Full Text Available Disruption of the blood brain barrier (BBB within the thrombolytic time window is an antecedent event to intracerebral hemorrhage in ischemic stroke. Our recent studies showed that 2-h cerebral ischemia induced BBB damage in non-infarcted area and secreted matrix metalloproteinase-2 (MMP-2 accounted for this disruption. However, the factors that affect MMP-2 secretion and regulate BBB damage remains unknown. Since hypoxia-inducible factor-1 alpha (HIF-1α was discovered as a mater regulator in hypoxia, we sought to investigate the roles of HIF-1α in BBB damage as well as the factors regulating HIF-1α expression in the ischemic brain. in vivo rat middle cerebral artery occlusion (MCAO and in vitro oxygen glucose deprivation (OGD models were used to mimic ischemia. Pretreatment with HIF-1α inhibitor YC-1 significantly inhibited 2-h MCAO-induced BBB damage, which was accompanied by suppressed occludin degradation and vascular endothelial growth factor (VEGF mRNA upregulation. Interestingly, β2-adrenergic receptor (β2-AR antagonist ICI 118551 attenuated ischemia-induced BBB damage by regulating HIF-1α expression. Double immunostaining showed that HIF-1α was upregulated in ischemic neurons but not in astrocytes andendothelial cells. Of note, HIF-1α inhibition with inhibitor YC-1 or siRNA significantly prevented OGD-induced VEGF upregulation as well as the secretion of VEGF and MMP-2 in neurons. More importantly, blocking β2-AR with ICI 118551 suppressedHIF-1α upregulation in ischemic neurons and attenuated occludin degradation induced by the conditioned media of OGD-treatedneurons. Taken together, blockade of β2-AR-mediated HIF-1α upregulation mediates BBB damage during acute cerebral ischemia. These findings provide new mechanistic understanding of early BBB damage in ischemic stroke and may help reduce thrombolysis-related hemorrhagic complications.

Imaging of rat cerebral ischemia-reperfusion injury using99mTc-labeled duramycin

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Zhang Yuqing; Stevenson, Gail D.; Barber, Christy; Furenlid, Lars R.; Barrett, Harrison H.; Woolfenden, James M.; Zhao Ming; Liu Zhonglin

2013-01-01

Objectives: Prompt identification of necrosis and apoptosis in the infarct core and penumbra region is critical in acute stroke for delineating the underlying ischemic/reperfusion molecular pathologic events and defining therapeutic alternatives. The objective of this study was to investigate the capability of 99m Tc-labeled duramycin in detecting ischemia-reperfusion injury in rat brain after middle cerebral artery (MCA) occlusion. Methods: Ischemic cerebral injury was induced in ten rats by vascular insertion of a nylon suture in the left MCA for 3 hr followed by 21–24 hr reperfusion. After i.v. injection of 99m Tc-duramycin (1.0-3.5 mCi), dynamic cerebral images were acquired for 1 hr in six rats using a small-animal SPECT imager. Four other rats were imaged at 2 hr post-injection. Ex vivo images were obtained by autoradiography after sacrifice. Histologic analyses were performed to assess cerebral infarction and apoptosis. Results: SPECT images showed that 99m Tc-duramycin uptake in the left cerebral hemisphere was significantly higher than that in the right at 1 and 2 hr post-injection. The level of radioactive uptake in the ischemic brain varied based on ischemic severity. The average ratio of left cerebral hot-spot uptake to right hemisphere radioactivity, as determined by computerized ROI analysis, was 4.92 ± 0.79. Fractional washout at 1 hr was 38.2 ± 4.5% of peak activity for left cerebral hot-spot areas and 80.9 ± 2.0% for remote control areas (P 99m Tc-duramycin SPECT imaging may be useful for detecting and quantifying ongoing apoptotic neuronal cell loss induced by ischemia-reperfusion injury.

Free Radical Damage in Ischemia-Reperfusion Injury: An Obstacle in Acute Ischemic Stroke after Revascularization Therapy

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Ming-Shuo Sun

2018-01-01

Full Text Available Acute ischemic stroke is a common cause of morbidity and mortality worldwide. Thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy are the main revascularization therapies for acute ischemic stroke. However, ischemia-reperfusion injury after revascularization therapy can result in worsening outcomes. Among all possible pathological mechanisms of ischemia-reperfusion injury, free radical damage (mainly oxidative/nitrosative stress injury has been found to play a key role in the process. Free radicals lead to protein dysfunction, DNA damage, and lipid peroxidation, resulting in cell death. Additionally, free radical damage has a strong connection with inducing hemorrhagic transformation and cerebral edema, which are the major complications of revascularization therapy, and mainly influencing neurological outcomes due to the disruption of the blood-brain barrier. In order to get a better clinical prognosis, more and more studies focus on the pharmaceutical and nonpharmaceutical neuroprotective therapies against free radical damage. This review discusses the pathological mechanisms of free radicals in ischemia-reperfusion injury and adjunctive neuroprotective therapies combined with revascularization therapy against free radical damage.

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

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

2016-01-01

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

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

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Fang, T.; Zhou, D.; Lu, L.; Tong, X.; Wu, J.; Yi, L. [Department of Neurology, Shenzhen Hospital, Peking University, Shenzhen (China)

2016-08-01

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

Impact of Cardiac Contractility during Cerebral Blood Flow in Ischemia

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Silver, Brian

2011-05-01

Full Text Available Objective: In cerebral regions affected by ischemia, intrinsic vascular autoregulation is often lost. Blood flow delivery depends upon cardiac function and may be influenced by neuro-endocrine mediated myocardial suppression. Our objective is to evaluate the relation between ejection fraction (EF and transcranial doppler (TCD peak systolic velocities (PSV in patients with cerebral ischemic events.Methods: We conducted a retrospective cohort study from an existing TCD registry. We evaluated patients admitted within 24 hours of onset of a focal neurological deficit who had an echocardiogram and TCD performed within 72 hours of admission.Results: We identified 58 patients from March to October 2003. Eighty-one percent (n=47 had a hospital discharge diagnosis of ischemic stroke and 18.9% (n=11 had a diagnosis of transient ischemic attack. Fourteen patients had systolic dysfunction (EF50% compared to those with systolic dysfunction (EF<50% was as follows: middle cerebral artery 62.0 + 28.6 cm/s vs. 51.0 + 23.3 cm/s, p=0.11; anterior cerebral artery 52.1 + 21.6 cm/s vs. 45.9 + 22.7 cm/s, p=0.28; internal carotid artery 56.5 + 20.1 cm/s vs. 46.4 + 18.4 cm/s, p=0.04; ophthalmic artery 18.6 + 7.2 cm/s vs. 15.3 + 5.2 cm/s, p=0.11; vertebral artery 34.0 + 13.9 cm/s vs. 31.6 + 15.0 cm/s, p=0.44.Conclusion: Cerebral blood flow in the internal carotid artery territory appears to be higher in cerebral ischemia patients with preserved left ventricular contractility. Our study was unable to differentiate pre-existing cardiac dysfunction from neuro-endocrine mediated myocardial stunning. Future research is necessary to better understand heart-brain interactions in this setting and to further explore the underlying mechanisms and consequences of neuro-endocrine mediated cardiac dysfunction. [West J Emerg Med. 2011;12(2:227-232.

Identification of proteins regulated by curcumin in cerebral ischemia.

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Shah, Fawad-Ali; Gim, Sang-Ah; Sung, Jin-Hee; Jeon, Seong-Jun; Kim, Myeong-Ok; Koh, Phil-Ok

2016-03-01

Curcumin is known to have a neuroprotective effect against cerebral ischemia. The objective of this study was to identify various proteins that are differentially expressed by curcumin treatment in focal cerebral ischemia using a proteomic approach. Adult male rats were treated with vehicle or curcumin 1 h after middle cerebral artery occlusion. Brain tissues were collected 24 h after the onset of middle cerebral artery occlusion, and cerebral cortices proteins were identified by two-dimensional gel electrophoresis and mass spectrometry. We detected several proteins with altered expression levels between vehicle- and curcumin-treated animals. Among these proteins, ubiquitin carboxy-terminal hydrolase L1, isocitrate dehydrogenase, adenosylhomocysteinase, and eukaryotic initiation factor 4A were decreased in the vehicle-treated animal, and curcumin treatment attenuated the injury-induced decreases of these proteins. Conversely, pyridoxal phosphate phosphatase was increased in the vehicle-treated animal, and curcumin treatment prevented decreases in this protein. The identified altered proteins are associated with cellular metabolism and differentiation. The results of this study suggest that curcumin exerts a neuroprotective effect by regulating the expression of various proteins in focal cerebral ischemia. Copyright © 2016 Elsevier Inc. All rights reserved.

Roles of Oxidative Stress, Apoptosis, PGC-1α and Mitochondrial Biogenesis in Cerebral Ischemia

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Ding-I Yang

2011-10-01

Full Text Available The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-γ (PPARγ co-activator 1α (PGC1-α. PGC1-α is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-α is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.

Anchusa italica extract: phytochemical and neuroprotective evaluation on global cerebral ischemia and reperfusion

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Akram Torki

2018-06-01

Full Text Available Abstract Stroke is the third leading cause of mortality and disability in industrial countries. Treatment with herbs with antioxidant properties has been reported to be an alternative to the conventional treatments. This study was conducted to investigate the effect of Anchusa italica extract on hippocampal injury induced by transient global cerebral ischemia and reperfusion in the rat. To do so, 50 rats were randomly assigned to five groups; control, sham, ischemia, and 50 or 100 mg/kg of Anchusa italica treated animals. Ischemia was induced by occlusion of carotid artery for 30 minutes. Afterward, behavioral tests and biochemical analyses were conducted. Induction of ischemia/reperfusion caused a decline in learning and passive avoidance memory in rats. Moreover, Anchusa italica caused an increase in learning and improved the passive avoidance memory. Induction of ischemia/reperfusion caused a decrease in the antioxidant capacity of the brain and serum as well as an increase in the malondialdehyde of the brain and serum. Anchusa italica led to an increase in the antioxidant capacity of the brain and serum and decrease in the malondialdehyde of the brain and serum. Overall, because of its protective effects on spatial memory, passive avoidance learning, antioxidant capacity, and lipid peroxidation during ischemia/reperfusion, Anchusa italica might be beneficial in ischemic patients.

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

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Xin-juan Li

2015-01-01

Full Text Available 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 P2X 7 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 P2X 7 receptors.

Electroacupuncture ameliorates cognitive impairment through inhibition of NF-κB-mediated neuronal cell apoptosis in cerebral ischemia-reperfusion injured rats.

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Feng, Xiaodong; Yang, Shanli; Liu, Jiao; Huang, Jia; Peng, Jun; Lin, Jiumao; Tao, Jing; Chen, Lidian

2013-05-01

Cognitive impairment is a serious mental deficit following stroke that severely affects the quality of life of stroke survivors. Nuclear factor‑κB (NF-κB)-mediated neuronal cell apoptosis is involved in the development of post-stroke cognitive impairment; therefore, it has become a promising target for the treatment of impaired cognition. Acupuncture at the Baihui (DU20) and Shenting (DU24) acupoints is commonly used in China to clinically treat post‑stroke cognitive impairment; however, the precise mechanism of its action is largely unknown. In the present study, we evaluated the therapeutic efficacy of electroacupuncture against post-stroke cognitive impairment and investigated the underlying molecular mechanisms using a rat model of focal cerebral ischemia-reperfusion (I/R) injury. Electroacupuncture at Baihui and Shenting was identified to significantly ameliorate neurological deficits and reduce cerebral infarct volume. Additionally, electroacupuncture improved learning and memory ability in cerebral I/R injured rats, demonstrating its therapeutic efficacy against post-stroke cognitive impairment. Furthermore, electroacupuncture significantly suppressed the I/R-induced activation of NF-κB signaling in ischemic cerebral tissues. The inhibitory effect of electroacupuncture on NF-κB activation led to the inhibition of cerebral cell apoptosis. Finally, electroacupuncture markedly downregulated the expression of pro-apoptotic Bax and Fas, two critical downstream target genes of the NF-κB pathway. Collectively, our findings suggest that inhibition of NF-κB‑mediated neuronal cell apoptosis may be one mechanism via which electroacupuncture at Baihui and Shenting exerts a therapeutic effect on post-stroke cognitive impairment.

Post-Traumatic Late Onset Cerebral Ischemia

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Gencer Genc

2014-03-01

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

Cerebral ischemia produced by four-vessel occlusion in the rat: a quantitative evaluation of cerebral blood flow

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Furlow, T.W. Jr.

1982-01-01

Cerebral ischemia was produced in the rat by simultaneous occlusion of the vertebral and carotid arteries according to the method of Pulsinelli and Brierley (Stroke 10: 267, 1979). Local cerebral blood flow (CBF) was determined by polarographic and autoradiographic techniques. Hydrogen-clearance measurements showed that mean CBF fell in four monitored regions of the hemispheres to between 0.11 and 0.18 ml/g/min, being least in deep rostal gray, intermediate in superficial gray, and greatest in deep caudal gray. However, individual animals had local CBF in excess of 0.20 and even 0.30 ml/g/min, and no animal showed zero CBF. When animals were rendered hypotensive (MABP of 50 Torr) during vascular occlusion, mean CBF ranged between 0.03 and 0.10 ml/g/min in the same regional order. With hypotension, total arrest of flow occurred. Autoradiographic data confirmed the above findings and indicated adequate CBF to the lower brainstem. During vascular occlusion, sufficient CBF may be present ot sustain cerebral tissue as in animals with a well developed spinal circulation or an inadvertently patent vertebral artery

Preconditioning with the traditional Chinese medicine Huang-Lian-Jie-Du-Tang initiates HIF-1α-dependent neuroprotection against cerebral ischemia in rats.

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Zhang, Qichun; Bian, Huimin; Li, Yu; Guo, Liwei; Tang, Yuping; Zhu, Huaxu

2014-06-11

Huang-Lian-Jie-Du-Tang (HLJDT) is a classical heat-clearing and detoxicating formula of traditional Chinese medicine that is widely used to treat stroke. The present study was designed to investigate the effects of HLJDT preconditioning on neurons under oxygen and glucose deprivation (OGD) and rats subjected to middle cerebral artery occlusion (MCAO). A stroke model of rats was obtained through MCAO. Following HLJDT preconditioning, the cerebral infarction volume, cerebral water content, and neurological deficient score were determined. Cerebral cortical neurons cultured in vitro were preconditioned with HLJDT and then subjected to OGD treatment. The release of lactate dehydrogenase (LDH) from neurons was detected. The levels of hypoxia-inducible factor-1α (HIF-1α) and PI3K/Akt signaling were analyzed by western blotting, and the levels of erythropoietin (EPO) and vascular endothelial growth factor (VEGF) in the supernatant of the neurons and the plasma of MCAO rats were measured through a radioimmunological assay. The apoptosis and proliferation of neurons were analyzed by immunohistochemistry. HLJDT preconditioning significantly reduced the cerebral infarction volume and cerebral water content and ameliorated the neurological deficient score of MCAO rats. In addition, HLJDT preconditioning protected neurons against OGD. Increased HIF-1α, EPO, and VEGF levels and the activation of PI3K/Akt signaling were observed as a result of HLJDT preconditioning. Furthermore, HLJDT preconditioning was found to inhibit ischemia-induced neuron apoptosis and to promote neuron proliferation under conditions of ischemia/reperfusion. Both rats and neurons subjected to HLJDT preconditioning were able to resist ischemia/reperfusion or hypoxia injury through the inhibition of apoptosis and the enhancement of proliferation, and these effects were primarily dependent on the activation of the PI3K/Akt signaling pathway and HIF-1α. Copyright © 2014 Elsevier Ireland Ltd. All rights

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

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Xiang-Long Hong

2016-07-01

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

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

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Hu, Xiaoming; De Silva, T. Michael; Chen, Jun; Faraci, Frank M.

2017-01-01

The consequences of cerebrovascular disease are among the leading health issues worldwide. Large and small cerebral vessel disease can trigger stroke and contribute to the vascular component of other forms of neurological dysfunction and degeneration. Both forms of vascular disease are driven by diverse risk factors, with hypertension as the leading contributor. Despite the importance of neurovascular disease and subsequent injury following ischemic events, fundamental knowledge in these areas lag behind our current understanding of neuroprotection and vascular biology in general. The goal of this review is to address select key structural and functional changes in the vasculature that promote hypoperfusion and ischemia, while also affecting the extent of injury and effectiveness of therapy. In addition, as damage to the blood-brain barrier (BBB) is one of the major consequences of ischemia, we discuss cellular and molecular mechanisms underlying ischemia-induced changes in BBB integrity and function, including alterations in endothelial cells and the contribution of pericytes, immune cells, and matrix metalloproteinases. Identification of cell types, pathways, and molecules that control vascular changes before and after ischemia may result in novel approaches to slow the progression of cerebrovascular disease and lessen both the frequency and impact of ischemic events. PMID:28154097

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

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Hyun Ah eKim

2014-11-01

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

Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia

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Kakihana, M.; Fukuda, N.; Suno, M.; Nagaoka, A.

1988-02-01

The effects of cytidine 5'-diphosphocholine (CDP-choline) on neurologic deficits and cerebral glucose metabolism were studied in a rat model of transient cerebral ischemia. Cerebral ischemia was induced by occluding both common carotid arteries for 20 or 30 minutes 24 hours after the vertebral arteries were permanently occluded by electrocautery. CDP-choline was administered intraperitoneally twice daily for 4 days after reestablishing carotid blood flow. CDP-choline at two dosages (50 and 250 mg/kg) shortened the time required for recovery of spontaneous motor activity in a dose-related manner; recovery time was measured early after reperfusion. Neurologic signs were observed for 10 days. High-dose CDP-choline improved neurologic signs in the rats within 20-30 minutes of ischemia. When cerebral glucose metabolism was assessed on Day 4, increases in the levels of glucose and pyruvate were accompanied by decreases in the synthesis of labeled acetylcholine from uniformly labeled (/sup 14/C)glucose measured in the cerebral cortex of rats with 30 minutes of ischemia. High-dose CDP-choline also attenuated changes in these variables. CDP-(1,2-/sup 14/C)choline injected intravenously 10 minutes after reperfusion was used for membrane lipid biosynthesis. These results indicate that CDP-choline has beneficial effects on brain dysfunction induced by cerebral ischemia, which may be due in part to the restorative effects of CDP-choline on disturbed cerebral glucose metabolism, probably by stimulating phospholipid biosynthesis.

Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia

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Kakihana, M.; Fukuda, N.; Suno, M.; Nagaoka, A.

1988-01-01

The effects of cytidine 5'-diphosphocholine (CDP-choline) on neurologic deficits and cerebral glucose metabolism were studied in a rat model of transient cerebral ischemia. Cerebral ischemia was induced by occluding both common carotid arteries for 20 or 30 minutes 24 hours after the vertebral arteries were permanently occluded by electrocautery. CDP-choline was administered intraperitoneally twice daily for 4 days after reestablishing carotid blood flow. CDP-choline at two dosages (50 and 250 mg/kg) shortened the time required for recovery of spontaneous motor activity in a dose-related manner; recovery time was measured early after reperfusion. Neurologic signs were observed for 10 days. High-dose CDP-choline improved neurologic signs in the rats within 20-30 minutes of ischemia. When cerebral glucose metabolism was assessed on Day 4, increases in the levels of glucose and pyruvate were accompanied by decreases in the synthesis of labeled acetylcholine from uniformly labeled [ 14 C]glucose measured in the cerebral cortex of rats with 30 minutes of ischemia. High-dose CDP-choline also attenuated changes in these variables. CDP-[1,2- 14 C]choline injected intravenously 10 minutes after reperfusion was used for membrane lipid biosynthesis. These results indicate that CDP-choline has beneficial effects on brain dysfunction induced by cerebral ischemia, which may be due in part to the restorative effects of CDP-choline on disturbed cerebral glucose metabolism, probably by stimulating phospholipid biosynthesis

Anti-Inflammatory Effects of Traditional Chinese Medicines against Ischemic Injury in In Vivo Models of Cerebral Ischemia

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Chin-Yi Cheng

2016-01-01

Full Text Available Inflammation plays a crucial role in the pathophysiology of acute ischemic stroke. In the ischemic cascade, resident microglia are rapidly activated in the brain parenchyma and subsequently trigger inflammatory mediator release, which facilitates leukocyte-endothelial cell interactions in inflammation. Activated leukocytes invade the endothelial cell junctions and destroy the blood-brain barrier integrity, leading to brain edema. Toll-like receptors (TLRs stimulation in microglia/macrophages through the activation of intercellular signaling pathways secretes various proinflammatory cytokines and enzymes and then aggravates cerebral ischemic injury. The secreted cytokines activate the proinflammatory transcription factors, which subsequently regulate cytokine expression, leading to the amplification of the inflammatory response and exacerbation of the secondary brain injury. Traditional Chinese medicines (TCMs, including TCM-derived active compounds, Chinese herbs, and TCM formulations, exert neuroprotective effects against inflammatory responses by downregulating the following: ischemia-induced microglial activation, microglia/macrophage-mediated cytokine production, proinflammatory enzyme production, intercellular adhesion molecule-1, matrix metalloproteinases, TLR expression, and deleterious transcription factor activation. TCMs also aid in upregulating anti-inflammatory cytokine expression and neuroprotective transcription factor activation in the ischemic lesion in the inflammatory cascade during the acute phase of cerebral ischemia. Thus, TCMs exert potent anti-inflammatory properties in ischemic stroke and warrant further investigation.

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

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Miyanohara, Jun [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Shirakawa, Hisashi, E-mail: shirakaw@pharm.kyoto-u.ac.jp [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Sanpei, Kazuaki [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Nakagawa, Takayuki [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan); Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital (Japan); Kaneko, Shuji [Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University (Japan)

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.

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

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

2015-01-01

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. - 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.

TRANSESOPHAGEAL ECHOCARDIOGRAPHY IN PATIENTS WITH CEREBRAL ISCHEMIA

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Kavian Ghandehari

2010-12-01

Full Text Available Abstract INTRODUCTION: Transesophageal echocardiography (TEE is superior to Transthoracic echocardiography (TTE in detection of atrial septal defects and aneurysm, aortic atheroma, left atrial thrombus and mitral valve abnormalities. TEE is indicated in young adults with cryptogenic ischemic stroke who are suspected of having cardioembolic mechanism despite non-diagnostic TTE. METHODS: A prospective clinical study was conducted in patients with ischemic stroke or TIA who had TTE done in Ghaem hospital, Mashhad during 2006-2007. Ischemic cerebrovascular events were detected by stroke neurologist. TEE was performed with VIPI3/GE device, USA and a 7 MHz transesophageal probe by an echocardiologist. Patients who did not have TTE before TEE were excluded. Comparison of TEE to TTE results was performed by the echocardiologist and stroke neurologist in each patient. Influence of TEE on therapeutic decisions in each patient was evaluated. RESULTS: Forty-seven patients (20 females, 27 males with a mean age of 42.6±7.3 years were studied. Cardiac and aortic abnormalities were detected in TEE of 35 cases (35/47; 74% with ischemic cerebrovascular events. Cardiac abnormalities of 17 cases (36% were only detectable by TEE. These seventeen cases included 7 patients with PFO, 1 case with ASD, 6 cases with aortic atheroma and 2 patients with clot in the left atrium. Comparing the preventive stroke strategies before and after TEE revealed that it was changed only in two cases (2/47; 4.3% due to performing TEE. These included one patient with a small high-risk PFO and another case with dehicense of mechanical mitral valve. CONCLUSION: TEE revealed cardiac or aortic abnormalities in one-third of the patients with cerebral ischemia and has not been detected by TEE previously. The influence of TEE in therapeutic decisions of patients with ischemic cerebrovascular events is very low.         Keywords: Transesophageal echocardiography, Stroke, Transient Ischemic

Diagnosis of hemodynamic compromise in patients with chronic cerebral ischemia

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Kuroda, Satoshi; Sakuragi, Mitsugi; Motomiya, Mineo; Nakagawa, Tango; Mitsumori, Kenji; Tsuru, Mitsuo; Takigawa, Shugo; Kamiyama, Hiroyasu; Abe, Hiroshi.

1990-01-01

To evaluate the efficacy of tests for selecting patients with hemodynamic compromise, measurement of cerebral blood volume (CBV) with 99m Tc-RBC single photon emission computed tomography (SPECT) was performed in thirteen patients with occlusive cerebrovascular disease, and was compared with results obtained by 133 Xe SPECT and acetazolamide (Diamox) test. All patients in our study suffered TIA, RIND, or minor completed stroke. Cerebral angiography demonstrated severe stenosis or occlusion in the ipsilateral internal carotid artery or middle cerebral artery, although plain CT scan or MRI revealed no or, if any, only localized infarcted lesions. Regional cerebral blood volume (rCBV) was measured with 99m Tc-RBC SPECT and regional cerebral blood flow (rCBF) was measured with 133 Xe SPECT before and after intravenous injection of 10 - 12 mg/kg acetazolamide (Diamox). Our results suggest that the ipsilateral rCBV/rCBF (mean transit time) is a more sensitive index of the cerebral perfusion reserve than the use of only rCBV or rCBF of the ipsilateral hemisphere. Also, the ipsilateral rCBV/rCBF is significantly correlated (r= -0.72) with the Diamox reactivity of rCBF, which is considered to represent the cerebral vasodilatory capacity in patients with chronic cerebral ischemia. Postoperative SPECT study revealed remarkable improvement of ipsilateral rCBV/rCBF and Diamox reactivity in four patients who underwent EC/IC bypass surgery to improve the hemodynamic compromise. In conclusion, our results suggest that the measurement of rCBV/rCBF with 133 Xe SPECT and 99m Tc-RBC SPECT is useful for detecting the hemodynamic compromise in patients with occlusive cerebrovascular disease. (author)

Effect of magnesium treatment and glucose levels on delayed cerebral ischemia in patients with subarachnoid hemorrhage: a substudy of the Magnesium in Aneurysmal Subarachnoid Haemorrhage trial (MASH-II).

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Leijenaar, Jolien F; Dorhout Mees, Sanne M; Algra, Ale; van den Bergh, Walter M; Rinkel, Gabriel J E

2015-10-01

subarachnoid hemorrhage, nor was there an interaction with glucose levels. It is therefore unlikely that glucose levels explain the failure of magnesium to prevent delayed cerebral ischemia and poor outcome after aneurysmal subarachnoid hemorrhage. © 2015 World Stroke Organization.

Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

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Cheng, Zhuo; Wang, Liping; Qu, Meijie; Liang, Huaibin; Li, Wanlu; Li, Yongfang; Deng, Lidong; Zhang, Zhijun; Yang, Guo-Yuan

2018-05-03

Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased blood-brain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. However, the underlying mechanism was largely unknown. We therefore hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1). Adult ICR male mice (n = 118) underwent 90-min middle cerebral artery occlusion and received 2 × 10 5 mesenchymal stem cell transplantation. Neurobehavioral outcome, infarct volume, and blood-brain barrier permeability were measured after ischemia. The relationship between myeloperoxidase (MPO) activity and ICAM-1 release was further determined. We found that intracranial injection of mesenchymal stem cells reduced infarct volume and improved behavioral function in experimental stroke models (p mesenchymal stem cell-treated mice compared to the control group following ischemia (p cells and myeloperoxidase activity were decreased in mesenchymal stem cell-treated mice (p mesenchymal stem cell therapy attenuated blood-brain barrier disruption in mice after ischemia. Mesenchymal stem cells attenuated the upward trend of MMP-9 and potentially via downregulating ICAM-1 in endothelial cells. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway may influence MMP-9 expression of neutrophils and resident cells, and ICAM-1 acted as a key factor in the paracrine actions of mesenchymal stem cell.

Effects of the combined treatment of bone marrow stromal cells with mild exercise and thyroid hormone on brain damage and apoptosis in a mouse focal cerebral ischemia model.

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Akhoundzadeh, Kobar; Vakili, Abedin; Sameni, Hamid Reza; Vafaei, Abbas Ali; Rashidy-Pour, Ali; Safari, Manouchehr; Mohammadkhani, Razieh

2017-08-01

This study examined whether post-stroke bone marrow stromal cells (BMSCs) therapy combined with exercise (EX) and/or thyroid hormone (TH) could reduce brain damage in an experimental ischemic stroke in mice. Focal cerebral ischemia was induced under Laser Doppler Flowmetry (LDF) guide by 45 min of middle cerebral artery occlusion (MCAO), followed by 7 days of reperfusion in albino mice. BMSCs were injected into the right cerebral ventricle 24 h after MCAO, followed by daily injection of T3 (20 μg/100 g weight S.C) and 6 days of running on a treadmill. Infarct size, neurobehavioral test, TUNEL and BrdU positive cells were evaluated at 7 days after MCAO. Treatment with BMSCs and mild EX alone significantly reduced the infarct volume by 23% and 44%, respectively (both, p cells (a marker of apoptosis) was significantly reduced in the EX, BMSCs, BMSCs + EX, BMSCs + TH, and BMSCs + EX + TH groups (all, p cells in the subventricular zone (SVZ) (p cells and the attenuation of apoptosis in ischemia stroke in young mice.

Neuroprotective effect of safranal, an active ingredient of Crocus sativus , in a rat model of transient cerebral ischemia

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Hamid R. Sadeghnia

2017-09-01

Full Text Available Safranal is a monoterpene aldehyde found in saffron (Crocus sativus L. petals. It has been previously reported that safranal has a wide range of activities such as antioxidant and anti-inflammatory effects. In this study, we examined the effect of safranal on brain injuries in a transient model of focal cerebral ischemia. Transient focal cerebral ischemia was induced by middle cerebral artery occlusion for 30 min, followed by 24 h of reperfusion. Safranal in the doses of 72.5 and 145 mg/kg was administered intraperitoneally at 0, 3, and 6 h after reperfusion. Neurobehavioral deficit, infarct volume, hippocampal cell loss and markers of oxidative stress including thiobarbituric acid reactive substances (TBARS, total sulfhydryl (SH content, and antioxidant capacity (using FRAP assay were also assessed. The focal cerebral ischemia induced a significant increase in the neurological score, infarct volume and neuronal cell loss in the ipsilateral hippocampal CA1 and CA3 subfields (p < 0.001 and also oxidative stress markers (p < 0.01. Following safranal administration, the total SH content and antioxidant capacity significantly increased, while marked decreases were observed in the neurological score, infarct volume and hippocampal cell loss, as well as TBARS level. This study concluded that safranal had protective effects on ischemic reperfusion injury in the rat model of stroke. Such effects of safranal may have been exerted mainly by suppressing the production of free radicals and increasing antioxidant activity.

Effect of electroacupuncture on TRPM7 mRNA expression after cerebral ischemia/reperfusion in rats via TrkA pathway.

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Zhao, Li; Shi, Jing; Sun, Ning; Tian, Shunlian; Meng, Xianfang; Liu, Xiaochun; Li, Lingli

2005-01-01

The effect of electroacupuncture (EA) on TRPM7 mRNA expression of focal cerebral ischemia in rats and further the role of EA in the relationship between TRPM7 and trkA pathway was investigated. Thirty SD rats were randomly divided into 5 groups : normal group, ischemia/reperfusion group, EA treated group (ischemic rats with EA treatment), TE infusion group (ischemic rats with EA treatment and TE buffer infusion), AS-ODN group (ischemic rats with EA treatment and antisense trkA oligonucleotide infusion). The stroke animal model was established by the modified method of middle cerebral artery occlusion. Antisense trkA oligonucleotide that blocked NGFs effects was injected into cerebroventricle before EA. The TRPM7 mRNA was detected by RT-PCR method. The results showed that there were low TRPM7 mRNA levels in cortex and hippocampus in normal group. Compared with normal group, TRPM7 mRNA expression was increased significantly in ischemia/reperfusion group (PPM7 mRNA was found in EA treated group in contrast to ischemia/reperfusion group (P<0.05). The expression of TRPM7 mRNA in AS-ODN group was remarkably increased compared with EA treated group and TE infusion group (P<0.05). The results indicated that TRPM7 channels in the ischemic cortex and hippocampus in rats might play a key role in ischemic brain injury. EA could reverse the overexpression of TRPM7 in cerebral ischemia/reperfusion rats. And the inhibitory effect of EA on TRPM7 channels might be through trkA pathway.

Breviscapine confers a neuroprotective efficacy against transient focal cerebral ischemia by attenuating neuronal and astrocytic autophagy in the penumbra.

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Pengyue, Zhang; Tao, Guo; Hongyun, He; Liqiang, Yang; Yihao, Deng

2017-06-01

Breviscapine is a flavonoid derived from a traditional Chinese herb Erigerin breviscapus (Vant.) Hand-Mazz, and has been extensively used in clinical treatment for cerebral stroke in China, but the underlying pharmacological mechanisms are still unclear. In present study, we investigated whether breviscapine could confer a neuroprotection against cerebral ischemia injury by targeting autophagy mechanisms. A cerebral stroke model in Sprague-Dawley rats was prepared by middle cerebral artery occlusion (MCAO), rats were then randomly divided into 5 groups: MCAO+Bre group, rats were treated with breviscapine; MCAO+Tat-Beclin-1 group, animals were administrated with specific autophagy inducer Tat-Beclin-1; MCAO+Bre+Tat-Beclin-1 group, rats were treated with both breviscapine and Tat-Beclin-1, MCAO+saline group, rats received the same volume of physiological saline, and Sham surgery group. The autophagy levels in infarct penumbra were evaluated by western blotting, real-time PCR and immunofluorescence 7days after the insult. Meanwhile, infarct volume, brain water content and neurological deficit score were assessed. The results illustrated that the infarct volume, brain water content and neurofunctional deficiency were significantly reduced by 7days of breviscapine treatment in MCAO+Bre group, compared with those in MCAO+saline group. Meanwhile, the western blotting, quantitative PCR and immunofluorescence showed that the autophagy in both neurons and astrocytes at the penumbra were markedly attenuated by breviscapine admininstration. Moreover, these pharmacological effects of breviscapine could be counteracted by autophagy inducer Tat-Beclin-1. Our study suggests that breviscapine can provide a neuroprotection against transient focal cerebral ischemia, and this biological function is associated with attenuating autophagy in both neurons and astrocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

13-Methyltetradecanoic acid mitigates cerebral ischemia/reperfusion injury

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Juan Yu

2016-01-01

Full Text Available 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.

[Brain protection against cerebral ischemia].

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Kitagawa, Kazuo

2013-01-01

Previous clinical trials failed to show the benefit of several potentially protective drugs in acute ischemic stroke. However, there would be three main approaches for brain protection against stroke. The first is to develop a novel thrombolytic agent which is more efficient and safer than alteplase. Tenecteplase and desmoteplase are in progress as a new thrombolytic drug. The second strategy is to augment collateral circulation through leptomeningeal anastomosis. Administration of G-CSF could enhance arteriogenesis, but it takes several days to develop functional collateral. For this purpose, partial aortic balloon clumping or stimulation of pterygopalatine ganglion may be promising. The third one is to protect neurovascular unit against reperfusion injury. Brain hypothermia is the most effective strategy in experimental ischemia, and the clinical trial for hypothermia combined with thrombolysis therapy is in progress. Activation of endogenous protective response, as presented by ischemic tolerance, has focused on remote ischemic conditioning. Although the precise mechanisms of remote preconditioning remain unclear, intermittent limb ischemia is a safe approach. Remote ischemic conditioning is now investigated in acute patients with thrombolysis therapy.

CSF transthyretin neuroprotection in a mouse model of brain ischemia

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

2010-01-01

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

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

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Xiao-ge Yan

2015-01-01

Full Text Available 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.

Endothelin-1-induced focal cerebral ischemia in the growth hormone/IGF-1 deficient Lewis Dwarf rat.

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Yan, Han; Mitschelen, Matthew; Toth, Peter; Ashpole, Nicole M; Farley, Julie A; Hodges, Erik L; Warrington, Junie P; Han, Song; Fung, Kar-Ming; Csiszar, Anna; Ungvari, Zoltan; Sonntag, William E

2014-11-01

Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia. Published by Oxford University Press on behalf of the Gerontological Society of America 2014.

Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

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Zun-Jing Liu

2013-01-01

Full Text Available Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPARγ agonist in that it upregulated PPARγ expression and PPARγ-PPRE binding activity. Administration of curcumin markedly decreased the infarct volume, improved neurological deficits, and reduced neuronal damage of rats. In addition, curcumin suppressed neuroinflammatory response by decreasing inflammatory mediators, such as IL-1β, TNF-α, PGE2, NO, COX-2, and iNOS induced by cerebral ischemia of rats. Furthermore, curcumin suppressed IκB degradation that was caused by cerebral ischemia. The present data also showed that PPARγ interacted with NF-κB-p65 and thus inhibited NF-κB activation. All the above protective effects of curcumin on cerebral ischemic injury were markedly attenuated by GW9662, an inhibitor of PPARγ. Our results as described above suggested that PPARγ induced by curcumin may play a critical role in protecting against brain injury through suppression of inflammatory response. It also highlights the potential of curcumin as a therapeutic agent against cerebral ischemia.

Reperfusion promotes mitochondrial dysfunction following focal cerebral ischemia in rats.

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Jun Li

Full Text Available BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been implicated in the cell death observed after cerebral ischemia, and several mechanisms for this dysfunction have been proposed. Reperfusion after transient cerebral ischemia may cause continued and even more severe damage to the brain. Many lines of evidence have shown that mitochondria suffer severe damage in response to ischemic injury. The purpose of this study was to observe the features of mitochondrial dysfunction in isolated mitochondria during the reperfusion period following focal cerebral ischemia. METHODS: Male Wistar rats were subjected to focal cerebral ischemia. Mitochondria were isolated using Percoll density gradient centrifugation. The isolated mitochondria were fixed for electron microscopic examination; calcium-induced mitochondrial swelling was quantified using spectrophotometry. Cyclophilin D was detected by Western blotting. Fluorescent probes were used to selectively stain mitochondria to measure their membrane potential and to measure reactive oxidative species production using flow cytometric analysis. RESULTS: Signs of damage were observed in the mitochondrial morphology after exposure to reperfusion. The mitochondrial swelling induced by Ca(2+ increased gradually with the increasing calcium concentration, and this tendency was exacerbated as the reperfusion time was extended. Cyclophilin D protein expression peaked after 24 hours of reperfusion. The mitochondrial membrane potential was decreased significantly during the reperfusion period, with the greatest decrease observed after 24 hours of reperfusion. The surge in mitochondrial reactive oxidative species occurred after 2 hours of reperfusion and was maintained at a high level during the reperfusion period. CONCLUSIONS: Reperfusion following focal cerebral ischemia induced significant mitochondrial morphological damage and Ca(2+-induced mitochondrial swelling. The mechanism of this swelling may be mediated by

Male-female differences in upregulation of vasoconstrictor responses in human cerebral arteries

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Ahnstedt, Hilda; Cao, Lei; Krause, Diana N

2013-01-01

Male-female differences may significantly impact stroke prevention and treatment in men and women, however underlying mechanisms for sexual dimorphism in stroke are not understood. We previously found in males that cerebral ischemia upregulates contractile receptors in cerebral arteries, which...

Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia

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Argibay, Bárbara; Trekker, Jesse; Himmelreich, Uwe; Beiras, Andrés; Topete, Antonio; Taboada, Pablo; Pérez-Mato, María; Vieites-Prado, Alba; Iglesias-Rey, Ramón; Rivas, José; Planas, Anna M.; Sobrino, Tomás; Castillo, José; Campos, Francisco

2017-01-01

Mesenchymal stem cells (MSCs) are a promising clinical therapy for ischemic stroke. However, critical parameters, such as the most effective administration route, remain unclear. Intravenous (i.v.) and intraarterial (i.a.) delivery routes have yielded varied outcomes across studies, potentially due to the unknown MSCs distribution. We investigated whether MSCs reached the brain following i.a. or i.v. administration after transient cerebral ischemia in rats, and evaluated the therapeutic effects of both routes. MSCs were labeled with dextran-coated superparamagnetic nanoparticles for magnetic resonance imaging (MRI) cell tracking, transmission electron microscopy and immunohistological analysis. MSCs were found in the brain following i.a. but not i.v. administration. However, the i.a. route increased the risk of cerebral lesions and did not improve functional recovery. The i.v. delivery is safe but MCS do not reach the brain tissue, implying that treatment benefits observed for this route are not attributable to brain MCS engrafting after stroke.

MRI of experimental focal cerebral ischemia in sheep; MR-Bildgebung eines experimentellen Schlaganfallmodells beim Schaf

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Foerschler, A. [Universitaetsklinikum Leipzig (Germany). Klinik und Poliklinik fuer Diagnostische und Interventionelle Radiologie, Abt. fuer Neuroradiologie; Boltze, J. [Universitaetsklinikum Leipzig (Germany). Inst. fuer Klinische Immunologie und Transfusionsmedizin; Fraunhofer-Inst. fuer Zelltherapie und Immunologie (Germany); Waldmin, D. [Leipzig Univ. (Germany). Veterinaer-Anatomisches Inst.; Gille, U. [Fraunhofer-Inst. fuer Zelltherapie und Immunologie (Germany); Leipzig Univ. (Germany). Veterinaer-Anatomisches Inst.; Zimmer, C. [Technische Univ. Muenchen (Germany). Klinikum rechts der Isar, Abt. fuer Neuroradiologie

2007-05-15

Purpose: With respect to the specific characteristic of rete mirabile epidurale rostrale in sheep, the aim of this study was to investigate the use of time of flight (TOF) magnetic resonance angiography (MRA) to observe vascular anatomy and to validate MCA occlusion in a new model of experimental focal cerebral ischemia by permanent middle cerebral artery (MCA) occlusion in sheep (designed to study stroke therapy using autologous stem cells from umbilical cord blood). Furthermore, we wanted to assess the extent and natural time course of ischemic focal brain injury in sheep using functional and morphological magnetic resonance imaging (MRI). Materials and Method: 13 Merino sheep were examined. In 4 of the animals all, in 5 sheep 1 or 2 MCA branches were occluded and in 1 one case touched (sham operation). 4 controls did not undergo a surgical procedure. 23 MRI sessions were performed in 10 sheep. These sessions included T1, T2, T2{sup *} sequences, diffusion-weighted imaging (DWI) and TOF MRA before and 2 - 46 days after the onset of stroke using a 1.5T clinical MR scanner. Corrosion casts of the cerebral arteries of 3 sheep were prepared and compared to MRA. Results: The MRA visualized the vessel anatomy or occlusion distal to the rete mirabile. Anatomical variants concerning the variant origin of the MCA and inconstant arteria choroidea rostralis and communicans rostralis were revealed. Sheep with occluded left MCA showed space occupying lesions with a drop in ADC values. Depending on the number of preserved MCA branches (0; 1; 2), highly significant (p < 0.001) differences in lesion size (21 {+-} 5.7; 13; 1.7 {+-} 1.3 ml) could be found. No indication of ischemia but minimal contusion damage was observed in the sham operated animal. (orig.)

A comparison study of PET, NMR, and CT imaging in cerebral ischemia

International Nuclear Information System (INIS)

Babikian, V.L.; Ford, C.S.; Buonanno, F.S.; Kistler, J.P.; Ackerman, R.H.; Alpert, N.M.; Correia, J.A.; Johnson, K.A.; Buxton, R.B.

1987-01-01

Whether ischemia without infarction produces recognizable changes in relaxation times of ischemic but viable brain is an important, unresolved issue. Therefore, a study was initiated of patients with cerebral ischemia, using positron emission tomography (PET), NMR, and computed tomography (CT) to compare and contrast the pathophysiologic information provided by each and to study the issue of whether cerebral ischemia without infarction can be appreciated by proton NMR imaging. Here the initial results are reported. 4 refs.; 2 figs.; 1 table

Recurrent cerebral thrombosis

International Nuclear Information System (INIS)

Iwamoto, Toshihiko; Abe, Shin-e; Kubo, Hideki; Hanyu, Haruo; Takasaki, Masaru

1992-01-01

Neuroradiological techniques were used to elucidate pathophysiology of recurrent cerebral thrombosis. Twenty-two patients with cerebral thrombosis who suffered a second attack under stable conditions more than 22 days after the initial stroke were studied. Hypertension, diabetes mellitus, and hypercholesterolemia were also seen in 20, 8, and 12 patients, respectively. The patients were divided into three groups according to their symptoms: (I) symptoms differed between the first and second strokes (n=12); (II) initial symptoms were suddenly deteriorated (n=6); and (III) symptoms occurring in groups I and II were seen (n=4). In group I, contralateral hemiparesis or suprabulbar palsy was often associated with the initial hemiparesis. The time of recurrent stroke varied from 4 months to 9 years. CT and MRI showed not only lacunae in both hemispheres, but also deep white-matter ischemia of the centrum semi-ovale. In group II, hemiparesis or visual field defect was deteriorated early after the initial stroke. In addition, neuroimaging revealed that infarction in the posterior cerebral artery was progressed on the contralateral side, or that white matter lesion in the middle artery was enlarged in spite of small lesion in the left cerebral hemisphere. All patients in group III had deterioration of right hemiparesis associated with aphasia. CT, MRI, SPECT, and angiography indicated deep white-matter ischemia caused by main trunk lesions in the left hemisphere. Group III seemed to be equivalent to group II, except for laterality of the lesion. Neuroradiological assessment of the initial stroke may help to predict the mode of recurrence, although pathophysiology of cerebral thrombosis is complicated and varies from patient to patient. (N.K.)

Analysis of arterial pressure variability in patients with acute cerebral stroke depending on the time of occurrence

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Volosovets A.O.

2017-12-01

Full Text Available Arterial hypertension can cause a pronounced negative influence on the state of the cerebral vascular system and lead to significant microtraumatization of the walls of the vessels and disruption of vascular autoregulation. This predictor has the greatest influence on the onset of ischemic stroke of atherothrombotic and lacunar subtypes, however, hypertension occurs almost in all patients with acute cerebral ischemia. Interesting and not at all presented in modern scientific literature is the question of the relationship of oscillation of blood pressure with the period of the onset of the focus of ischemia, which predetermined the purpose of our work. The purpose of our study was to determine the relationship between deformation of the profile of fluctuations in blood pressure of patients in the acute period of ischemic stroke, depending on the time of the occurrence of cerebrovascular accident. We examined 300 patients who suffered acute ischemic stroke (men - 196, women - 104 aged 42 to 84 years (average age - 65.2 ± 8.7 years. All patients were divided into 3 groups according to the period of the day when an ischemic stroke occurred: 1 group (n=146, patients suffering from cerebral ischemia during the day (8.00-14.59; In group 2 (n=107, patients stroke was observed in the evening (15.00-21.59; Group 3 (n=47, patients had an ischemic stroke at night (22.00-7.59. For the 1st group of patients who have had ischemic stroke during the day and as a rule with an increase in blood pressure, a marked increase in blood pressure was at 12.00 and 15.00 and a tendency towards compensatory parasympathetic effect in the form of blood pressure decrease at night (over-dipper was typical. At the same time, in the 2nd group of patients with stroke in the evening, elevated blood pressure at 18.00 and 21.00 and parasympathetic activity disorders with prevalence of insufficient reduction of blood pressure in the evening and during sleep (non-dipper was observed

Is chlormethiazole neuroprotective in experimental global cerebral ischemia? A microdialysis and behavioral study.

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Thaminy, S; Reymann, J M; Heresbach, N; Allain, H; Lechat, P; Bentué-Ferrer, D

1997-04-01

Chlormethiazole, an anticonvulsive agent, has been shown to have a possible neuroprotective effect against cerebral ischemia. In addition, chlormethiazole inhibits methamphetamine-induced release of dopamine, protecting against this neurotransmitter's neurotoxicity. The aim of this work was to ascertain whether, in experimental cerebral ischemia, chlormethiazole administration attenuated the ischemia-induced rise of the extracellular concentration of aminergic neurotransmitters and whether it reduces ischemia-induced deficits in memory and learning. Histology for assessment of ischemic damage was a so included. The four-vessel occlusion rat model was used to induce global cerebral ischemia. Aminergic neurotransmitters and their metabolites in the striatal extracellular fluid obtained by microdialysis were assayed by high-performance liquid chromatography-electrochemical detection. The drug was administered either IP (50 mg/kg-1) or directly through the dialysis probe (30 microM) 80 min before ischemia. For the behavioral test and histology, the drug was given IP (100 mg/kg-1) 1 h postischemia. The results obtained did not demonstrate any statistically significant evidence that chlormethiazole has an effect on the ischemia-induced rise in extracellular dopamine and serotonin levels. There was also no variation in metabolite levels. Behavioral measures (learning, recall) were not changed appreciably by the treatment. We observed no significant cell protection in the hippocampus (CA1, CA1), striatum, and entorhinal cortex in animals treated with chlormethiazole. We conclude that, under our experimental conditions, chlormethiazole has little or no effect on the neurochemical, neurobehavioral, and histological consequences of global cerebral ischemia.

PET imaging of cerebral perfusion and oxygen consumption in acute ischemic stroke: Relation to outcome

International Nuclear Information System (INIS)

Marchal, G.; Serrati, C.; Rioux, P.; Petit-Taboue, M.C.; Viader, F.; Sayette, V. de la; Doze, F. le; Lonchon, P; Derlon, J.M.; Orgogozo, J.M.; Baron, J.C.

1993-01-01

The authors used positron emission tomography (PET) to assess the relation between combined imaging of cerebral blood flow and oxygen consumption 5-18 h after first middle cerebral artery (MCA) stroke and neurological outcome at 2 months. All 18 patients could be classified into three visually defined PET patterns of perfusion and oxygen consumption changes. Pattern 1 suggested extensive irreversible damage and was consistently associated with poor outcome. Pattern 2 suggested continuing ischemia and was associated with variable outcome. Pattern 3 with hyperperfusion and little or no metabolic alteration, was associated with excellent recovery, which suggests that early reperfusion is beneficial. This relation between PET and outcome was highly significant. The results suggest that within 5-18 h of stroke onset, PET is a good predictor of outcome in patterns 1 and 3, for which therapy seems limited. The absence of predictive value for pattern 2 suggests that it is due to a reversible ischemic state that is possibly amenable to therapy. These findings may have important implications for acute MCA stroke management and for patients' selection for therapeutic trials

Radiologic manifestations of focal cerebral hyperemia in acute stroke

DEFF Research Database (Denmark)

Olsen, Tom Skyhøj; Skriver, E B; Herning, M

1991-01-01

In 16 acute stroke patients with focal cerebral hyperemia angiography and regional cerebral blood flow (rCBF) were studied 1 to 4 days post stroke. CT was performed twice with and without contrast enhancement 3 +/- 1 days and 16 +/- 4 days post stroke. Angiographic evidence of focal cerebral hype...

Adoptive regulatory T-cell therapy preserves systemic immune homeostasis after cerebral ischemia.

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Li, Peiying; Mao, Leilei; Zhou, Guoqing; Leak, Rehana K; Sun, Bao-Liang; Chen, Jun; Hu, Xiaoming

2013-12-01

Cerebral ischemia has been shown to result in peripheral inflammatory responses followed by long-lasting immunosuppression. Our recent study demonstrated that intravenous delivery of regulatory T cells (Tregs) markedly protected against transient cerebral ischemia by suppressing neutrophil-derived matrix metallopeptidase 9 production in the periphery. However, the effect of Tregs on systemic inflammatory responses and immune status has not been fully characterized. Cerebral ischemia was induced by middle cerebral artery occlusion for 60 minutes in mice or 120 minutes in rats. Tregs were isolated from donor animals by CD4 and CD25 double selection and transferred intravenously to ischemic recipients at 2 hours after middle cerebral artery occlusion. Animals were euthanized on different days after reperfusion. The effects of Tregs on systemic inflammation and immune status were evaluated using flow cytometry, ELISAs, and immunohistochemistry. Systemic administration of purified Tregs raises functional Tregs in the blood and peripheral organs, including spleen and lymph nodes. These exogenous Tregs remain in the blood and peripheral organs for ≥12 days. Functionally, Treg adoptive transfer markedly inhibits middle cerebral artery occlusion-induced elevation of inflammatory cytokines (interleukin-6 and tumor necrosis factor α) in the blood. Furthermore, Treg treatment corrects long-term lymphopenia and improves cellular immune functions after ischemic brain injury. As a result, Treg-treated animals exhibit decreased bacterial loads in the blood during recovery from cerebral ischemic attack. Treg treatment did not exacerbate poststroke immunosuppression. On the contrary, Treg-treated animals displayed improved immune status after focal cerebral ischemia.

Endogenous IFN-β signaling exerts anti-inflammatory actions in experimentally induced focal cerebral ischemia

DEFF Research Database (Denmark)

Inácio, Ana R; Liu, Yawei; Clausen, Bettina H

2015-01-01

of infiltrating leukocytes in the brain 2 days after stroke. Concomitantly, in the blood of IFN-βKO mice, we found a higher percentage of total B cells but a similar percentage of mature and activated B cells, collectively indicating a higher proliferation rate. The additional differential regulation......BACKGROUND: Interferon (IFN)-β exerts anti-inflammatory effects, coupled to remarkable neurological improvements in multiple sclerosis, a neuroinflammatory condition of the central nervous system. Analogously, it has been hypothesized that IFN-β, by limiting inflammation, decreases neuronal death...... strength tests, and cerebral infarct volumes were given by lack of neuronal nuclei immunoreactivity. RESULTS: Here, we report alterations in local and systemic inflammation in IFN-β knockout (IFN-βKO) mice over 8 days after induction of focal cerebral ischemia. Notably, IFN-βKO mice showed a higher number...

Determining Optimal Post-Stroke Exercise (DOSE)

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2018-02-13

Cerebrovascular Accident; Stroke; Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

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

Science.gov (United States)

Garry, Payashi S; Rowland, Matthew J; Ezra, Martyn; Herigstad, Mari; Hayen, Anja; Sleigh, Jamie W; Westbrook, Jon; Warnaby, Catherine E; Pattinson, Kyle T S

2016-11-01

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. Unblinded pilot study testing response to drug intervention. Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom. Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41-69 yr]; 11 women). IV sodium nitrite (10 μg/kg/min) for 1 hour. 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 frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to -31%) (p = 0.006, multivariate analysis accounting for major confounds). 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.

[Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction].

Science.gov (United States)

Litvinov, A A; Volotova, E V; Kurkin, D V; Logvinova, E O; Darmanyan, A P; Tyurenkov, I N

2017-01-01

To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

Aerobic exercise combined with huwentoxin-I mitigates chronic cerebral ischemia injury

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Hai-feng Mao

2017-01-01

Full Text Available Ca2+ channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I (HWTX-I, a spider peptide toxin that blocks Ca2+ channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I + aerobic exercise group. The combined effects of HWTX-I and exercise were superior to HWTX-I or aerobic exercise alone. HWTX-I effectively activated the Notch signal transduction pathway in brain tissue. Aerobic exercise up-regulated synaptophysin mRNA expression. These results demonstrated that aerobic exercise, in combination with HWTX-I, effectively relieved neuronal injury induced by chronic cerebral ischemia via the Notch signaling pathway and promoting synaptic regeneration.

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

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Xiaoli Yan

2017-03-01

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

Protective effect of estrogen in endothelin-induced middle cerebral artery occlusion in female rats.

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Glendenning, Michele L; Lovekamp-Swan, Tara; Schreihofer, Derek A

2008-11-14

Estrogen is a powerful endogenous and exogenous neuroprotective agent in animal models of brain injury, including focal cerebral ischemia. Although this protection has been demonstrated in several different treatment and injury paradigms, it has not been demonstrated in focal cerebral ischemia induced by intraparenchymal endothelin-1 injection, a model with many advantages over other models of experimental focal ischemia. Reproductively mature female Sprague-Dawley rats were ovariectomized and divided into placebo and estradiol-treated groups. Two weeks later, halothane-anesthetized rats underwent middle cerebral artery (MCA) occlusion by interparenchymal stereotactic injection of the potent vasoconstrictor endothelin 1 (180pmoles/2microl) near the middle cerebral artery. Laser-Doppler flowmetry (LDF) revealed similar reductions in cerebral blood flow in both groups. Animals were behaviorally evaluated before, and 2 days after, stroke induction, and infarct size was evaluated. In agreement with other models, estrogen treatment significantly reduced infarct size evaluated by both TTC and Fluoro-Jade staining and behavioral deficits associated with stroke. Stroke size was significantly correlated with LDF in both groups, suggesting that cranial perfusion measures can enhance success in this model.

Chinese medicines and bioactive compounds for treatment of stroke.

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Jayakumar, Thanasekaran; Elizebeth, Antoinet Ramola; Yen, Ting-lin; Sheu, Joen-rong

2015-02-01

Stroke is an important cause of mortality and morbidity worldwide but effective therapeutic strategy for the prevention of brain injury in patients with cerebral ischemia is lacking. Although tissue plasminogen activator has been used to treat stroke patients, this therapeutic strategy is confronted with ill side effects and is limited to patients within 3 h of a stroke. Due to the complexity of the events and the disappointing results from single agent trials, the combination of thrombolytic therapy and effective neural protection therapy may be an alternative strategy for patients with cerebral ischemia. Chinese medicine (CM) is the most widely practiced form of herbalism worldwide, as it is a sophisticated system of medical theory and practice that is specifically different from Western medicine. Most traditional therapeutic formulations consist of a combination of several drugs. The combination of multiple drugs is thought to maximize therapeutic efficacy by facilitating synergistic actions and preventing possible adverse effects while at the same time marking at multiple targets. CM has been labeled in ancient medicine systems as a treatment for various diseases associated with stroke. This review summarizes various CMs, bioactive compounds and their effects on cerebral ischemia.

Effects of dexmedetomidine on microregional O2 balance during reperfusion after focal cerebral ischemia.

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Chi, Oak Z; Grayson, Jeremy; Barsoum, Sylviana; Liu, Xia; Dinani, Aliraza; Weiss, Harvey R

2015-01-01

This study was performed to determine whether there is an association between microregional O2 balance and neuronal survival in cerebral ischemia-reperfusion using dexmedetomidine, an α2-adrenoreceptor agonist and a sedative. Rats were subjected to 1 hour middle cerebral artery occlusion and a 2-hour reperfusion. During reperfusion, normal saline (n = 14) or dexmedetomidine 1 μg/kg/minute (n = 14) was infused intravenously. At 2 hours of reperfusion, regional cerebral blood flow using (14)C-iodoantipyrine autoradiography, microregional arterial and venous (20-60 μm in diameter) O2 saturation (SvO2) using cryomicrospectrophotometry, and the size of cortical infarction were determined. Ischemia-reperfusion decreased microregional SvO2 (52.9 ± 3.7% vs. 61.1 ± .6%, P < .005) with increased variation or heterogeneity (P < .0001) with similar regional cerebral blood flow and O2 consumption. Dexmedetomidine during reperfusion decreased the heterogeneity of SvO2 that was analyzed with an analysis of variance (P < .01) and reported as coefficient of variation (100 × standard deviation/Mean) (11.8 vs. 16.4). The number of veins with O2 saturation less than 50% decreased with dexmedetomidine (13/80 vs. 27/81, P < .01). The percentage of cortical infarct in total cortex was smaller with dexmedetomidine (8.3 ± 2.2% vs. 12.6 ± 1.5%, P < .005). In the cerebral ischemic reperfused cortex, dexmedetomidine decreased the heterogeneity of SvO2 and the number of small veins with low O2 saturation suggesting improved microregional O2 supply/consumption balance. The improvement was accompanied by the reduced size of cortical infarction. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Clinical aspects and characteristics of the course of Parkinson’s disease with chronic cerebral ischemia

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Voskresenskaya O.N.

2012-06-01

Full Text Available

The article is devoted characteristics current of Parkinson’s disease with chronic cerebral ischemia. Objective: to study the clinical presentation and features of PD against cerebral ischemia. Methods. A total of 44 patients with a diagnosis of “Parkinson’s disease”, 20 of which were determined by accurate clinical and instrumental signs of chronic cerebral ischemia. Comparative characteristics of the neurological status, cognitive functions, some laboratory and instrumental data in the two groups of patients: Parkinson’s disease with a background of chronic ischemia of the brain and without it. Results. Statistically signifcant differences between groups are observed on the following variables: duration of illness, severity of depression, the concentration of glucose in the blood. Formed groups of signifcant difference in the severity of atherosclerosis of cerebral vessels. Conclusion. The data of the acceleration of the progression of Parkinson’s disease with chronic cerebral ischemia, as well as the more frequent occurrence of depression in this patient group.

Prediction of cerebral ischemia due to cerebral vasospasm in SAH using SPECT and 123I-IMP with acetazolamide test

International Nuclear Information System (INIS)

Nakagawara, Jyoji; Wada, Keiji; Takeda, Rihei; Usami, Takashi; Hashimoto, Ikuo; Shimazaki, Mitsuteru; Tanaka, Chiharu; Nakamura, Jun-ichi; Suematsu, Katsumi.

1989-01-01

To investigate the possibility of predicting cerebral ischemia due to cerebral vasospasm in subarachnoid hemorrhage (SAH), serial evaluation of the cerebral vasodilatory capacity by the acetazolamide test was conducted, using single photon emission computed tomography (SPECT) and N-isopropyl 123 I-p-iodoamphetamine (IMP), in 17 patients with cerebral vasospasm following early surgery for ruptured aneurysms. The degree of vasospasm measured on the angiograms was classified into the following three types; mild degree (25%>stenosis), moderate degree (25∼50% stenosis), and severe degree(50%cerebral vasodilatory capacity was preserved at the normal level during the period of vasospasm. In eight patients with asymptomatic vasospasm (moderate degree), a transient limitation of cerebral vasodiratory capacity was observed between the 6th and 16th day after a rupture of the cerebral aneurysm. In five patients with symptomatic vasospasm resulting in reversible ischemia, a marked limitation of cerebral vasodilatory capacity was noted between the 7th and 15th day, and a delayed recovery of cerebral vasodilatory capacity was observed. This reversibility of cerebral vasodilatory capacity in patients with cerebral vasospasm suggests that a local decrease of purfusion pressure due to cerebral vasospasm causes compensatory vasodilation of intraparenchymal arteries and the vasodilatory reaction to acetazolamide was limited until the release of the cerebral vasospasm. Therefore, assessment of cerebral vasodilatory capacity in SAH by the acetazolamide test might predict the appearance and continuation of potential ischemia of the brain caused by the reduction of perfusion pressure due to cerebral vasospasm. (J.P.N.)

Focal ischemia of the brain after neuroprotected carotid artery stenting.

Science.gov (United States)

Schlüter, Michael; Tübler, Thilo; Steffens, Johann C; Mathey, Detlef G; Schofer, Joachim

2003-09-17

This study sought to assess the incidence of cerebral ischemia in nonselected patients undergoing neuroprotected carotid angioplasty and stenting (CAS) without preceding multiple-vessel diagnostic angiography. Protection devices to prevent distal embolization during CAS are presently under clinical investigation. Diffusion-weighted magnetic resonance imaging (MRI) visualizes recent ischemia of the brain and may aid in assessing the efficacy of protection devices. Elective CAS was performed in 42 consecutive patients (15 female, 27 male; mean age, 67 +/- 9 years) using six different types of cerebral protection systems. All patients underwent MRI of the brain before and after a total of 44 interventions. Placement and retrieval of the devices and stent deployment was achieved in all procedures. New ischemic foci were seen on postinterventional MRI in 10 cases (22.7%). One patient had sustained a major stroke, whereas no adverse neurological sequelae were associated with the other nine procedures. In the latter, one to three foci (maximum area 43.0 mm(2)) were detected in cerebral regions subtended by the ipsilateral carotid artery in eight cases and by the contralateral carotid artery in one case. In the stroke patient, 12 ischemic foci (maximum area 84.5 mm(2)) were exclusively located in the contralateral hemisphere. Follow-up MRI at 4.1 months (median, n = 7) identified residuals of cerebral ischemia only in this patient. Neuroprotected CAS is associated in about 25% of cases with predominantly silent cerebral ischemia. Our findings suggest manipulation of endoluminal equipment in the supraaortic vessels to be a major risk factor for cerebral embolism during neuroprotected CAS.

Hemopexin induces neuroprotection in the rat subjected to focal cerebral ischemia

OpenAIRE

Dong, Beibei; Cai, Min; Fang, Zongping; Wei, Haidong; Zhu, Fangyun; Li, Guochao; Dong, Hailong; Xiong, Lize

2013-01-01

Background The plasma protein hemopexin (HPX) exhibits the highest binding affinity to free heme. In vitro experiments and gene-knock out technique have suggested that HPX may have a neuroprotective effect. However, the expression of HPX in the brain was not well elucidated and its expression after cerebral ischemia-reperfusion injury was also poorly studied. Furthermore, no in vivo data were available on the effect of HPX given centrally on the prognosis of focal cerebral ischemia. Results I...

Diagnosis of hemodynamic compromise in patients with chronic cerebral ischemia

International Nuclear Information System (INIS)

Kuroda, Satoshi; Sakuragi, Mitsugi; Motomiya, Mineo; Nakagawa, Tango; Mitsumori, Kenji; Tsuru, Mitsuo; Takigawa, Shugo; Kamiyama, Hiroyasu; Abe, Hiroshi.

1990-01-01

Tests using 133 Xe inhalation method and single photon emission computed tomography (SPECT) with acetazolamide (Diamox) were performed in 23 patients with chronic cerebral ischemia, before and after extracranial-intracranial bypass surgery or carotid-endarterectomy. All patients complained of TIA, RIND, or minor completed stroke. Cerebral angiography demonstrated severe stenosis or occlusion in the ipsilateral internal carotid artery or middle cerebral artery. Cerebral blood flow (CBF) was measured with 133 Xe SPECT, and was measured 15 minutes after intravenous administration of 10-12 mg/kg Diamox, which is known as a cerebral vasodilatory agent (Diamox test). Our results revealed that all patients could be divided into four types according to their resting rCBF and Diamox reactivity. The patients who had normal resting rCBF and normal Diamox reactivity (type 1) were considered to have well-developed collateral circulation and normal cerebral perfusion pressure (CPP) in spite of severe occlusive lesions in the carotid system. Moderate vasodilation due to reduced CPP was considered to occur in patients who had normal resting rCBF and decreased Diamox reactivity (type 2). The resting rCBF remained unchanged, but Diamox reactivity improved to normal after surgery in the patients of type 2, which indicated the improvement of CPP and the resolution of the autoregulatory vasodilation. Maximum vasodilation or dysautoregulation was considered to occur due to the inadequate collateral flow and the severely reduced CPP in patients whose findings revealed decrease in the resting rCBF and impaired Diamox reactivity (type 3). Remarkable improvement was seen in both resting rCBF and Diamox reactivity after surgery in the patients of type 3. In the patients who had decreased resting rCBF and normal Diamox reactivity (type 4), the decreased resting rCBF was considered to result from the reduction in metabolic demand because of irreversible ischemic neuronal damage. (J.P.N.)

Developmental Status of Translational Medicine on Cerebral Stroke

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Yun-chuan WU

2016-12-01

Full Text Available Translational medicine, as a new research theory and disciplinary branch, aims at the translation from bench to bedside. It can shorten the gap between basic scientific research and clinical treatment, and promote the highly efficient application of basic research results in clinical practice through bidirectional connection and feedback process between them. Cerebral stroke, as a common cerebrovascular circulatory disorder in clinic, is characterized by high morbidity, high disability rate and high mortality. After disease onset, patients are frequently complicated with severe functional disorders and sequelae, such as aphasia, paralysis, and partial or complete loss of self-care capacity, thus bringing about great burdens to the patients’ families and to the society. In China, there are more than 2 000 000 new cases with cerebral stroke annually, > 50% of whom are complicated with different-degree neurological functional decrease or deletion, and more than 1 000 000 die of cerebral stroke annually. Therefore, cerebral stroke is also an important concern in translational medicine study. In recent years, International Stroke Conference has emphasized the necessity of translational medicine research, and the bidirectional translation of bench to bedside (B2B is of great significance in guiding the development of depth and width of translational medicine on stroke. This study mainly reviewed the advances of translational medicine at home and abroad and its significance in guiding the clinical treatment of cerebral stroke.

Protective effects of geniposide and ginsenoside Rg1 combination treatment on rats following cerebral ischemia are mediated via microglial microRNA‑155‑5p inhibition.

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Wang, Jun; Li, Dan; Hou, Jincai; Lei, Hongtao

2018-02-01

Geniposide, an active component of Gardenia, has been reported to protect against cerebral ischemia in animals. Ginsenoside Rg1, a component of Panax notoginseng, is usually administered in combination with Gardenia for the treatment of acute ischemic stroke; however, there are unknown effects of ginsenoside Rg1 that require further investigation. In the present study, the effects of geniposide and ginsensoide Rg1 combination treatment on focal cerebral ischemic stroke were investigated. For in vivo analysis, male rats were separated into three groups, including the (control), model and geniposide + ginsenoside Rg1 groups (n=8 per group). A middle cerebral artery occlusion model was established as the model group. The treatment group was treated with geniposide (30 mg/kg, tail vein injection) + ginsenoside Rg1 (6 mg/kg, tail vein injection), and the model group received saline instead. Neurobehavioral deficits, infarct volume, brain edema, and the expression of microRNA (miR)‑155‑5p and CD11b by reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry, were assessed following 24 h of ischemia. For in vitro analysis, BV2 mouse microglial cells were cultured and exposed to geniposide (40 µg/ml) + ginsenoside Rg1 (8 µg/ml) during various durations of oxygen‑glucose deprivation (OGD). The expression levels of miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 were detected by RT‑qPCR. The results demonstrated that increases in brain infarct volume, edema volume, CD11b‑positive cells and miR‑155‑5p levels were alleviated following geniposide + ginsenoside administration in rats exposed to ischemia. Furthermore, geniposide + ginsenoside Rg1 treatment suppressed the miR‑155‑5p, pri‑miR‑155 and pre‑miR‑155 expression levels in OGD‑injured BV2 microglial cells. The results of the present study demonstrated that tail vein administration of geniposide in combination with ginsenoside Rg1

Attenuation of Cerebral Ischemic Injury in Smad1 Deficient Mice.

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Jamie K Wong

Full Text Available Stroke results in brain tissue damage from ischemia and oxidative stress. Molecular regulators of the protective versus deleterious cellular responses after cerebral ischemia remain to be identified. Here, we show that deletion of Smad1, a conserved transcription factor that mediates canonical bone morphogenetic protein (BMP signaling, results in neuroprotection in an ischemia-reperfusion (I/R stroke model. Uninjured mice with conditional deletion of Smad1 in the CNS (Smad1 cKO displayed upregulation of the reactive astrocyte marker GFAP and hypertrophic morphological changes in astrocytes compared to littermate controls. Additionally, cultured Smad1(-/- astrocytes exhibited an enhanced antioxidant capacity. When subjected to I/R injury by transient middle cerebral artery occlusion (tMCAO, Smad1 cKO mice showed enhanced neuronal survival and improved neurological recovery at 7 days post-stroke. This neuroprotective phenotype is associated with attenuated reactive astrocytosis and neuroinflammation, along with reductions in oxidative stress, p53 induction, and apoptosis. Our data suggest that Smad1-mediated signaling pathway is involved in stroke pathophysiology and may present a new potential target for stroke therapy.

Transplanted Dental Pulp Stem Cells Migrate to Injured Area and Express Neural Markers in a Rat Model of Cerebral Ischemia.

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Zhang, Xuemei; Zhou, Yinglian; Li, Hulun; Wang, Rui; Yang, Dan; Li, Bing; Cao, Xiaofang; Fu, Jin

2018-01-01

Ischemic stroke is a major cause of disability and mortality worldwide, while effective restorative treatments are limited at present. Stem cell transplantation holds therapeutic potential for ischemic vascular diseases and may provide an opportunity for neural regeneration. Dental pulp stem cells (DPSCs) origin from neural crest and have neuro-ectodermal features including proliferation and multilineage differentiation potentials. The rat model of middle cerebral artery occlusion (MCAO) was used to evaluate whether intravenous administration of DPSCs can reduce infarct size and to estimate the migration and trans-differentiation into neuron-like cells in focal cerebral ischemia models. Brain tissues were collected at 4 weeks following cell transplantation and analyzed with immunofluorescence, immunohistochemistry and real-time polymerase chain reaction (RT-PCR) methods. Intravenously administration of rat-derived DPSCs were found to migrate into the boundary of ischemic areas and expressed neural specific markers, reducing infarct volume and cerebral edema. These results suggest that DPSCs treatment may serve as a potential therapy for clinical stroke patients in the future. © 2018 The Author(s). Published by S. Karger AG, Basel.

MR of experimental cerebral ischemia

International Nuclear Information System (INIS)

DeLaPaz, R.; Steinberg, G.; Rocklage, S.; Glover, G.H.

1990-01-01

This paper reports on MR imaging of cerebral ischemia and treatment with N-methyl-D-aspartate (NMDA) antagonists in an animal model. Forty-four New Zealand white rabbits underwent 1-hour transorbital ICA-MCA-ACA occlusion and pretreatment or immediate posttreatment with systemic dextromethorphan (DM, n = 14), dextrorphan (DX, n = 14), or normal saline (NS, n = 16). Serial MR studies (1.5 T) were performed 1--6 hours after occlusion with T1- and T2-weighted spinecho, IVIM (b = 1,352), gradient recalled acquisition in a steady-state, and chemical shift sequences (for magnetic susceptibility, T2* and T2') and DyDTPA-BMA intravenous contrast material (Salutar). Spatial correlation between MR findings, histologic findings (ischemic neuronal damage), and regional cerebral blood flow (microspheres) was done

Effect of Panax notoginseng saponins on the content of IL-8 in serum after cerebral ischemia-reperfusion in rat

International Nuclear Information System (INIS)

He Wei; Zhu Zunping

2002-01-01

Objective: To investigate the effect of Panax notoginseng saponins (Pns) against cerebral ischemia-reperfusion injury. Methods: Focal cerebral ischemia-reperal ischemia-reperfusion model in rat was established by occlusion the middle cerebral artery for 2 h, after 3 h reperfusion. The serum concentration of IL-8 was detected with radioimmunoassay (RIA). Results: Png 50 mg·kg -1 ip, qd x 7d before MCAO decreased the serum content of IL-8 after ischemia-reperfusion. Conclusion: Pns has protective effect against cerebral ischemia-reperfusion injury by decreased the serum content of IL-8

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

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

2015-09-15

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

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

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Yaqian Zhao

2016-07-01

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

Prediction of cerebral ischemia due to cerebral vasospasm in SAH using SPECT and sup 123 I-IMP with acetazolamide test

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Nakagawara, Jyoji; Wada, Keiji; Takeda, Rihei; Usami, Takashi; Hashimoto, Ikuo; Shimazaki, Mitsuteru; Tanaka, Chiharu; Nakamura, Jun-ichi (Nakamura Memorial Hospital, Sapporo (Japan)); Suematsu, Katsumi

1989-11-01

To investigate the possibility of predicting cerebral ischemia due to cerebral vasospasm in subarachnoid hemorrhage (SAH), serial evaluation of the cerebral vasodilatory capacity by the acetazolamide test was conducted, using single photon emission computed tomography (SPECT) and N-isopropyl {sup 123}I-p-iodoamphetamine (IMP), in 17 patients with cerebral vasospasm following early surgery for ruptured aneurysms. The degree of vasospasm measured on the angiograms was classified into the following three types; mild degree (25%>stenosis), moderate degree (25{approx}50% stenosis), and severe degree(50%cerebral vasodilatory capacity was preserved at the normal level during the period of vasospasm. In eight patients with asymptomatic vasospasm (moderate degree), a transient limitation of cerebral vasodiratory capacity was observed between the 6th and 16th day after a rupture of the cerebral aneurysm. In five patients with symptomatic vasospasm resulting in reversible ischemia, a marked limitation of cerebral vasodilatory capacity was noted between the 7th and 15th day, and a delayed recovery of cerebral vasodilatory capacity was observed. This reversibility of cerebral vasodilatory capacity in patients with cerebral vasospasm suggests that a local decrease of purfusion pressure due to cerebral vasospasm causes compensatory vasodilation of intraparenchymal arteries and the vasodilatory reaction to acetazolamide was limited until the release of the cerebral vasospasm. Therefore, assessment of cerebral vasodilatory capacity in SAH by the acetazolamide test might predict the appearance and continuation of potential ischemia of the brain caused by the reduction of perfusion pressure due to cerebral vasospasm. (J.P.N.).

Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model

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Yisong Qian

2016-08-01

Full Text Available Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC staining, neuronal damage was assessed by Haematoxylin Eosin (H&E staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.

Neuroprotection by Combined Administration with Maslinic Acid, a Natural Product from Olea europaea, and MK-801 in the Cerebral Ischemia Model.

Science.gov (United States)

Qian, Yisong; Tang, Xuzhen; Guan, Teng; Li, Yunman; Sun, Hongbin

2016-08-19

Glutamate-mediated excitotoxicity is a major cause of ischemic brain damage. MK-801 confers neuroprotection by attenuating the activation of the N-methyl-d-aspartate (NMDA) receptor, but it failed in clinical use due to the short therapeutic window. Here we aim to investigate the effects of maslinic acid, a natural product from Olea europaea, on the therapeutic time window and dose range for the neuroprotection of MK-801. Rats were administered with maslinic acid intracerebroventricularly and cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) followed by reperfusion. MK-801 was administered at 1 h, 2 h, 3 h and 4 h after ischemia, respectively. The cerebral infarct volume was determined by 2,3,5-Triphenyltetrazolium chloride (TTC) staining, neuronal damage was assessed by Haematoxylin Eosin (H&E) staining, and the expression of glial glutamate transporters and glial fibrillary acidic protein (GFAP) was evaluated by immunohistochemistry and Western blot post-ischemia. Results showed that the presence of maslinic acid extended the therapeutic time window for MK-801 from 1 h to 3 h. Co-treatment of maslinic acid and MK-801 at a subthreshold dosage obviously induced neuroprotection after ischemia. The combination of these two compounds improved the outcome in ischemic rats. Moreover, maslinic acid treatment promoted the expression of GLT-1 and GFAP post-ischemia. These data suggest that the synergistic effect of maslinic acid on neurological protection might be associated with the improvement of glial function, especially with the increased expression of GLT-1. The combination therapy of maslinic acid and MK-801 may prove to be a potential strategy for treating acute ischemic stroke.

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

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

2015-01-01

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

Glatiramer Acetate administration does not reduce damage after cerebral ischemia in mice.

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Poittevin, Marine; Deroide, Nicolas; Azibani, Feriel; Delcayre, Claude; Giannesini, Claire; Levy, Bernard I; Pocard, Marc; Kubis, Nathalie

2013-01-15

Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo. Copyright © 2012 Elsevier B.V. All rights

Mixed models in cerebral ischemia study

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Matheus Henrique Dal Molin Ribeiro

2016-06-01

Full Text Available The data modeling from longitudinal studies stands out in the current scientific scenario, especially in the areas of health and biological sciences, which induces a correlation between measurements for the same observed unit. Thus, the modeling of the intra-individual dependency is required through the choice of a covariance structure that is able to receive and accommodate the sample variability. However, the lack of methodology for correlated data analysis may result in an increased occurrence of type I or type II errors and underestimate/overestimate the standard errors of the model estimates. In the present study, a Gaussian mixed model was adopted for the variable response latency of an experiment investigating the memory deficits in animals subjected to cerebral ischemia when treated with fish oil (FO. The model parameters estimation was based on maximum likelihood methods. Based on the restricted likelihood ratio test and information criteria, the autoregressive covariance matrix was adopted for errors. The diagnostic analyses for the model were satisfactory, since basic assumptions and results obtained corroborate with biological evidence; that is, the effectiveness of the FO treatment to alleviate the cognitive effects caused by cerebral ischemia was found.

Association of Automatically Quantified Total Blood Volume after Aneurysmal Subarachnoid Hemorrhage with Delayed Cerebral Ischemia

NARCIS (Netherlands)

Zijlstra, I. A.; Gathier, C. S.; Boers, A. M.; Marquering, H. A.; Slooter, A. J.; Velthuis, B. K.; Coert, B. A.; Verbaan, D.; van den Berg, R.; Rinkel, G. J.; Majoie, C. B.

2016-01-01

The total amount of extravasated blood after aneurysmal subarachnoid hemorrhage, assessed with semiquantitative methods such as the modified Fisher and Hijdra scales, is known to be a predictor of delayed cerebral ischemia. However, prediction rates of delayed cerebral ischemia are moderate, which

Inflammation and the neurovascular unit in the setting of focal cerebral ischemia.

Science.gov (United States)

del Zoppo, G J

2009-02-06

Responses to focal cerebral ischemia by neurons and adjacent microvessels are rapid, simultaneous, and topographically related. Recent observations indicate the simultaneous appearance of proteases by components of nearby microvessels that are also expressed by neurons in the ischemic territory, implying that the events could be coordinated. The structural relationship of neurons to their microvascular supply, the direct functional participation of glial cells, and the observation of a highly ordered microvessel-neuron response to ischemia suggest that these elements are arranged in and behave in a unitary fashion, the neurovascular unit. Their roles as a unit in the stimulation of cellular inflammation and the generation of inflammatory mediators during focal cerebral ischemia have not been explored yet. However, components of the neurovascular unit both generate and respond to these influences under the conditions of ischemia. Here we briefly explore the potential inter-relationships of the components of the neurovascular unit with respect to their potential roles in ischemia-induced inflammatory responses.

HIMALAIA (Hypertension Induction in the Management of AneurysmaL subArachnoid haemorrhage with secondary IschaemiA): a randomized single-blind controlled trial of induced hypertension vs. no induced hypertension in the treatment of delayed cerebral ischemia after subarachnoid hemorrhage.

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Gathier, C S; van den Bergh, W M; Slooter, A J C

2014-04-01

Delayed cerebral ischemia (DCI) is a major complication after aneurysmal subarachnoid hemorrhage (SAH). One option to treat delayed cerebral ischemia is to use induced hypertension, but its efficacy on the eventual outcome has not been proven in a randomized clinical trial. This article describes the design of the HIMALAIA trial (Hypertension Induction in the Management of AneurysmaL subArachnoid haemorrhage with secondary IschaemiA), designed to assess the effectiveness of induced hypertension on neurological outcome in patients with DCI after SAH. To investigate whether induced hypertension improves the functional outcome in patients with delayed cerebral ischemia after SAH. The HIMALAIA trial is a multicenter, singe-blinded, randomized controlled trial in patients with DCI after a recent SAH. Eligible patients will be randomized to either induced hypertension (n = 120) or to no induced hypertension (n = 120). In selected centers, the efficacy of induced hypertension in augmenting cerebral blood flow will be measured by means of cerebral perfusion computerized tomography scanning. Follow-up assessments will be performed at 3 and 12 months after randomization by trial nurses who are blinded to the treatment allocation and management. We will include patients during five years. The primary outcome is the proportion of subarachnoid hemorrhage patients with delayed cerebral ischemia with poor outcome three-months after randomization, defined as a modified Rankin scale of more than 3. Secondary outcome measures are related to treatment failure, functional outcome, adverse events, and cerebral hemodynamics. The HIMALAIA trial is registered at clinicaltrials.gov under identifier NCT01613235. © 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.

Suppressing Receptor-Interacting Protein 140: a New Sight for Salidroside to Treat Cerebral Ischemia.

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Chen, Tong; Ma, Zhanqiang; Zhu, Lingpeng; Jiang, Wenjiao; Wei, Tingting; Zhou, Rui; Luo, Fen; Zhang, Kai; Fu, Qiang; Ma, Chunhua; Yan, Tianhua

2016-11-01

The purpose of the current study was to detect the effect of salidroside (Sal) on cerebral ischemia and explore its potential mechanism. Middle cerebral artery occlusion (MCAO) was performed to investigate the effects of Sal on cerebral ischemia. The rats were randomly divided into five groups: sham group, vehicle group, clopidogrel (7.5 mg/kg) group, Sal (20 mg/kg) group, and Sal (40 mg/kg) group. SH-SY5Y cells were exposed to ischemia-reperfusion (I/R) injury to verify the protective effect of Sal in vitro. We also built the stable receptor-interacting protein 140 (RIP140)-overexpressing SH-SY5Y cells. The results showed that Sal significantly reduces brain infarct size and cerebral edema. Sal could effectively decrease the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in serum of the MCAO rats and supernatant of I/R-induced SH-SY5Y cells. Immunohistochemical and Western blot results demonstrated that Sal inhibited RIP140-mediated inflammation and apoptosis in the MCAO rats and SH-SY5Y cells. In addition, we further confirmed that RIP140/NF-κB signaling plays a crucial role by evaluating the protein expression in RIP140-overexpressing SH-SY5Y cells. Our findings suggested that Sal could be used as an effective neuroprotective agent for cerebral ischemia due to its significant effect on preventing neuronal cell injury after cerebral ischemia both in vivo and in vitro by the inhibitions of RIP140-mediated inflammation and apoptosis.

Hyperexpressed netrin-1promoted neural stem cells migration in mice after focal cerebral ischemia

OpenAIRE

Haiyan Lu; Xiaoyan Song; Feng Wang; Guodong Wang; Yuncheng Wu; Qiaoshu Wang; Yongting Wang; Guoyuan Yang; Zhijun Zhang

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 ...

Exercise preconditioning improves behavioral functions following transient cerebral ischemia induced by 4-vessel occlusion (4-VO) in rats.

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Tahamtan, Mahshid; Allahtavakoli, Mohammad; Abbasnejad, Mehdi; Roohbakhsh, Ali; Taghipour, Zahra; Taghavi, Mohsen; Khodadadi, Hassan; Shamsizadeh, Ali

2013-12-01

There is evidence that exercise decreases ischemia/reperfusion injury in rats. Since behavioral deficits are the main outcome in patients after stroke, our study was designed to investigate whether exercise preconditioning improves the acute behavioral functions and also brain inflammatory injury following cerebral ischemia. Male rats weighing 250-300 g were randomly allocated into five experimental groups. Exercise was performed on a treadmill 30min/day for 3 weeks. Ischemia was induced by 4-vessel occlusion method. Recognition memory was assessed by novel object recognition task (NORT) and step-through passive avoidance task. Sensorimotor function and motor movements were evaluated by adhesive removal test and ledged beam-walking test, respectively. Brain inflammatory injury was evaluated by histological assessment. In NORT, the discrimination ratio was decreased after ischemia (P test, a significant reduction in response latency was observed in the ischemic group. Exercise preconditioning significantly decreased the response latency in the ischemic rats (P test, latency to touch and remove the sticky labels from forepaw was increased following induction of ischemia (all P beam-walking test, the slip ratio was increased following ischemia (P < 0.05).  In the ischemia group, marked neuronal injury in hippocampus was observed. These neuropathological changes were attenuated by exercise preconditioning (P < 0.001). Our results showed that exercise preconditioning improves behavioral functions and maintains more viable cells in the dorsal hippocampus of the ischemic brain.

[Mechanism of treatment effect of Huanglian-Huangqin herb pairs on cerebral ischemia rats based on metabolomic approach].

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Cao, Hui-Ting; Zhu, Hua-Xu; Zhang, Qi-Chun; Guo, Li-Wei

2017-06-01

The metabolic effect of Huanglian-Huangqin herb pairs on cerebral ischemia rats was studied by using metabolomic method. The rat model of ischemia reperfusion injury induced by introduction of transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Ultra high performance liquid chromatography-series four pole time of flight mass spectrometry method（UPLC-Q-TOF/MS）, Markerlynx software, and principal component analysis and partial least-squares discriminant analysis were used to analyze the different endogenous metabolites among the urine samples of sham rats, cerebral ischemia model rats, Huanglian groups (HL), Huangqin groups (HQ) and Huanglian-Huangqin herb pairs groups (LQ) was achieved, combined with accurate information about the endogenous metabolites level and secondary fragment ions, retrieval and identification of possible biological markers, metabolic pathway which build in MetPA database. The 20 potential biomarkers were found in the urine of rats with cerebral ischemia, which mainly involved in the neurotransmitter regulation, amino acid metabolism, energy metabolism, lipid metabolism and so on. Those metabolic pathways were disturbed in cerebral ischemia model rats, the principal component analysis showed that the normal and cerebral ischemia model is clearly distinguished, and the compound can be given to the normal state of change after HL, HQ, LQ administration. This study index the interpretation of cerebral ischemia rat metabolism group and mechanism, the embodiment of metabonomics can reflect the physiological and metabolic state, which can better reflect the traditional Chinese medicine as a whole view, system view and the features of multi ingredient synergistic or antagonistic effects. Copyright© by the Chinese Pharmaceutical Association.

Fluoxetine Opens Window to Improve Motor Recovery After Stroke

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2018-05-01

Stroke; Cerebrovascular Accident; Cerebral Infarction; Brain Infarction; Brain Ischemia; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases

Electroacupuncture pretreatment induces tolerance against focal cerebral ischemia through activation of canonical Notch pathway

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Zhao Yu

2012-09-01

Full Text Available Abstract Background Electroacupuncture (EA pretreatment can induce the tolerance against focal cerebral ischemia. However, the underlying mechanisms have not been fully understood. Emerging evidences suggest that canonical Notch signaling may be involved in ischemic brain injury. In the present study, we tested the hypothesis that EA pretreatment-induced tolerance against focal cerebral ischemia is mediated by Notch signaling. Results EA pretreatment significantly enhanced Notch1, Notch4 and Jag1 gene transcriptions in the striatum, except Notch1 intracellular domain level, which could be increased evidently by ischemia. After ischemia and reperfusion, Hes1 mRNA and Notch1 intracellular domain level in ischemic striatum in EA pretreatment group were increased and reached the peak at 2 h and 24 h, respectively, which were both earlier than the peak achieved in control group. Intraventricular injection with the γ-secretase inhibitor MW167 attenuated the neuroprotective effect of EA pretreatment. Conclusions EA pretreatment induces the tolerance against focal cerebral ischemia through activation of canonical Notch pathway.

Posterior Cerebral Infarction following Loss of Guide Wire

OpenAIRE

Bugnicourt, Jean-Marc; Belhomme, Denis; Bonnaire, Bruno; Constans, Jean-Marc; Manaouil, Cécile

2013-01-01

Stroke after internal jugular venous cannulation typically leads to acute carotid or vertebral arteries injury and cerebral ischemia. We report the first case of delayed posterior cerebral infarction following loss of guide wire after left internal jugular venous cannulation in a 46-year-old woman with a history of inflammatory bowel disease. Our observation highlights that loss of an intravascular guide wire can be a cause of ischemic stroke in patients undergoing central venous catheterizat...

Cost-effectiveness of CT angiography and perfusion imaging for delayed cerebral ischemia and vasospasm in aneurysmal subarachnoid hemorrhage

NARCIS (Netherlands)

P.C. Sanelli (Pina C.); A. Pandya; A.Z. Segal; A. Gupta; S. Hurtado-Rua; J. Ivanidze; K. Kesavabhotla; D. Mir; A.I. Mushlin; M.G.M. Hunink (Myriam)

2014-01-01

textabstractBACKGROUND AND PURPOSE: Delayed cerebral ischemia and vasospasm are significant complications following SAH leading to cerebral infarction, functional disability, and death. In recent years, CTA and CTP have been used to increase the detection of delayed cerebral ischemia and vasospasm.

Genistein attenuates brain damage induced by transient cerebral ischemia through up-regulation of ERK activity in ovariectomized mice.

Science.gov (United States)

Wang, Shiquan; Wei, Haidong; Cai, Min; Lu, Yan; Hou, Wugang; Yang, Qianzi; Dong, Hailong; Xiong, Lize

2014-01-01

Stroke has severe consequences in postmenopausal women. As replacement therapy of estrogen have various adverse effects and the undermined outcomes. Genistein, a natural phytoestrogen, has been suggested to be a potential neuroprotective agent for such stroke patients. However, the role of genistein and its underlying mechanism in ovariectomized mice has not yet been evaluated. In the present study, ovariectomized mice were treated with genistein (10 mg/kg) or vehicle daily for two weeks before developing transient cerebral ischemia (middle cerebral artery occlusion). The neurological manifestation was evaluated, and infarct volumes were demonstrated by 2,3,5-triphenyltetrazolium chloride staining at 24 h after reperfusion. In addition, phosphorylation of extracellular signal-regulated kinase (ERK) was detected by Western blotting and immunofluorescence staining, and cellular apoptosis was evaluated in the ischemic penumbra. We found that treatment with genistein reduced infarct volumes, improved neurological outcomes and attenuated cellular apoptosis at 24 h after reperfusion. ERK1/2 showed increased phosphorylation by genistein treatment after reperfusion, and an ERK1/2 inhibitor U0126 abolished this protective effect of genistein in terms of infarct volumes, neurological scores and cellular apoptosis. Our findings indicate that treatment with genistein can reduce the severity of subsequent stroke episodes, and that this beneficial function is associated with ERK activation.

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

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Shinichiro Teramoto

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

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

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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 (ppills had protective effects on focal cerebral ischemia rats. Copyright © 2013 Elsevier GmbH. All rights reserved.

Expression of Neurotrophin-3 and trkC following Focal Cerebral Ischemia in Adult Rat Brain with Treadmill Exercise

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Jin-Young Chung

2017-01-01

Full Text Available Neurotrophin-3 (NT-3 is a neurotrophic factor that mainly binds to the tyrosine kinase C (trkC receptor. NT-3 has been shown to have neuroprotective effects in focal cerebral ischemia. Exercise also has ability to induce functional recovery in focal cerebral ischemia. However, the relationship between NT-3, its receptor trkC, and exercise has not been revealed. In this study, we assessed the expressions of NT-3 and trkC in focal cerebral ischemia. We also assessed the expression of NT-3 and trkC with treadmill exercise in focal cerebral ischemia. The results showed that, in a permanent middle cerebral artery occlusion rat model, exercise increased NT-3 and trkC expression. However, the patterns of expression of NT-3 and trkC at different time points varied. These results suggest that exercise-induced functional recovery in focal cerebral ischemia was related to NT-3 and trkC, but the role on times of NT-3 and trkC differed, although trkC is the receptor kinase for NT-3.

Protective Effect of Extract of Folium Ginkgo on Repeated Cerebral Ischemia-Reperfusion Injury

Institute of Scientific and Technical Information of China (English)

无

2000-01-01

Objective: To study the protective effect of extract of Folium Ginkgo (FGE) on repeated cerebral ischemia-reperfusion injury. Methods: The model in waking mice induced by repeated cerebral ischemia-reperfusion were used in the experiment to observe the effect of FGE on behavior, oxygen free radical metabolism and prostaglandin E2 (PGE2) content by step-through experiment, diving stand and colorimetric method. Results: FGE could obviously improve the learning ability and memory of model animals, and could lower obviously the content of malonyldialdehyde, nitric oxide and PGE2, restore the lowered activity of superoxide dismutase and catalase in cerebral tissue. Conclusion: FGE has highly protective effect against repeated ischemia-reperfusion injury, the mechanism might be related with its action on anti-lipid oxidatin, improve the activity of antioxidase and inhibit the producing of PGE2.

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

Science.gov (United States)

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.

Scutellarin Attenuates Microglia-Mediated Neuroinflammation and Promotes Astrogliosis in Cerebral Ischemia - A Therapeutic Consideration.

Science.gov (United States)

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

2017-01-01

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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Aging increases microglial proliferation, delays cell migration, and decreases cortical neurogenesis after focal cerebral ischemia.

Science.gov (United States)

Moraga, Ana; Pradillo, Jesús M; García-Culebras, Alicia; Palma-Tortosa, Sara; Ballesteros, Ivan; Hernández-Jiménez, Macarena; Moro, María A; Lizasoain, Ignacio

2015-05-10

Aging is not just a risk factor of stroke, but it has also been associated with poor recovery. It is known that stroke-induced neurogenesis is reduced but maintained in the aged brain. However, there is no consensus on how neurogenesis is affected after stroke in aged animals. Our objective is to determine the role of aging on the process of neurogenesis after stroke. We have studied neurogenesis by analyzing proliferation, migration, and formation of new neurons, as well as inflammatory parameters, in a model of cerebral ischemia induced by permanent occlusion of the middle cerebral artery in young- (2 to 3 months) and middle-aged mice (13 to 14 months). Aging increased both microglial proliferation, as shown by a higher number of BrdU(+) cells and BrdU/Iba1(+) cells in the ischemic boundary and neutrophil infiltration. Interestingly, aging increased the number of M1 monocytes and N1 neutrophils, consistent with pro-inflammatory phenotypes when compared with the alternative M2 and N2 phenotypes. Aging also inhibited (subventricular zone) SVZ cell proliferation by decreasing both the number of astrocyte-like type-B (prominin-1(+)/epidermal growth factor receptor (EGFR)(+)/nestin(+)/glial fibrillary acidic protein (GFAP)(+) cells) and type-C cells (prominin-1(+)/EGFR(+)/nestin(-)/Mash1(+) cells), and not affecting apoptosis, 1 day after stroke. Aging also inhibited migration of neuroblasts (DCX(+) cells), as indicated by an accumulation of neuroblasts at migratory zones 14 days after injury; consistently, aged mice presented a smaller number of differentiated interneurons (NeuN(+)/BrdU(+) and GAD67(+) cells) in the peri-infarct cortical area 14 days after stroke. Our data confirm that stroke-induced neurogenesis is maintained but reduced in aged animals. Importantly, we now demonstrate that aging not only inhibits proliferation of specific SVZ cell subtypes but also blocks migration of neuroblasts to the damaged area and decreases the number of new interneurons in

A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice.

Science.gov (United States)

Atochin, Dmitriy N; Schepetkin, Igor A; Khlebnikov, Andrei I; Seledtsov, Victor I; Swanson, Helen; Quinn, Mark T; Huang, Paul L

2016-04-08

The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

CSF and Serum Biomarkers Focusing on Cerebral Vasospasm and Ischemia after Subarachnoid Hemorrhage

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Carla S. Jung

2013-01-01

Full Text Available Delayed cerebral vasospasm (CVS and delayed cerebral ischemia (DCI remain severe complications after subarachnoid hemorrhage (SAH. Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF of patients after SAH. CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC. In serum, neuron-specific enolase (NSE and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT scans. All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts.

Posterior Cerebral Infarction following Loss of Guide Wire

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Jean-Marc Bugnicourt

2013-01-01

Full Text Available Stroke after internal jugular venous cannulation typically leads to acute carotid or vertebral arteries injury and cerebral ischemia. We report the first case of delayed posterior cerebral infarction following loss of guide wire after left internal jugular venous cannulation in a 46-year-old woman with a history of inflammatory bowel disease. Our observation highlights that loss of an intravascular guide wire can be a cause of ischemic stroke in patients undergoing central venous catheterization.

Cocktail treatment, a promising strategy to treat acute cerebral ischemic stroke?

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Li-jun Liang

2016-01-01

Full Text Available Up to now, over 1,000 experimental treatments found in cells and rodents have been difficult to translate to human ischemic stroke. Since ischemia and reperfusion, two separate stages of ischemic stroke, have different pathophysiological mechanisms leading to brain injury, a combination of protective agents targeting ischemia and reperfusion respectively may obtain substantially better results than a single agent. Normobaric hyperoxia (NBO has been shown to exhibit neuro- and vaso-protective effects by improving tissue oxygenation when it is given during ischemia, however the effect of NBO would diminish when the duration of ischemia and reperfusion was extended. Therefore, during reperfusion drug treatment targeting inflammation, oxidative stress and free radical scavenger would be a useful adjuvant to extend the therapeutic window of tissue plasminogen activator, the only United States Food and Drug Administration (FDA approved treatment for acute ischemic stroke. In this review, we discussed the neuro- and vaso-protective effects of NBO and recent finding of combining NBO with other drugs.

Alpha-Tocopherol Reduces Brain Edema and Protects Blood-Brain Barrier Integrity following Focal Cerebral Ischemia in Rats.

Science.gov (United States)

Haghnejad Azar, Adel; Oryan, Shahrbanoo; Bohlooli, Shahab; Panahpour, Hamdollah

2017-01-01

This study was conducted to examine the neuroprotective effects of α-tocopherol against edema formation and disruption of the blood-brain barrier (BBB) following transient focal cerebral ischemia in rats. Ninety-six male Sprague-Dawley rats were divided into 3 major groups (n = 32 in each), namely the sham, and control and α-tocopherol-treated (30 mg/kg) ischemic groups. Transient focal cerebral ischemia (90 min) was induced by occlusion of the left middle cerebral artery. At the end of the 24-hour reperfusion period, the animals were randomly selected and used for 4 investigations (n = 8) in each of the 3 main groups: (a) assessment of neurological score and measurement of infarct size, (b) detection of brain edema formation by the wet/dry method, (c) evaluation of BBB permeability using the Evans blue (EB) extravasation technique, and (d) assessment of the malondialdehyde (MDA) and reduced glutathione (GSH) concentrations using high-performance liquid chromatography methods. Induction of cerebral ischemia in the control group produced extensive brain edema (brain water content 83.8 ± 0.11%) and EB leakage into brain parenchyma (14.58 ± 1.29 µg/g) in conjunction with reduced GSH and elevated MDA levels (5.86 ± 0.31 mmol/mg and 63.57 ± 5.42 nmol/mg, respectively). Treatment with α-tocopherol significantly lowered brain edema formation and reduced EB leakage compared with the control group (p < 0.001, 80.1 ± 0.32% and 6.66 ± 0.87 µg/g, respectively). Meanwhile, treatment with α-tocopherol retained tissue GSH levels and led to a lower MDA level (p < 0.01, 10.17 ± 0.83 mmol/mg, and p < 0.001, 26.84 ± 4.79 nmol/mg, respectively). Treatment with α-tocopherol reduced ischemic edema formation and produced protective effects on BBB function following ischemic stroke occurrence. This effect could be through increasing antioxidant activity. © 2016 S. Karger AG, Basel.

Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: clinicoanatomic correlations

NARCIS (Netherlands)

Hijdra, A.; van Gijn, J.; Stefanko, S.; van Dongen, K. J.; Vermeulen, M.; van Crevel, H.

1986-01-01

Fifty-seven of 176 prospectively studied patients with aneurysmal subarachnoid hemorrhage (SAH) developed delayed cerebral ischemia. Clinical features included hemispheric focal signs (13), decrease in level of consciousness (14), or both (30), and mutism (15). Forty-seven patients showed hypodense

Magnetic resonance imaging in acute stage of cerebral ischemia

International Nuclear Information System (INIS)

Yamagata, Sen; Kikuchi, Haruhiko; Ihara, Ikuo

1986-01-01

The value of the nuclear magnetic resonance image (MRI) was investigated in the acute stage of experimental cerebral ischemia. The MRI system employed was designed for clinical use, and the superconducting magnet was operated at a field strength of 1.5 tesla. Ischemic insult was made by transorbital occlusion of the middle cerebral artery (MCA) permanently in 4 cats and temporarily in 2 cats. After MCA occlusion the regional cerebral blood flow (rCBF) was measured on the affected cortex, and 5 cats with rCBF below 10 ml/100 g/min and one with rCBF over 15 ml/100 g/min were studied. In the permanent occlusion group, MRI was performed every 2 hours from 4 to 12 hours after MCA occlusion and another MRI was carried out 20 min after gadolinium-diethylenetriamine-pentaacetic acid (Gd-DTPA) intravenous administration. The earliest changes were found 6 to 8 hours after MCA occlusion on the spin echo image (repetition time = 1.4 sec, echo time = 70 msec) in 3 cats with severe ischemia. It was postulated that the ischemic lesion could be depicted less than 6 hours on more T 2 -weighted images. The increased intensity area was markedly enhanced with Gd-DTPA 12 hours after occlusion. In the recirculation group, the increased intensity area was observed on enhanced MRI in a cat with recirculation as early as one hour after MCA occlusion, although it was not found on the plain MRI. In the other cat with recirculation after 2 hours' occlusion, definite lesion was found in all parameter images without enhancement. The results suggest that changes in cerebral ischemia can be obtained on the MRI earlier than X-ray computed tomography, and that it may be possible to determine the severity of the ischemic brain injury by the MRI findings. (author)

Cerebrovascular endothelin receptor upregulation in cerebral ischemia

DEFF Research Database (Denmark)

Edvinsson, Lars

2009-01-01

Stroke is a serious neurological disease and the third leading cause of death in the western world. In roughly 15 % of the cases, the cause is due to an intracranial haemorrhage, and the remaining 85 % represent ischemic strokes. Ischemic stroke is caused by the occlusion of a cerebral artery...... either by an embolus or by local thrombosis. Several studies have shown an involvement of the endothelin system in ischemic stroke. This review aims to examine the alterations of vascular endothelin receptor expression in ischemic stroke. Furthermore, studies of the intracellular signalling pathways...... leading to the enhanced expression of vascular endothelin receptors show that both protein kinase C (PKC) and mitogen activating protein kinase (MAPK) play important roles. The results from this work provide new perspectives on the pathophysiology of ischemic stroke, and give a possible explanation...

Sequential changes in ischemic edema following transient focal cerebral ischemia in rats; Magnetic resonance imaging study

Energy Technology Data Exchange (ETDEWEB)

Nagahiro, Shinji; Goto, Satoshi; Kogo, Kasei; Sumi, Minako; Takahashi, Mutsumasa; Ushio, Yukitaka [Kumamoto Univ. (Japan). School of Medicine

1994-07-01

Sequential and regional changes in ischemic edema following various durations of focal cerebral ischemia were studied by magnetic resonance (MR) imaging in a rat unilateral intraluminal middle cerebral artery occlusion model. Occlusion was performed from 5 minutes to 5 hours. T[sub 2]-weighted images were obtained chronologically 6 hours after onset of ischemia, on day 1 and day 7. An immunohistochemical study using antibodies to calcineurin and glial fibrillary acidic protein was performed to observe histological changes in the ischemic brain. The T[sub 2] high-signal-intensity areas representing ischemic edema were observed in the lateral striatum and/or the cerebral cortex by day 1 in all rats with 1- to 5-hour ischemia, and the areas were larger and detected earlier with longer durations of ischemia. In three of six rats with 15-minute ischemia and five of six rats with 30-minute ischemia, the T[sub 2] high-signal-intensity areas appeared transiently on day 1 in the dorsolateral striatum where loss of neurons expressing calcineurin immunoreactivity and associated gliosis were found. MR imaging in animal models of reversible focal ischemia can achieve sequential and noninvasive evaluation of dynamic regional changes in ischemic edema. (author).

Inhibition of CD147 (Cluster of Differentiation 147) Ameliorates Acute Ischemic Stroke in Mice by Reducing Thromboinflammation.

Science.gov (United States)

Jin, Rong; Xiao, Adam Y; Chen, Rui; Granger, D Neil; Li, Guohong

2017-12-01

Inflammation and thrombosis currently are recognized as critical contributors to the pathogenesis of ischemic stroke. CD147 (cluster of differentiation 147), also known as extracellular matrix metalloproteinase inducer, can function as a key mediator of inflammatory and immune responses. CD147 expression is increased in the brain after cerebral ischemia, but its role in the pathogenesis of ischemic stroke remains unknown. In this study, we show that CD147 acts as a key player in ischemic stroke by driving thrombotic and inflammatory responses. Focal cerebral ischemia was induced in C57BL/6 mice by a 60-minute transient middle cerebral artery occlusion. Animals were treated with anti-CD147 function-blocking antibody (αCD147) or isotype control antibody. Blood-brain barrier permeability, thrombus formation, and microvascular patency were assessed 24 hours after ischemia. Infarct size, neurological deficits, and inflammatory cells invaded in the brain were assessed 72 hours after ischemia. CD147 expression was rapidly increased in ischemic brain endothelium after transient middle cerebral artery occlusion. Inhibition of CD147 reduced infarct size and improved functional outcome on day 3 after transient middle cerebral artery occlusion. The neuroprotective effects were associated with (1) prevented blood-brain barrier damage, (2) decreased intravascular fibrin and platelet deposition, which in turn reduced thrombosis and increased cerebral perfusion, and (3) reduced brain inflammatory cell infiltration. The underlying mechanism may include reduced NF-κB (nuclear factor κB) activation, MMP-9 (matrix metalloproteinase-9) activity, and PAI-1 (plasminogen activator inhibitor-1) expression in brain microvascular endothelial cells. Inhibition of CD147 ameliorates acute ischemic stroke by reducing thromboinflammation. CD147 might represent a novel and promising therapeutic target for ischemic stroke and possibly other thromboinflammatory disorders. © 2017 American Heart

Imaging of cerebral ischemic edema and neuronal death

Energy Technology Data Exchange (ETDEWEB)

Kummer, Ruediger von [Universitaetsklinikum Carl Gustav Carus, Institut fuer Diagnostische und Interventionelle Neuroradiologie, Dresden (Germany); Dzialowski, Imanuel [Elblandklinikum Meissen, Neurologische Rehabilitationsklinik Grossenhain, Meissen (Germany)

2017-06-15

In acute cerebral ischemia, the assessment of irreversible injury is crucial for treatment decisions and the patient's prognosis. There is still uncertainty how imaging can safely differentiate reversible from irreversible ischemic brain tissue in the acute phase of stroke. We have searched PubMed and Google Scholar for experimental and clinical papers describing the pathology and pathophysiology of cerebral ischemia under controlled conditions. Within the first 6 h of stroke onset, ischemic cell injury is subtle and hard to recognize under the microscope. Functional impairment is obvious, but can be induced by ischemic blood flow allowing recovery with flow restoration. The critical cerebral blood flow (CBF) threshold for irreversible injury is ∝15 ml/100 g x min. Below this threshold, ischemic brain tissue takes up water in case of any residual capillary flow (ionic edema). Because tissue water content is linearly related to X-ray attenuation, computed tomography (CT) can detect and measure ionic edema and, thus, determine ischemic brain infarction. In contrast, diffusion-weighted magnetic resonance imaging (DWI) detects cytotoxic edema that develops at higher thresholds of ischemic CBF and is thus highly sensitive for milder levels of brain ischemia, but not specific for irreversible brain tissue injury. CT and MRI are complimentary in the detection of ischemic stroke pathology and are valuable for treatment decisions. (orig.)

Clinical neurogenetics: stroke.

Science.gov (United States)

Rost, Natalia S

2013-11-01

Understanding the genetic architecture of cerebrovascular disease holds promise of novel stroke prevention strategies and therapeutics that are both safe and effective. Apart from a few single-gene disorders associated with cerebral ischemia or intracerebral hemorrhage, stroke is a complex genetic phenotype that requires careful ascertainment and robust association testing for discovery and validation analyses. The recently uncovered shared genetic contribution between clinically manifest stroke syndromes and closely related intermediate cerebrovascular phenotypes offers effective and efficient approaches to complex trait analysis. Copyright © 2013 Elsevier Inc. All rights reserved.

A study on regional cerebral circulation in stroke patients with aphasia

International Nuclear Information System (INIS)

Kudo, Ryozo

1985-01-01

To study the pathophysiology of aphasia due to cerebral stroke, regional cerebral blood flow (rCBF) was measured by the 133 Xe clearance method and the volume of low density area (LDA) was estimated on the basis of computerized tomography in 43 thrombotic (24 aphasia and 19 non-aphasia), 30 hemorrhagic (16 aphasia and 14 non-aphasia) and 6 non-stroke cases. 1) In the healthy hemisphere, rCBF showed no significant difference between aphasia and non-aphasia in both thrombotic and hemorrhagic cases. In the affected hemisphere, thrombotic cases showed significantly decreased rCBF in aphasic cases as compared to non-aphasic, however, hemorrhagic cases revealed no difference. 2) LDA volume showed no significant difference between aphasia and non-aphasia in cerebral thrombosis, however, LDA volume in non-aphasia was smaller than that in aphasia in cerebral hemorrage. 3) Significant differences in the pathophysiology of aphasia due to cerebral stroke were recognized between cerebral thrombosis and cerebral hemorrhage. Such differences should be taken into consideration in the management and treatment of aphasia caused by cerebral stroke. (author)

Nutrition for brain recovery after ischemic stroke: an added value to rehabilitation.

Science.gov (United States)

Aquilani, Roberto; Sessarego, Paolo; Iadarola, Paolo; Barbieri, Annalisa; Boschi, Federica

2011-06-01

In patients who undergo rehabilitation after ischemic stroke, nutrition strategies are adopted to provide tube-fed individuals with adequate nutrition and/or to avoid the body wasting responsible for poor functional outcome and prolonged stay in the hospital. Investigations have documented that nutrition interventions can enhance the recovery of neurocognitive function in individuals with ischemic stroke. Experimental studies have shown that protein synthesis is suppressed in the ischemic penumbra. In clinical studies on rehabilitation patients designed to study the effects of counteracting or limiting this reduction of protein synthesis by providing protein supplementation, patients receiving such supplementation had enhanced recovery of neurocognitive function. Cellular damage in cerebral ischemia is also partly caused by oxidative damage secondary to free radical formation and lipid peroxidation. Increased oxidative stress negatively affects a patient's life and functional prognosis. Some studies have documented that nutrition supplementation with B-group vitamins may mitigate oxidative damage after acute ischemic stroke. Experimental investigations have also shown that cerebral ischemia changes synaptic zinc release and that acute ischemia increases zinc release, aggravating neuronal injury. In clinical practice, patients with ischemic stroke were found to have a lower than recommended dietary intake of zinc. Patients in whom daily zinc intake was normalized had better recovery of neurological deficits than subjects given a placebo. The aim of this review is to highlight those brain metabolic alterations susceptible to nutrition correction in clinical practice. The mechanisms underlying the relationship between cerebral ischemia and nutrition metabolic conditions are discussed.

Salvinorin A preserves cerebral pial artery autoregulation after forebrain ischemia via the PI3K/AKT/cGMP pathway

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H.P. Dong

2018-03-01

Full Text Available This study aimed to investigate the protective effect of salvinorin A on the cerebral pial artery after forebrain ischemia and explore related mechanisms. Thirty Sprague-Dawley rats received forebrain ischemia for 10 min. The dilation responses of the cerebral pial artery to hypercapnia and hypotension were assessed in rats before and 1 h after ischemia. The ischemia reperfusion (IR control group received DMSO (1 µL/kg immediately after ischemia. Two different doses of salvinorin A (10 and 20 µg/kg were administered following the onset of reperfusion. The 5th, 6th, and 7th groups received salvinorin A (20 µg/kg and LY294002 (10 µM, L-NAME (10 μM, or norbinaltorphimine (norBIN, 1 μM after ischemia. The levels of cGMP in the cerebrospinal fluid (CSF were also measured. The phosphorylation of AKT (p-AKT was measured in the cerebral cortex by western blot at 24 h post-ischemia. Cell necrosis and apoptosis were examined by hematoxylin-eosin staining (HE and TUNEL staining, respectively. The motor function of the rats was evaluated at 1, 2, and 5 days post-ischemia. The dilation responses of the cerebral pial artery were significantly impaired after ischemia and were preserved by salvinorin A treatment. In addition, salvinorin A significantly increased the levels of cGMP and p-AKT, suppressed cell necrosis and apoptosis of the cerebral cortex and improved the motor function of the rats. These effects were abolished by LY294002, L-NAME, and norBIN. Salvinorin A preserved cerebral pial artery autoregulation in response to hypercapnia and hypotension via the PI3K/AKT/cGMP pathway.

Discussion on the treatment of cerebral ischemia-reperfusion injuries following intra-arterial thrombolysis

International Nuclear Information System (INIS)

Tian Hong; Song Chuan; Fan Ruxiong; Zhou Huchuan; Zhang Yubo; Zang Qiaoli; Zhang Yunquan; Liu Lei

2011-01-01

Objective: To investigate the therapeutic method of cerebral ischemia-reperfusion injuries occurred after arterial thrombolytic therapy for acute cerebral infarction. Methods: Thirty-five patients, encountered in authors' Department since Oct. 2005, with cerebral ischemia-reperfusion injuries, which occurred after thrombolytic therapy by using arterial perfusion of urokinase for acute cerebral infarction, were enrolled in this study. The clinical data were retrospectively analyzed. Results: After the thrombolytic therapy, completer or partial recanalization of the occluded cerebral arteries was obtained in 33 cases, while secondary cerebral hemorrhage occurred in 13 cases, of whom cerebral parenchyma bleeding was seen in 2 and hemorrhagic infarction in 11. Different degrees of cerebral edema were found in all 33 cases. Among them significant shift of the midline structures was detected in 18 (54.5%), which was manifested clinically as the worsening of disturbance of consciousness. Strict control of blood pressure, prompt adjustment of dehydration medication, strengthening the cerebral protection measures, cerebral decompression by fenestration, etc. were carried out. All the patients took a turn for the better and were out of danger with remarkable improvement of neurological functions except one patient who died from massive intracerebral hemorrhage. Conclusion: Usually, different degrees of reperfusion injuries will develop after thrombolytic therapy for cerebral arterial infarction. Strictly controlling blood pressure, promptly adjusting dehydration medication and strengthening cerebral protection are the keys to reduce the severity of cerebral reperfusion injuries. (authors)

Electroacupuncture promotes post-stroke functional recovery via enhancing endogenous neurogenesis in mouse focal cerebral ischemia.

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Yu Ri Kim

Full Text Available To investigate the question of whether electroacupuncture (EA promotes functional recovery via enhancement of proliferation and differentiation of neuronal stem cells (NSCs in ischemic stroke, EA stimulation with 2 Hz was applied at bilateral acupoints to Baihui (GV20 and Dazhui (GV14 in middle cerebral artery occlusion (MCAO mice. EA stimulation improved neuromotor function and cognitive ability after ischemic stroke. EA stimulation resulted in an increase in the number of proliferated cells, especially in the subventricular zone (SVZ of the ipsilateral hemisphere. Although a very limited number of NSCs survived and differentiated into neurons or astrocytes, EA treatment resulted in a significant increase in the number of proliferative cells and differentiated cells in the hippocampus and SVZ of the ipsilateral hemisphere compared to MCAO mice. EA stimulation resulted in significantly increased mRNA expression of brain-derived neurotrophic factor (BDNF and vascular endothelial growth factor (VEGF. Protein levels of these factors were confirmed in the ipsilateral hippocampus and SVZ by immunohistochemical and Western blotting analyses. Expression of phosphorylated phosphatidylinositol-3-kinase, BDNF, and VEGF-mediated down-stream were enhanced by EA stimulation in newly formed neuroblasts. These results indicate that EA treatment after ischemic stroke may promote post-stroke functional recovery by enhancement of proliferation and differentiation of NSCs via the BDNF and VEGF signaling pathway.

Nootropics in a Complex Therapy of Chronic Cerebral Ischemia

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Chekman, I.S.; Belenichev, I.F.; Demchenko, A.V.; Bobrova, V.I.; Kucherenko, L.I.; Gorchakova, N.A.; Bukhtiyarova, N.V.

2014-01-01

Clinical and pharmacological characteristics of nootropics — one of the most productive groups of neuropsychotropic drugs, are considered. Classification of nootropics based on the main mechanism of action is constructed. The examples of clinical use of drugs in patients with chronic cerebral ischemia are presented.

Hyperglycemia decreases preoxiredoxin-2 expression in a middle cerebral artery occlusion model.

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Koh, Phil-Ok

2017-06-01

Diabetes is a major risk factor for stroke and is also associated with worsened outcomes following a stroke. Peroxiredoxin-2 exerts potent neuroprotective effects against oxidative stress. In the present study, we identified altered peroxiredoxin-2 expression in an ischemic stroke model under hyperglycemic conditions. Adult male rats were administrated streptozotocin (40 mg/kg) via intraperitoneal injection to induce diabetes. Middle cerebral artery occlusion (MCAO) was induced surgically 4 weeks after streptozotocin treatment and cerebral cortex tissues were isolated 24 hours after MCAO. Peroxiredoxin-2 expression was evaluated in the cerebral cortex of MCAO-operated animals using a proteomics approach, and was found to be decreased. In addition, the reduction in peroxiredoxin-2 levels was more severe in cerebral ischemia with diabetes compared to animals without diabetes. Reverse-transcriptase PCR and Western blot analyses confirmed the significantly reduced peroxiredoxin-2 expression in MCAO-operated animals under hyperglycemic conditions. It is an accepted fact that peroxiredoxin-2 has antioxidative activity against ischemic injury. Thus, the findings of this study suggest that a more severe reduction in peroxiredoxin-2 under hyperglycemic conditions leads to worsened brain damage during cerebral ischemia with diabetes.

Increased Expression Of Toll-Like Receptor 2 Mrna Following Permanent Middle Cerebral Artery Occlusion In Rat: Role Of TRPV1 Receptors

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Amir Moghadam Ahmadi

2017-02-01

Full Text Available Background: Stroke is a major cause of mortality and long term disability in adults. TRPV1 has a pivotal role in neuroinflammation. Among TLRs, TLR2 significantly participate in induction of inflammation in brain. In this study, the effect of TRPV1 receptor agonist and antagonist on outcome and gene expression of TLR2 in a rat model of permanent middle cerebral artery occlusion (MCAO was investigated. Methods: Forty male rats were assigned to the following groups: sham, vehicle stroke, AMG9810 (selective TRPV1 antagonist, 0.5 mg/kg; 3 h after stroke, and capsaicin (1 mg/kg; 3 h after stroke. Stroke was induced by permanent middle cerebral artery occlusion and behavioral functions were assessed 1, 3, and 7 days after stroke. Infarct volume, brain edema and mRNA expression of TLR2 were also evaluated at the end of the study. Results: While stroke animals showed infarctions and behavioral functions, we did not observe any cerebral infarction and behavioral functions in sham-operated animals. AMG9810 decreased neurological deficits 7 days after cerebral ischemia (P<0.01. In the ledged beam-walking test, the slip ratio was increased following ischemia (*P < 0.05. AMG9810 improved this index in animals undergone stroke. However, capsaicin enhanced the slip ratio 3 and 7 days after cerebral ischemia (#P<0.05. TLR2 P<0.05(mRNA expression was elevated in ischemic rats.   Conclusion: Our data indicate that pharmacological blockade of TRPV1 by AMG9810 attenuates behavioral function and mRNA expression of TLR2. Therefore, it might be useful as a potential target for the treatment of ischemic stroke.

Frequency of cerebral infarction and haemorrhage in the patients of stroke

International Nuclear Information System (INIS)

Shah, A.N.; Ataullah, S.

2009-01-01

Stroke is rapidly developing phenomena of symptoms and signs of focal, and at times global, loss of cerebral function with no apparent cause other than that of vascular origin. The Objective was to know the frequency of cerebral infarction and haemorrhage in one hundred patients of stroke in a period of one year. Data was collected by consecutive sampling technique. Total one hundred patients of stroke were collected for the study. They were assessed through a detailed history of hypertension, diabetes mellitus, smoking, previous stroke, transient ischemic attack (TIA), previous myocardial infarction, angina, atrial fibrillation, alcohol intake, drugs used for hypertension/diabetes mellitus. Blood pressure was recorded at arrival and 24 hours after admission. There were 70% males and 30% females. Twenty percent of the patients were in the age range of 51-60 years, 26% of the patients were in the age range of 61-70 years and 18% were in the age range of 71-80 years. Cerebral infarction was present in 72% patients while cerebral haemorrhage was present in 28% patients. Hypertension was the most common risk factor among these stroke patients. Average blood pressure was 180/100 mmHg. Cerebral infarction is the commonest form of stroke. Hypertension is the leading risk factor in stroke patients. (author)

Salvia miltiorrhiza Bunge (Danshen) extract attenuates permanent cerebral ischemia through inhibiting platelet activation in rats.

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Fei, Yu-Xiang; Wang, Si-Qi; Yang, Li-Jian; Qiu, Yan-Ying; Li, Yi-Ze; Liu, Wen-Yuan; Xi, Tao; Fang, Wei-Rong; Li, Yun-Man

2017-07-31

Danshen is a crude herbal drug isolated from dried roots of Salvia miltiorrhiza Bunge. This plant is widely used in oriental medicine for the treatment of cardiovascular and cerebrovascular diseases. The supercritical CO 2 extract from Danshen (SCED) (57.85%, 5.67% and 4.55% for tanshinone IIA, tanshinone I and cryptotanshinone respectively) was studied in this article, whose potential molecular mechanism remains unclear, especially in anti-thrombosis. The present study was designed to observe the protective effect of SCED on ischemic stroke in rats and to explore the underlying anti-thrombosis mechanism. Following induction of cerebral ischemia in rats by permanent middle cerebral artery occlusion (pMCAO). Neurological defect score, cerebral blood flow, infarct size, and brain edema were measured to evaluate the injury. Arteriovenous shunt thrombosis model and adenosine 5'-diphosphate (ADP) induced acute pulmonary embolism model were conducted to estimate the antithrombotic effect of SCED. In order to investigate the effects of SCED on platelet aggregation, rat platelet-rich-plasma (PRP) were incubated with SCED prior to the addition of the stimuli (ADP or 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619)). Aggregation was monitored in a light transmission aggregometer. Inhibitory effect of SCED on thromboxane A2 (TXA 2 ) release was detected by ELISA kit. Phospholipase C (PLC)/ Protein kinase C (PKC) signaling pathway was analyzed by a Western blot technique. The effect of the SCED was also studied in vivo on bleeding time in mice. SCED improved the neurological defect score, increased cerebral blood flow, reduced infarct size and alleviated brain edema in rats exposed to pMCAO. After administration of SCED, thrombosis formation in arteriovenous shunt was inhibited and recovery time in pulmonary embolism was shortened. The inhibitory effect of SCED on platelet activation was further confirmed by TXB 2 ELISA kit and Western blot analysis of PLC

Curcumin Protects Neuron against Cerebral Ischemia-Induced Inflammation through Improving PPAR-Gamma Function

OpenAIRE

Zun-Jing Liu; Wei Liu; Lei Liu; Cheng Xiao; Yu Wang; Jing-Song Jiao

2013-01-01

Cerebral ischemia is the most common cerebrovascular disease worldwide. Recent studies have demonstrated that curcumin had beneficial effect to attenuate cerebral ischemic injury. However, it is unclear how curcumin protects against cerebral ischemic injury. In the present study, using rat middle cerebral artery occlusion model, we found that curcumin was a potent PPAR ? agonist in that it upregulated PPAR ? expression and PPAR ? -PPRE binding activity. Administration of curcumin markedly dec...

Nootropics in a Complex Therapy of Chronic Cerebral Ischemia

Directory of Open Access Journals (Sweden)

Chekman, I.S.

2014-07-01

Full Text Available Clinical and pharmacological characteristics of nootropics — one of the most productive groups of neuropsychotropic drugs, are considered. Classification of nootropics based on the main mechanism of action is constructed. The examples of clinical use of drugs in patients with chronic cerebral ischemia are presented.

Intermittent fasting attenuates inflammasome activity in ischemic stroke.

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Fann, David Yang-Wei; Santro, Tomislav; Manzanero, Silvia; Widiapradja, Alexander; Cheng, Yi-Lin; Lee, Seung-Yoon; Chunduri, Prasad; Jo, Dong-Gyu; Stranahan, Alexis M; Mattson, Mark P; Arumugam, Thiruma V

2014-07-01

Recent findings have revealed a novel inflammatory mechanism that contributes to tissue injury in cerebral ischemia mediated by multi-protein complexes termed inflammasomes. Intermittent fasting (IF) can decrease the levels of pro-inflammatory cytokines in the periphery and brain. Here we investigated the impact of IF (16h of food deprivation daily) for 4months on NLRP1 and NLRP3 inflammasome activities following cerebral ischemia. Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion (I/R). IF decreased the activation of NF-κB and MAPK signaling pathways, the expression of NLRP1 and NLRP3 inflammasome proteins, and both IL-1β and IL-18 in the ischemic brain tissue. These findings demonstrate that IF can attenuate the inflammatory response and tissue damage following ischemic stroke by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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

2005-01-01

-vessel occlusion forebrain ischemia on core temperature (CT) and brain temperature (BT), respectively. After 10 min cerebral ischemia, BT was lower in alpha-MSH- than in saline-injected animals. After 10 min reperfusion, both CT and BT were lower than the corresponding pre-ischemic levels after injection of alpha...

Pathophysiological studies of experimental brain edema and cerebral ischemia using MRI/S

International Nuclear Information System (INIS)

Naruse, Shoji; Higuchi, Toshihiro; Horikawa, Yoshiharu; Tanaka, Chuzo; Hirakawa, Kimiyoshi

1987-01-01

Pathophysiological changes in experimental brain edema and cerebral ischemia were examined by the in vivo 1 H- and 31 P-NMR method. Two types of experimental brain edema were induced in rats by cold injury and by triethyltin (TET) intoxication. Experimental cerebral ischemia was induced in rats by the four-vessel occlusion method. During the course of these pathological conditions, the 1 H-MRIs and 31 P-NMR spectra were measured sequentially with a single NMR spectrometer (4.8 tesla, 9 cm bore magnet). In the cold-injury edema, high-intensity lesions were detected in the gray and white matters of the injured hemisphere by means of SE images with a long Te 3 hours after the injury. The intensity reached its maximum 16 to 24 hours after the injury, and then returned to normal 7 days later. These high-intensity lesions indicated an increase in the T2 value in the edematous tissue. There were no changes in the 31 P-NMR spectra during the course of edema formation and absorption. In the TET-induced edema, high-intensity lesions were also detected in the bilateral white matter by means of SE images with a long Te from the 3rd day up to the 7th day during the injection of TET. These high-intensity lesions subsided 42 days after the discontinuance of injecting TET. There were no changes in the 31 P-NMR spectra during the whole course of TET-induced edema. In the cerebral ischemia, no remarkable changes in the MRI were detected in either SE or IR images during the ischemic and recirculated periods. However, dynamic changes in the 31 P-NMR spectra were detected during the course of cerebral ischemia. In the pre-ischemic period, the peaks of the ATP, PCr, phosphodiesters (PDE), Pi, and phosphomonoesters (PME) were detected. After the induction of ischemia, the ATP and PCr peaks decreased, while one Pi peak increased rapidly. (J.P.N.)

Pathophysiological studies of experimental brain edema and cerebral ischemia using MRI/S

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Naruse, S; Higuchi, T; Horikawa, Y; Tanaka, C; Hirakawa, K

1987-02-01

Pathophysiological changes in experimental brain edema and cerebral ischemia were examined by the in vivo /sup 1/H- and /sup 31/P-NMR method. Two types of experimental brain edema were induced in rats by cold injury and by triethyltin (TET) intoxication. Experimental cerebral ischemia was induced in rats by the four-vessel occlusion method. During the course of these pathological conditions, the /sup 1/H-MRIs and /sup 31/P-NMR spectra were measured sequentially with a single NMR spectrometer (4.8 tesla, 9 cm bore magnet). In the cold-injury edema, high-intensity lesions were detected in the gray and white matters of the injured hemisphere by means of SE images with a long Te 3 hours after the injury. The intensity reached its maximum 16 to 24 hours after the injury, and then returned to normal 7 days later. These high-intensity lesions indicated an increase in the T2 value in the edematous tissue. There were no changes in the /sup 31/P-NMR spectra during the course of edema formation and absorption. In the TET-induced edema, high-intensity lesions were also detected in the bilateral white matter by means of SE images with a long Te from the 3rd day up to the 7th day during the injection of TET. These high-intensity lesions subsided 42 days after the discontinuance of injecting TET. There were no changes in the /sup 31/P-NMR spectra during the whole course of TET-induced edema. In the cerebral ischemia, no remarkable changes in the MRI were detected in either SE or IR images during the ischemic and recirculated periods. However, dynamic changes in the /sup 31/P-NMR spectra were detected during the course of cerebral ischemia. In the pre-ischemic period, the peaks of the ATP, PCr, phosphodiesters (PDE), Pi, and phosphomonoesters (PME) were detected. After the induction of ischemia, the ATP and PCr peaks decreased, while one Pi peak increased rapidly.

Diagnosis of hemodynamic compromise in patients with chronic cerebral ischemia; Measurement of cerebral blood volume (CBV) with sup 99m Tc-RBC SPECT

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Kuroda, Satoshi; Sakuragi, Mitsugi; Motomiya, Mineo; Nakagawa, Tango; Mitsumori, Kenji; Tsuru, Mitsuo (Hokkaido Neurosurgical Memorial Hospital (Japan)); Takigawa, Shugo; Kamiyama, Hiroyasu; Abe, Hiroshi

1990-03-01

To evaluate the efficacy of tests for selecting patients with hemodynamic compromise, measurement of cerebral blood volume (CBV) with {sup 99m}Tc-RBC single photon emission computed tomography (SPECT) was performed in thirteen patients with occlusive cerebrovascular disease, and was compared with results obtained by {sup 133}Xe SPECT and acetazolamide (Diamox) test. All patients in our study suffered TIA, RIND, or minor completed stroke. Cerebral angiography demonstrated severe stenosis or occlusion in the ipsilateral internal carotid artery or middle cerebral artery, although plain CT scan or MRI revealed no or, if any, only localized infarcted lesions. Regional cerebral blood volume (rCBV) was measured with {sup 99m}Tc-RBC SPECT and regional cerebral blood flow (rCBF) was measured with {sup 133}Xe SPECT before and after intravenous injection of 10 - 12 mg/kg acetazolamide (Diamox). Our results suggest that the ipsilateral rCBV/rCBF (mean transit time) is a more sensitive index of the cerebral perfusion reserve than the use of only rCBV or rCBF of the ipsilateral hemisphere. Also, the ipsilateral rCBV/rCBF is significantly correlated (r= -0.72) with the Diamox reactivity of rCBF, which is considered to represent the cerebral vasodilatory capacity in patients with chronic cerebral ischemia. Postoperative SPECT study revealed remarkable improvement of ipsilateral rCBV/rCBF and Diamox reactivity in four patients who underwent EC/IC bypass surgery to improve the hemodynamic compromise. In conclusion, our results suggest that the measurement of rCBV/rCBF with {sup 133}Xe SPECT and {sup 99m}Tc-RBC SPECT is useful for detecting the hemodynamic compromise in patients with occlusive cerebrovascular disease. (author).

Epileptiform abnormalities predict delayed cerebral ischemia in subarachnoid hemorrhage.

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Kim, J A; Rosenthal, E S; Biswal, S; Zafar, S; Shenoy, A V; O'Connor, K L; Bechek, S C; Valdery Moura, J; Shafi, M M; Patel, A B; Cash, S S; Westover, M B

2017-06-01

To identify whether abnormal neural activity, in the form of epileptiform discharges and rhythmic or periodic activity, which we term here ictal-interictal continuum abnormalities (IICAs), are associated with delayed cerebral ischemia (DCI). Retrospective analysis of continuous electroencephalography (cEEG) reports and medical records from 124 patients with moderate to severe grade subarachnoid hemorrhage (SAH). We identified daily occurrence of seizures and IICAs. Using survival analysis methods, we estimated the cumulative probability of IICA onset time for patients with and without delayed cerebral ischemia (DCI). Our data suggest the presence of IICAs indeed increases the risk of developing DCI, especially when they begin several days after the onset of SAH. We found that all IICA types except generalized rhythmic delta activity occur more commonly in patients who develop DCI. In particular, IICAs that begin later in hospitalization correlate with increased risk of DCI. IICAs represent a new marker for identifying early patients at increased risk for DCI. Moreover, IICAs might contribute mechanistically to DCI and therefore represent a new potential target for intervention to prevent secondary cerebral injury following SAH. These findings imply that IICAs may be a novel marker for predicting those at higher risk for DCI development. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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

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

2007-01-01

cerebral ischemia and endogenous NAEs. Over the first 24 h after induction of permanent middle cerebral artery occlusion, we observed a time-dependent increase in all the investigated NAEs, except for anandamide. Moreover, we found an accumulation of 2-AG at 4 h that returned to basal level 12 h after.......5 h before arterial occlusion decreased the infarct volume in our model system. Our results suggest that NAEs and 2-AG may be involved in regulation of neuroprotection during focal cerebral ischemia in mice....

Review on herbal medicine on brain ischemia and reperfusion简

Institute of Scientific and Technical Information of China (English)

Nahid; Jivad; Zahra; Rabiei

2015-01-01

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

Therapeutic potential of the novel hybrid molecule JM-20 against focal cortical ischemia in rats

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Yanier Núñez Figueredo

2016-08-01

Full Text Available Context: Despite the great mortality and morbidity of stroke, treatment options remain limited. We previously showed that JM-20, a novel synthetic molecule, possessed a strong neuroprotective effect in rats subjected to transient middle cerebral artery occlusion. However, to verify the robustness of the pre-clinical neuroprotective effects of JM-20 to get good prognosis in the translation to the clinic, it is necessary to use other experimental models of brain ischemia. Aims: To evaluate the neuroprotective effects of JM-20 following the onset of permanent focal cerebral ischemia induced in rats by thermocoagulation of blood into pial blood vessels of cerebral cortices. Methods: Ischemic lesion was induced by thermocoagulation of blood into pial blood vessels of primary motor and somatosensory cortices. Behavioral performance was evaluated by the cylinder testing for a period of 2, 3 and 7 days after surgery, and was followed by histopathological study in brain cortex stained with hematoxylin- eosin. Results: Ischemic injury resulted in impaired function of the forelimb evidenced by high asymmetry punctuation, and caused histopathological alterations indicative of tissue damage at cerebral cortex. JM-20 treatment (4 and 8 mg/kg significantly decreased asymmetry scores and histological alterations with a marked preservation of cortical neurons. Conclusions: The effects of permanent brain ischemia were strongly attenuated by JM-20 administration, which expands and improves the current preclinical data of JM-20 as neuroprotector against cerebral ischemia, and strongly support the examination of its translation to the clinic to treat acute ischemic stroke.

Smooth muscle cell phenotypic switching in stroke.

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Poittevin, Marine; Lozeron, Pierre; Hilal, Rose; Levy, Bernard I; Merkulova-Rainon, Tatiana; Kubis, Nathalie

2014-06-01

Disruption of cerebral blood flow after stroke induces cerebral tissue injury through multiple mechanisms that are not yet fully understood. Smooth muscle cells (SMCs) in blood vessel walls play a key role in cerebral blood flow control. Cerebral ischemia triggers these cells to switch to a phenotype that will be either detrimental or beneficial to brain repair. Moreover, SMC can be primarily affected genetically or by toxic metabolic molecules. After stroke, this pathological phenotype has an impact on the incidence, pattern, severity, and outcome of the cerebral ischemic disease. Although little research has been conducted on the pathological role and molecular mechanisms of SMC in cerebrovascular ischemic diseases, some therapeutic targets have already been identified and could be considered for further pharmacological development. We examine these different aspects in this review.

Impairment of neuropsychological function in patients with hemodynamic cerebral ischemia and efficacy of bypass surgery

International Nuclear Information System (INIS)

Sasoh, Masayuki

1999-01-01

In order to evaluate the relation between neuropsychological functions and hemodynamic cerebral ischemia, the author analyzed neuropsychological examination and the cerebral blood flow and metabolism of patients before and after bypass surgery. Twenty-five patients were defined by clinical and laboratory criteria as suffering from hemodynamic cerebral ischemia. All patients had one or more episodes of focal cerebral ischemia due to unilateral internal carotid or middle cerebral artery occlusion. Computerized tomography scans either were normal or showed evidence of watershed infarction. Based on these criteria, superficial temporal artery-proximal middle cerebral artery anastomosis was performed. The baseline cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO 2 ) and cerebrovascular reserve capacity (CVRC) were studied using positron emission computerized tomography (PET) and the acetazolamide test. Neuropsychological evaluations including Hasegawa Dementia Scale-Revised, Mini-Mental State and Wechsler Adult Intelligence Scale-Revised (WAIS-R), and PET study were completed one month after the last ischemic event and 3-6 months after the operation. A significant negative correlation was observed between OEF and neuropsychological functions. Postoperative neuropsychological functions showed significant improvement. Significant correlations were observed for ΔWAIS-R (preoperative WAIS-R postoperative WAIS-R) versus preoperative CMRO 2 (r=0.52), for ΔWAIS-R versus preoperative OEF (r=0.47). In view of these findings, the author concludes that elevation of OEF impairs neuropsychological functions and bypass surgery improves neuropsychological functions in patients with normal CMRO 2 and elevated OEF. (author)

Talampanel improves the functional deficit after transient focal cerebral ischemia in rats. A 30-day follow up study.

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Erdo, Franciska; Berzsenyi, Pál; Német, László; Andrási, Ferenc

2006-01-15

The neuroprotective effect of talampanel, a negative allosteric modulator of alpha-amino-3-hydroxy-methyl-4-isoxazolyl-propionic acid (AMPA) receptors has been described previously. However, in these studies the histological changes and not the functional consequences of the brain damage were evaluated. The aim of present investigation was to analyze the sensorimotor function after stroke and to test the influence of talampanel (GYKI-53773, LY-300164) by 30-day monitoring in rats. After 1h middle cerebral artery occlusion (MCAO) general 'well-being', neurological status, spontaneous motor activity, rotation, motor coordination, balancing, muscle strength and reaction time were followed for 1 month. Talampanel (6 x 10 mg/kg i.p. given on the day of stroke) improved the motor coordination in rotarod (p beam walking (p tests, reduced the number of stroke-induced rotations (p < 0.05), shortened the reflex time on the forelimb contralateral to brain ischemia and improved the survival rate comparing with vehicle treated control. After stroke, serious sensorimotor deficits appeared in rats but they showed partial spontaneous recovery after 30 days. Talampanel treatment enhanced the rate of functional improvement without changing the morphology at the end of the experiment. Our results indicate that modulation of AMPA receptors by talampanel can be a promising therapeutic approach to the treatment of stroke.

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

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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, ...

Electroacupuncture ameliorates post-stroke learning and memory through minimizing ultrastructural brain damage and inhibiting the expression of MMP-2 and MMP-9 in cerebral ischemia-reperfusion injured rats.

Science.gov (United States)

Lin, Ruhui; Yu, Kunqiang; Li, Xiaojie; Tao, Jing; Lin, Yukun; Zhao, Congkuai; Li, Chunyan; Chen, Li-Dian

2016-07-01

The aim of the present study was to investigate the potential neuroprotective effects of electroacupuncture (EA) in the treatment of cerebral ischemia/reperfusion (I/R) injury, and to elucidate the association between this neuroprotective effect and brain ultrastructure and expression of matrix metalloproteinase (MMP)‑2 and 9. Rats underwent focal cerebral I/R injury by arterial ligation and received in vivo therapeutic EA at the Baihui (DU20) and Shenting (DU24) acupoints. The therapeutic efficacy was then evaluated following the surgery. The results of the current study demonstrated that EA treatment significantly ameliorated neurological deficits and reduced cerebral infarct volume compared with I/R injured rats. Furthermore, EA improved the learning and memory ability of rats following I/R injury, inhibited blood brain barrier breakdown and reduced neuronal damage in the ischemic penumbra. Furthermore, EA attenuated ultrastructural changes in the brain tissue following ischemia and inhibited MMP‑2/MMP‑9 expression in cerebral I/R injured rats. The results suggest that EA ameliorates anatomical deterioration, and learning and memory deficits in rats with cerebral I/R injury.

Timing of Incident Stroke Risk After Cervical Artery Dissection Presenting Without Ischemia.

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Morris, Nicholas A; Merkler, Alexander E; Gialdini, Gino; Kamel, Hooman

2017-03-01

Cervical artery dissection is a common cause of stroke in young people. The temporal profile of stroke risk after cervical artery dissection presenting without ischemia remains uncertain. We performed a crossover cohort study using administrative claims data on all emergency department visits and acute care hospitalizations from 2005 to 2011 in CA, 2006 to 2013 in NY, and 2005 to 2013 in FL. Using previously validated International Classification of Diseases, Ninth Revision, Clinical Modification codes, we identified patients with a cervical artery dissection and no previous or concurrent stroke or transient ischemic attack diagnosis. We compared the risk of stroke in successive 2-week periods during the 12 weeks after dissection versus the corresponding 2-week period 1 year later. Absolute risk increases were calculated using McNemar test for matched data. In a sensitivity analysis, we limited our population to patients presenting with typical symptoms of cervical artery dissection. We identified 2791 patients with dissection without ischemia. The absolute increase in stroke risk was 1.25% (95% confidence interval, 0.84-1.67%) in the first 2 weeks after dissection compared with the same time period 1 year later. The absolute risk increase was 0.18% (95% confidence interval, 0.02-0.34%) during weeks 3 to 4 and was no longer significant during the remainder of the 12-week postdissection period. Our findings were similar in a sensitivity analysis identifying patients who presented with typical symptoms of acute dissection. The risk of stroke after cervical artery dissection unaccompanied by ischemia at time of diagnosis seems to be limited to the first 2 weeks. © 2017 American Heart Association, Inc.

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

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Wang-shu Xu

2016-01-01

Full Text Available 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.

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

OpenAIRE

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

2015-01-01

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and may represent a promising target for treatment. Sulforaphane exerts protective effects in a rat model of focal cerebral ischemia/reperfusion injury by alleviating brain edema. However, the possible mechanisms of sulforaphane after cerebral ischemia/reperfusion injury have not been fully elucidated. Therefore, in the present study, we investigated the effect of sulforaphane on inflammatory reaction and the potent...

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

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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.

The influence of stachydrine hydrochloride on the reperfusion model of mice with repetitive cerebral ischemia

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Mingsan Miao

2017-03-01

Full Text Available To study the influence of stachydrine hydrochloride on the inflammatory cytokines and tissue morphology of the re-perfusion model of mice with repetitive cerebral ischemia and probe into the protection mechanism of stachydrine hydrochloride for cerebral ischemia reperfusion impairment. Build a repetitive cerebral ischemia reperfusion model by first blocking the common carotid artery on both sides for 10 min, then resuming perfusion for 10 min and then blocking the common carotid artery on both sides again for 10 min. Before the operation, all the mice in the Nimodipine group, and the big, medium and small stachydrine hydrochloride dose groups were given corresponding gastric perfusion, the mice in the sham operation group and the modeled groups were at the same time given 0.5% sodium carboxymethyl cellulose for gastric perfusion of the same volume. The medicine was fed daily for 7 consecutive days. The model was built 1 h after the last feed and the perfusion continued for 24 h after the operation. Then the death rate of the mice was calculated. The mouse brains were taken out to test the ICAM-1 level and the TNF-α level, and the serum was taken out to test the NSE level and the MPO level. The tissue morphology changes were also observed. All the repetitive cerebral ischemia reperfusion models were successfully duplicated. The stachydrine hydrochloride in all the dose groups significantly reduced the death rates of big and small mice, reduced the level of ICAM-1 and the level of TNF-α in the brain tissues and the NSE level and the MPO level in the serum, significantly alleviating the pathological impairment in the hippocampus. Stachydrine hydrochloride can significantly reduce the death rate of mice, improve the pathological changes in the hippocampus, inhibit inflammatory reactions after ischemia, thus reducing the re-perfusion impairment after cerebral ischemia.

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

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

2014-01-01

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

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

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Fang-fang Liu

2015-01-01

Full Text Available 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.

Role of unphosphorylated transcription factor STAT3 in late cerebral ischemia after subarachnoid hemorrhage

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Samraj, Ajoy K; Müller, Anne H; Grell, Anne-Sofie

2014-01-01

Molecular mechanisms behind increased cerebral vasospasm and local inflammation in late cerebral ischemia after subarachnoid hemorrhage (SAH) are poorly elucidated. Using system biology tools and experimental SAH models, we have identified signal transducer and activator of transcription 3 (STAT3...

Fatty Acid Methyl Esters and Solutol HS 15 Confer Neuroprotection After Focal and Global Cerebral Ischemia

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Lin, Hung Wen; Saul, Isabel; Gresia, Victoria L.; Neumann, Jake T.; Dave, Kunjan R.; Perez-Pinzon, Miguel A.

2013-01-01

We previously showed that palmitic methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Soluto...

Ischemic strokes and migraine

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Bousser, M.G.; Baron, J.C.; Chiras, J.

1985-11-01

Lasting neurological deficits, though most infrequent, do occur in migrainous subjects and are well documented by clinical angiographic computed tomographic (CT scan) and even pathological studies. However the mechanism of cerebral ischemia in migraine remains widely unknown and the precise role of migraine in the pathogenesis of ischemic strokes is still debated. (orig./MG).

Impairment of neuropsychological function in patients with hemodynamic cerebral ischemia and efficacy of bypass surgery

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Sasoh, Masayuki [Iwate Medical Univ., Morioka (Japan). School of Medicine

1999-08-01

In order to evaluate the relation between neuropsychological functions and hemodynamic cerebral ischemia, the author analyzed neuropsychological examination and the cerebral blood flow and metabolism of patients before and after bypass surgery. Twenty-five patients were defined by clinical and laboratory criteria as suffering from hemodynamic cerebral ischemia. All patients had one or more episodes of focal cerebral ischemia due to unilateral internal carotid or middle cerebral artery occlusion. Computerized tomography scans either were normal or showed evidence of watershed infarction. Based on these criteria, superficial temporal artery-proximal middle cerebral artery anastomosis was performed. The baseline cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO{sub 2}) and cerebrovascular reserve capacity (CVRC) were studied using positron emission computerized tomography (PET) and the acetazolamide test. Neuropsychological evaluations including Hasegawa Dementia Scale-Revised, Mini-Mental State and Wechsler Adult Intelligence Scale-Revised (WAIS-R), and PET study were completed one month after the last ischemic event and 3-6 months after the operation. A significant negative correlation was observed between OEF and neuropsychological functions. Postoperative neuropsychological functions showed significant improvement. Significant correlations were observed for {delta}WAIS-R (preoperative WAIS-R postoperative WAIS-R) versus preoperative CMRO{sub 2} (r=0.52), for {delta}WAIS-R versus preoperative OEF (r=0.47). In view of these findings, the author concludes that elevation of OEF impairs neuropsychological functions and bypass surgery improves neuropsychological functions in patients with normal CMRO{sub 2} and elevated OEF. (author)

Recurrent cerebral thrombosis; With special reference to the neuroradiological study

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Iwamoto, Toshihiko; Abe, Shin-e; Kubo, Hideki; Hanyu, Haruo; Takasaki, Masaru (Tokyo Medical Coll. (Japan))

1992-10-01

Neuroradiological techniques were used to elucidate pathophysiology of recurrent cerebral thrombosis. Twenty-two patients with cerebral thrombosis who suffered a second attack under stable conditions more than 22 days after the initial stroke were studied. Hypertension, diabetes mellitus, and hypercholesterolemia were also seen in 20, 8, and 12 patients, respectively. The patients were divided into three groups according to their symptoms: (I) symptoms differed between the first and second strokes (n=12); (II) initial symptoms were suddenly deteriorated (n=6); and (III) symptoms occurring in groups I and II were seen (n=4). In group I, contralateral hemiparesis or suprabulbar palsy was often associated with the initial hemiparesis. The time of recurrent stroke varied from 4 months to 9 years. CT and MRI showed not only lacunae in both hemispheres, but also deep white-matter ischemia of the centrum semi-ovale. In group II, hemiparesis or visual field defect was deteriorated early after the initial stroke. In addition, neuroimaging revealed that infarction in the posterior cerebral artery was progressed on the contralateral side, or that white matter lesion in the middle artery was enlarged in spite of small lesion in the left cerebral hemisphere. All patients in group III had deterioration of right hemiparesis associated with aphasia. CT, MRI, SPECT, and angiography indicated deep white-matter ischemia caused by main trunk lesions in the left hemisphere. Group III seemed to be equivalent to group II, except for laterality of the lesion. Neuroradiological assessment of the initial stroke may help to predict the mode of recurrence, although pathophysiology of cerebral thrombosis is complicated and varies from patient to patient. (N.K.).

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

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Mustafa Guven

2015-04-01

Conclusion:Our results showed that p-coumaric acid is a neuroprotective agent on account of its strong anti-oxidant and anti-apoptotic features. Moreover, p-coumaric acid decreased the focal ischemia. Extra effort should be made to introduce p-coumaric acid as a promising therapeutic agent to be utilized for treatment of human cerebral ischemia in the future.

Momordica charantia polysaccharides could protect against cerebral ischemia/reperfusion injury through inhibiting oxidative stress mediated c-Jun N-terminal kinase 3 signaling pathway.

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Gong, Juanjuan; Sun, Fumou; Li, Yihang; Zhou, Xiaoling; Duan, Zhenzhen; Duan, Fugang; Zhao, Lei; Chen, Hansen; Qi, Suhua; Shen, Jiangang

2015-04-01

Momordica charantia (MC) is a medicinal plant for stroke treatment in Traditional Chinese Medicine, but its active compounds and molecular targets are unknown yet. M. charantia polysaccharide (MCP) is one of the important bioactive components in MC. In the present study, we tested the hypothesis that MCP has neuroprotective effects against cerebral ischemia/reperfusion injury through scavenging superoxide (O2(-)), nitric oxide (NO) and peroxynitrite (ONOO(-)) and inhibiting c-Jun N-terminal protein kinase (JNK3) signaling cascades. We conducted experiments with in vivo global and focal cerebral ischemia/reperfusion rat models and in vitro oxygen glucose deprivation (OGD) neural cells. The effects of MCP on apoptotic cell death and infarction volume, the bioactivities of scavenging O2(-), NO and ONOO(-), inhibiting lipid peroxidation and modulating JNK3 signaling pathway were investigated. Major results are summarized as below: (1) MCP dose-dependently attenuated apoptotic cell death in neural cells under OGD condition in vitro and reduced infarction volume in ischemic brains in vivo; (2) MCP had directing scavenging effects on NO, O2(-) and ONOO(-) and inhibited lipid peroxidation; (3) MCP inhibited the activations of JNK3/c-Jun/Fas-L and JNK3/cytochrome C/caspases-3 signaling cascades in ischemic brains in vivo. Taken together, we conclude that MCP could be a promising neuroprotective ingredient of M. charantia and its mechanisms could be at least in part attributed to its antioxidant activities and inhibiting JNK3 signaling cascades during cerebral ischemia/reperfusion injury. Copyright © 2014 Elsevier Ltd. All rights reserved.

Review on herbal medicine on brain ischemia and reperfusion

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Nahid Jivad

2015-10-01

Cerebral ischemia and reperfusion is known to induce the generation of reactive oxygen species that can lead to oxidative damage of proteins, membrane lipids and nucleic acids. A decrease in tissue antioxidant capacity, an increase in lipid peroxidation as well as an increase in lipid peroxidation inhibitors have been demonstrated in several models of brain ischemia. This paper reviews the number of commonly used types of herbal medicines effective for the treatment of stroke. The aim of this paper was to review evidences from controlled studies in order to discuss whether herbal medicine can be helpful in the treatment of brain ischemia and reperfusion.

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

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Hakimizadeh, Elham; Shamsizadeh, Ali; Roohbakhsh, Ali; Arababadi, Mohammad Kazemi; Hajizadeh, Mohammad Reza; Shariati, Mehdi; Fatemi, Iman; Moghadam-ahmadi, Amir; Bazmandegan, Gholamreza; Rezazadeh, Hossein; Allahtavakoli, Mohammad

2017-01-01

Objective(s): Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1) channels and toll-like receptors (TLRs) are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist) -treated and capsaicin (TRPV1 agonist) -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke. PMID:29085577

Deep Sequencing Reveals Uncharted Isoform Heterogeneity of the Protein-Coding Transcriptome in Cerebral Ischemia.

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Bhattarai, Sunil; Aly, Ahmed; Garcia, Kristy; Ruiz, Diandra; Pontarelli, Fabrizio; Dharap, Ashutosh

2018-06-03

Gene expression in cerebral ischemia has been a subject of intense investigations for several years. Studies utilizing probe-based high-throughput methodologies such as microarrays have contributed significantly to our existing knowledge but lacked the capacity to dissect the transcriptome in detail. Genome-wide RNA-sequencing (RNA-seq) enables comprehensive examinations of transcriptomes for attributes such as strandedness, alternative splicing, alternative transcription start/stop sites, and sequence composition, thus providing a very detailed account of gene expression. Leveraging this capability, we conducted an in-depth, genome-wide evaluation of the protein-coding transcriptome of the adult mouse cortex after transient focal ischemia at 6, 12, or 24 h of reperfusion using RNA-seq. We identified a total of 1007 transcripts at 6 h, 1878 transcripts at 12 h, and 1618 transcripts at 24 h of reperfusion that were significantly altered as compared to sham controls. With isoform-level resolution, we identified 23 splice variants arising from 23 genes that were novel mRNA isoforms. For a subset of genes, we detected reperfusion time-point-dependent splice isoform switching, indicating an expression and/or functional switch for these genes. Finally, for 286 genes across all three reperfusion time-points, we discovered multiple, distinct, simultaneously expressed and differentially altered isoforms per gene that were generated via alternative transcription start/stop sites. Of these, 165 isoforms derived from 109 genes were novel mRNAs. Together, our data unravel the protein-coding transcriptome of the cerebral cortex at an unprecedented depth to provide several new insights into the flexibility and complexity of stroke-related gene transcription and transcript organization.

Rapamycin preconditioning attenuates transient focal cerebral ischemia/reperfusion injury in mice.

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Yin, Lele; Ye, Shasha; Chen, Zhen; Zeng, Yaoying

2012-12-01

Rapamycin, an mTOR inhibitor and immunosuppressive agent in clinic, has protective effects on traumatic brain injury and neurodegenerative diseases. But, its effects on transient focal ischemia/reperfusion disease are not very clear. In this study, we examined the effects of rapamycin preconditioning on mice treated with middle cerebral artery occlusion/reperfusion operation (MCAO/R). We found that the rapamycin preconditioning by intrahippocampal injection 20 hr before MCAO/R significantly improved the survival rate and longevity of mice. It also decreased the neurological deficit score, infracted areas and brain edema. In addition, rapamycin preconditioning decreased the production of NF-κB, TNF-α, and Bax, but not Bcl-2, an antiapoptotic protein in the ischemic area. From these results, we may conclude that rapamycin preconditioning attenuate transient focal cerebral ischemia/reperfusion injury and inhibits apoptosis induced by MCAO/R in mice.

Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia

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Bolanle Famakin

2012-07-01

Full Text Available Abstract Background Deletion of some Toll-like receptors (TLRs affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT, MyD88−/− and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO. Methods Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. Results IL-6, keratinocyte chemoattractant (KC, granulocyte colony-stimulating factor (G-CSF and IL-10 were significantly decreased in MyD88−/− mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88−/− mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88−/− mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Conclusions Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88−/− mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.

Acute stroke magnetic resonance imaging: current status and future perspective

International Nuclear Information System (INIS)

Kloska, Stephan P.; Wintermark, Max; Engelhorn, Tobias; Fiebach, Jochen B.

2010-01-01

Cerebral stroke is one of the most frequent causes of permanent disability or death in the western world and a major burden in healthcare system. The major portion is caused by acute ischemia due to cerebral artery occlusion by a clot. The minority of strokes is related to intracerebral hemorrhage or other sources. To limit the permanent disability in ischemic stroke patients resulting from irreversible infarction of ischemic brain tissue, major efforts were made in the last decade. To extend the time window for thrombolysis, which is the only approved therapy, several imaging parameters in computed tomography and magnetic resonance imaging (MRI) have been investigated. However, the current guidelines neglect the fact that the portion of potentially salvageable ischemic tissue (penumbra) is not dependent on the time window but the individual collateral blood flow. Within the last years, the differentiation of infarct core and penumbra with MRI using diffusion-weighted images (DWI) and perfusion imaging (PI) with parameter maps was established. Current trials transform these technical advances to a redefined patient selection based on physiological parameters determined by MRI. This review article presents the current status of MRI for acute stroke imaging. A special focus is the ischemic stroke. In dependence on the pathophysiology of cerebral ischemia, the basic principle and diagnostic value of different MRI sequences are illustrated. MRI techniques for imaging of the main differential diagnoses of ischemic stroke are mentioned. Moreover, perspectives of MRI for imaging-based acute stroke treatment as well as monitoring of restorative stroke therapy from recent trials are discussed. (orig.)

Pharmacokinetic Study of Piracetam in Focal Cerebral Ischemic Rats.

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Paliwal, Pankaj; Dash, Debabrata; Krishnamurthy, Sairam

2018-04-01

Cerebral ischemia affects hepatic enzymes and brain permeability extensively. Piracetam was investigated up to phase III of clinical trials and there is lack of data on brain penetration in cerebral ischemic condition. Thus, knowledge of the pharmacokinetics and brain penetration of piracetam during ischemic condition would aid to improve pharmacotherapeutics in ischemic stroke. Focal cerebral ischemia was induced by middle cerebral artery occlusion for 2 h in male Wistar rats followed by reperfusion. After 24 h of middle cerebral artery occlusion or 22 h of reperfusion, piracetam was administered for pharmacokinetic, brain penetration, and pharmacological experiments. In pharmacokinetic study, blood samples were collected at different time points after 200-mg/kg (oral) and 75-mg/kg (intravenous) administration of piracetam through right external jugular vein cannulation. In brain penetration study, the cerebrospinal fluid, systemic blood, portal blood, and brain samples were collected at pre-designated time points after 200-mg/kg oral administration of piracetam. In a separate experiment, the pharmacological effect of the single oral dose of piracetam in middle cerebral artery occlusion was assessed at a dose of 200 mg/kg. All the pharmacokinetic parameters of piracetam including area under curve (AUC 0-24 ), maximum plasma concentration (C max ), time to reach the maximum plasma concentration (t max ), elimination half-life (t 1/2 ), volume of distribution (V z ), total body clearance, mean residence time, and bioavailability were found to be similar in ischemic stroke condition except for brain penetration. Piracetam exposure (AUC 0-2 ) in brain and CSF were found to be 2.4- and 3.1-fold higher, respectively, in ischemic stroke compared to control rats. Piracetam significantly reduced infarct volume by 35.77% caused by middle cerebral artery occlusion. There was no change in the pharmacokinetic parameters of piracetam in the ischemic stroke model except for

Neurotherapeutic activity of the recombinant heat shock protein Hsp70 in a model of focal cerebral ischemia in rats

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Shevtsov MA

2014-05-01

Full Text Available Maxim A Shevtsov,1,2 Boris P Nikolaev,3 Ludmila Y Yakovleva,3 Anatolii V Dobrodumov,4 Anastasiy S Dayneko,5 Alexey A Shmonin,5,6 Timur D Vlasov,5 Elena V Melnikova,5 Alexander D Vilisov,4,5 Irina V Guzhova,1 Alexander M Ischenko,3 Anastasiya L Mikhrina,7 Oleg V Galibin,5 Igor V Yakovenko,2 Boris A Margulis1 1Institute of Cytology of the Russian Academy of Sciences (RAS, St Petersburg, Russia; 2AL Polenov Russian Research Scientific Institute of Neurosurgery, St Petersburg, Russia; 3Research Institute of Highly Pure Biopreparations, St Petersburg, Russia; 4Institute of Macromolecular Compounds of the Russian Academy of Sciences (RAS, St Petersburg, Russia; 5First St Petersburg IP Pavlov State Medical University, St Petersburg, Russia; 6Federal Almazov Medical Research Centre, St Petersburg, Russia; 7IM Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences (RAS, St Petersburg, Russia Abstract: Recombinant 70 kDa heat shock protein (Hsp70 is an antiapoptotic protein that has a cell protective activity in stress stimuli and thus could be a useful therapeutic agent in the management of patients with acute ischemic stroke. The neuroprotective and neurotherapeutic activity of recombinant Hsp70 was explored in a model of experimental stroke in rats. Ischemia was produced by the occlusion of the middle cerebral artery for 45 minutes. To assess its neuroprotective capacity, Hsp70, at various concentrations, was intravenously injected 20 minutes prior to ischemia. Forty-eight hours after ischemia, rats were sacrificed and brain tissue sections were stained with 2% triphenyl tetrazolium chloride. Preliminary treatment with Hsp70 significantly reduced the ischemic zone (optimal response at 2.5 mg/kg. To assess Hsp70’s neurotherapeutic activity, we intravenously administered Hsp70 via the tail vein 2 hours after reperfusion (2 hours and 45 minutes after ischemia. Rats were then kept alive for 72 hours. The

Protective Effects and Mechanism of Puerarin on Learning-Memory Disorder after Global Cerebral Ischemia-Reperfusion Injury in Rats

Institute of Scientific and Technical Information of China (English)

WU Hai-qin; GUO He-na; WANG Hu-qing; CHANG Ming-ze; ZHANG Gui-lian; ZHAO Ying-xian

2009-01-01

Objective: To observe the effect of puerarin on the learning-memory disorder after global cerebral ischemia-reperfusion injury in rats, and to explore its mechanism of action. Methods: The global cerebral ischemia-reperfusion injury model was established using the modified Pulsinelli four-vessel occlusion in Sprague-Dawley rats. Rats were intraperitoneally injected with puerarin (100 mg/kg) 1 h before ischemia and once every 6 h afterwards. The learning-memory ability was evaluated by the passive avoidance test. The dynamic changes of the cell counts of apoptosis and positive expression of Bcl-2 in the hippocampus CA1 region were determined by the TUNEL and immunohistochemical methods, respectively. Results: (1) Compared with the reperfusion group, the step through latency (STL) in the passive avoidance test in the puerarin group was prolonged significantly (P<0.01). (2) The apoptotic neurons were injured most severely on the 3rd day in the hippocampal CA1 region after global ischemia and reperfusion. In the pueradn group, the number of apoptotic cells decreased at respective time points after ischemia-reperfusion (P<0.01). (3) The level of positive expression of Bcl-2 varied according to the duration of reperfusion and the peak level occurred on day 1 in the hippocampal CA1 region after global cerebral ischemia. Compared with the reperfusion group, the expression of Bcl-2 in the pueradn group was up-regulated at the respective time points after ischemia raperfusion (P<0.01), reaching the peak on day 1. Conclusions: Puerarin could improve the learning-memory ability after global cerebral ischemia and reperfusion in rats. The protective mechanism might be related to the effect of inhibiting or delaying the cell apoptosis through up-regulating the expression of Bcl-2 after ischemia and reperfusion.

Preliminary experience on early mechanical recanalization of middle cerebral artery for acute ischemic stroke and literature review

International Nuclear Information System (INIS)

Bai Weixing; Li Tianxiao; Zhu Liangfu; Xue Jiangyu; Wang Ziliang

2012-01-01

Objective: To evaluate the feasibility,efficacy and complication of early middle cerebral artery (MCA) mechanical recanalization (MER) for treatment of acute ischemic stroke. Methods: Seven cases undergone MER of MCA for the treatment of acute cerebral infarct were retrospectively reviewed and analyzed, including the etiology, mechanism, Qureshi grading scale, location and size of infarcts, NIHSS score of pre and post procedure, endovascular technique and complications. Referring to the literature, the indications of MCA recanalization were further identified. Results: A total of 7 cases with mean age of 48 yrs were reviewed, which included 3 cases of atherosclerotic thrombosis and 4 embolic cases with pre NIHSS score ranging from 3 to 22. Mechanical recanalization succeeded in 6 cases, but 2 cases of cardiogenic embolism died of intracranial hemorrhage postoperatively. Favorable clinical outcomes were achieved in 4 cases whereas 1 deteriorated. Overall complications seemed to be consistent with literatures reviewed. Conclusions: Early MER of MCA may benefit to a certain subset of acute ischemia stroke patients, however, embolic cases, elder patients and those with severe neurologic deficits are often accompanied by higher complications and unfavorable outcome. (authors)

Regulatory mechanism of endothelin receptor B in the cerebral arteries after focal cerebral ischemia

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Grell, Anne-Sofie; Thigarajah, Rushani; Edvinsson, Lars

2014-01-01

BACKGROUND AND PURPOSE: Increased expression of endothelin receptor type B (ETBR), a vasoactive receptor, has recently been implied in the reduced cerebral blood flow and exacerbated neuronal damage after ischemia-reperfusion (I/R). The study explores the regulatory mechanisms of ETBR to identify...... drug targets to restore normal cerebral artery contractile function as part of successful neuroprotective therapy. METHODS: We have employed in vitro methods on human and rat cerebral arteries to study the regulatory mechanisms and the efficacy of target selective inhibitor, Mithramycin A (Mit...... the ETBR mRNA and protein levels. It also significantly reduced the ETBR mediated cerebrovascular contractility. Detailed analysis indicated that ERK1/2 mediated phosphorylation of Sp1 might be essential for ETBR transcription. CONCLUSION: Transcription factor Sp1 regulates the ETBR mediated...

The role of the endoplasmic reticulum stress response following cerebral ischemia.

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Hadley, Gina; Neuhaus, Ain A; Couch, Yvonne; Beard, Daniel J; Adriaanse, Bryan A; Vekrellis, Kostas; DeLuca, Gabriele C; Papadakis, Michalis; Sutherland, Brad A; Buchan, Alastair M

2018-06-01

Background Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death. We investigated endoplasmic reticulum stress responses in CA1 and CA3 regions following global cerebral ischemia, and whether pharmacological modulation of endoplasmic reticulum stress or autophagy altered neuronal viability . Methods In vivo: male Wistar rats underwent sham or 10 min of transient global cerebral ischemia. CA1 and CA3 areas were microdissected and endoplasmic reticulum stress protein expression quantified at 3 h and 12 h of reperfusion. In vitro: primary neuronal cultures (E18 Wistar rat embryos) were exposed to 2 h of oxygen and glucose deprivation or normoxia in the presence of an endoplasmic reticulum stress inducer (thapsigargin or tunicamycin), an endoplasmic reticulum stress inhibitor (salubrinal or 4-phenylbutyric acid), an autophagy inducer ([4'-(N-diethylamino) butyl]-2-chlorophenoxazine (10-NCP)) or autophagy inhibitor (3-methyladenine). Results In vivo, decreased endoplasmic reticulum stress protein expression (phospho-eIF2α and ATF4) was observed at 3 h of reperfusion in CA3 neurons following ischemia, and increased in CA1 neurons at 12 h of reperfusion. In vitro, endoplasmic reticulum stress inducers and high doses of the endoplasmic reticulum stress inhibitors also increased cell death. Both induction and inhibition of autophagy also increased cell death. Conclusion Endoplasmic reticulum stress is associated with neuronal cell death following ischemia. Neither reduction of endoplasmic reticulum stress nor induction of autophagy demonstrated neuroprotection in vitro, highlighting their complex role in neuronal biology following ischemia.

Neuroprotective effect of TAT-14-3-3ε fusion protein against cerebral ischemia/reperfusion injury in rats.

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Yuanjun Zhu

Full Text Available Stroke is the major cause of death and disability worldwide, and the thrombolytic therapy currently available was unsatisfactory. 14-3-3ε is a well characterized member of 14-3-3 family, and has been reported to protect neurons against apoptosis in cerebral ischemia. However, it cannot transverse blood brain barrier (BBB due to its large size. A protein transduction domain (PTD of HIV TAT protein, is capable of delivering a large variety of proteins into the brain. In this study, we generated a fusion protein TAT-14-3-3ε, and evaluated its potential neuroprotective effect in rat focal ischemia/reperfusion (I/R model. Western blot analysis validated the efficient transduction of TAT-14-3-3ε fusion protein into brain via a route of intravenous injection. TAT-14-3-3ε pre-treatment 2 h before ischemia significantly reduced cerebral infarction volume and improved neurologic score, while post-treatment 2 h after ischemia was less effective. Importantly, pre- or post-ischemic treatment with TAT-14-3-3ε significantly increased the number of surviving neurons as determined by Nissl staining, and attenuated I/R-induced neuronal apoptosis as showed by the decrease in apoptotic cell numbers and the inhibition of caspase-3 activity. Moreover, the introduction of 14-3-3ε into brain by TAT-mediated delivering reduced the formation of autophagosome, attenuated LC3B-II upregulation and reversed p62 downregulation induced by ischemic injury. Such inhibition of autophagy was reversed by treatment with an autophagy inducer rapamycin (RAP, which also attenuated the neuroprotective effect of TAT-14-3-3ε. Conversely, autophagy inhibitor 3-methyladenine (3-MA inhibited I/R-induced the increase in autophagic activity, and attenuated I/R-induced brain infarct. These results suggest that TAT-14-3-3ε can be efficiently transduced into brain and exert significantly protective effect against brain ischemic injury through inhibiting neuronal apoptosis and autophagic

[Cerebral protection].

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Cattaneo, A D

1993-09-01

Cerebral protection means prevention of cerebral neuronal damage. Severe brain damage extinguishes the very "human" functions such as speech, consciousness, intellectual capacity, and emotional integrity. Many pathologic conditions may inflict injuries to the brain, therefore the protection and salvage of cerebral neuronal function must be the top priorities in the care of critically ill patients. Brain tissue has unusually high energy requirements, its stores of energy metabolites are small and, as a result, the brain is totally dependent on a continuous supply of substrates and oxygen, via the circulation. In complete global ischemia (cardiac arrest) reperfusion is characterized by an immediate reactive hyperemia followed within 20-30 min by a delayed hypoperfusion state. It has been postulated that the latter contributes to the ultimate neurologic outcome. In focal ischemia (stroke) the primary focus of necrosis is encircled by an area (ischemic penumbra) that is underperfused and contains neurotoxic substances such as free radicals, prostaglandins, calcium, and excitatory neurotransmitters. The variety of therapeutic effort that have addressed the question of protecting the brain reflects their limited success. 1) Barbiturates. After an initial enthusiastic endorsement by many clinicians and years of vigorous controversy, it can now be unequivocally stated that there is no place for barbiturate therapy following resuscitation from cardiac arrest. One presumed explanation for this negative statement is that cerebral metabolic suppression by barbiturates (and other anesthetics) is impossible in the absence of an active EEG. Conversely, in the event of incomplete ischemia EEG activity in usually present (albeit altered) and metabolic suppression and hence possibly protection can be induced with barbiturates. Indeed, most of the animal studies led to a number of recommendations for barbiturate therapy in man for incomplete ischemia. 2) Isoflurane. From a cerebral

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

DEFF Research Database (Denmark)

Lassen, N A

1990-01-01

Current knowledge of the pathophysiology of cerebral ischemia, summarized in the present study, predicts that neurological deficits caused by moderate ischemia (flows in the penumbral range between 23 and 10 ml/100 g/min) are reversible provided flow is restored within 3-4 h of onset. It also...

High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.

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Brückner, Melanie; Lasarzik, Irina; Jahn-Eimermacher, Antje; Peetz, Dirk; Werner, Christian; Engelhard, Kristin; Thal, Serge C

2013-09-13

Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10. rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity. Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Manual Aspiration Thrombectomy in Patients with Acute Stroke-Related Calcified Cerebral Emboli.

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Koh, Esther; Kwak, Hyo Sung; Chung, Gyung-Ho

2017-10-01

The aim of this study was to evaluate the effectiveness of mechanical aspiration thrombectomy (MAT) in patients with acute ischemic stroke from calcified cerebral emboli. Procedural results were reviewed for acute stroke patients with clinically neurological deficits who underwent recanalization from October 2012 through September 2015. Initial imaging studies and cerebral angiography were analyzed. Of the total number of patients with acute stroke, 5 patients were confirmed to have acute ischemic stroke by calcified cerebral emboli. On initial brain computed tomographic imaging, all patients showed small, dense single calcifications in the middle cerebral artery with no definitive ischemic low-density lesions (M1: 3, M2: 2, mean size: 4.8 mm). All patients had angiographic findings of filling defects from calcified emboli. Four patients had good collateral flow and two had continuous distal flow. All patients underwent MAT using a Penumbra catheter (Penumbra Inc., Alameda, CA). MAT did not remove calcified emboli in all patients. Two patients with good collateral flow had favorable functional outcomes (modified Rankin Scale score ≤2). Four patients had diffuse calcification in the aortic arch, carotid artery, and aortic valve. Cerebral angiography supports a diagnosis of stroke when calcified cerebral emboli have contrast-filling defects and a degree of vascular occlusion. However, in this study, MAT was not an effective treatment for patients with calcified cerebral emboli because of hardness of the calcified plaque and packing into the arterial lumen. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages.

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Virginie Desestret

Full Text Available THE INFLAMMATORY RESPONSE FOLLOWING ISCHEMIC STROKE IS DOMINATED BY INNATE IMMUNE CELLS: resident microglia and blood-derived macrophages. The ambivalent role of these cells in stroke outcome might be explained in part by the acquisition of distinct functional phenotypes: classically (M1 and alternatively activated (M2 macrophages. To shed light on the crosstalk between hypoxic neurons and macrophages, an in vitro model was set up in which bone marrow-derived macrophages were co-cultured with hippocampal slices subjected to oxygen and glucose deprivation. The results showed that macrophages provided potent protection against neuron cell loss through a paracrine mechanism, and that they expressed M2-type alternative polarization. These findings raised the possibility of using bone marrow-derived M2 macrophages in cellular therapy for stroke. Therefore, 2 million M2 macrophages (or vehicle were intravenously administered during the subacute stage of ischemia (D4 in a model of transient middle cerebral artery occlusion. Functional neuroscores and magnetic resonance imaging endpoints (infarct volumes, blood-brain barrier integrity, phagocytic activity assessed by iron oxide uptake were longitudinally monitored for 2 weeks. This cell-based treatment did not significantly improve any outcome measure compared with vehicle, suggesting that this strategy is not relevant to stroke therapy.

Transient cerebral ischemia induces albumin expression in microglia only in the CA1 region of the gerbil hippocampus.

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Park, Joon Ha; Park, Jin-A; Ahn, Ji Hyeon; Kim, Yang Hee; Kang, Il Jun; Won, Moo-Ho; Lee, Choong-Hyun

2017-07-01

Albumin, the most abundant plasma protein, is known to exhibit a neuroprotective effect in animal models of focal and global cerebral ischemia. In the present study, the expression and immunoreactivity of albumin was examined in the hippocampus following 5 min of transient cerebral ischemia in gerbils. Albumin immunoreactivity was observed in microglia of the CA1 hippocampal region 2 days post‑ischemic insult, and it was significantly increased at 4 days following ischemia-reperfusion. In addition, at 4 days post‑ischemic insult, albumin‑immunoreactive microglia were abundant in the stratum pyramidale of the CA1 region. The present results demonstrated that albumin was newly expressed post‑injury in microglia in the CA1 region, suggesting ischemia‑induced neuronal loss. Albumin expression may therefore be associated with ischemia‑induced delayed neuronal death in the CA1 region following transient cerebral ischemia.

Changes of resting cerebral activities in subacute ischemic stroke patients

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Ping Wu

2015-01-01

Full Text Available This study aimed to detect the difference in resting cerebral activities between ischemic stroke patients and healthy participants, define the abnormal site, and provide new evidence for pathological mechanisms, clinical diagnosis, prognosis prediction and efficacy evaluation of ischemic stroke. At present, the majority of functional magnetic resonance imaging studies focus on the motor dysfunction and the acute stage of ischemic stroke. This study recruited 15 right-handed ischemic stroke patients at subacute stage (15 days to 11.5 weeks and 15 age-matched healthy participants. A resting-state functional magnetic resonance imaging scan was performed on each subject to detect cerebral activity. Regional homogeneity analysis was used to investigate the difference in cerebral activities between ischemic stroke patients and healthy participants. The results showed that the ischemic stroke patients had lower regional homogeneity in anterior cingulate and left cerebrum and higher regional homogeneity in cerebellum, left precuneus and left frontal lobe, compared with healthy participants. The experimental findings demonstrate that the areas in which regional homogeneity was different between ischemic stroke patients and healthy participants are in the cerebellum, left precuneus, left triangle inferior frontal gyrus, left inferior temporal gyrus and anterior cingulate. These locations, related to the motor, sensory and emotion areas, are likely potential targets for the neural regeneration of subacute ischemic stroke patients.

Arctigenin protects focal cerebral ischemia-reperfusion rats through inhibiting neuroinflammation.

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Fan, Tao; Jiang, Wei Long; Zhu, Jian; Feng Zhang, Yu

2012-01-01

Stroke is the third leading cause of death in industrialized countries and the most important cause of acquired adult disability. Many evidences suggest that inflammation accounts for the progression of cerebral ischemic injury. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignin isolated from certain plants, has shown anti-inflammatory activity against diabetes and Alzheimer's disease. In this study, we tested whether arctigenin can protect middle cerebral artery occluded (MCAO) rats. Male Sprague-Dawley rats were pretreated with arctigenin or vehicle for 7 d before being subjected to transient occlusion of middle cerebral artery and reperfusion. Rats were evaluated at 24 h after MCAO for neurological deficit scoring. Furthermore, the mechanism of the anti-inflammatory effect of arctigenin was investigated with a focus on inflammatory cells, proinflammatory cytokines, and transcriptional factors. Arctigenin significantly reduced cerebral infarction and improved neurological outcome. Arctigenin suppressed the activation of microglia and decreased the expression of interleukin (IL)- 1β and tumor necrosis factor (TNF)-α. These results revealed that arctigenin has a promising therapeutic effect in ischemic stroke treatment through an anti-inflammatory mechanism.

Clinical usefulness of a biomarker-based diagnostic test for acute stroke: the Biomarker Rapid Assessment in Ischemic Injury (BRAIN) study.

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Laskowitz, Daniel T; Kasner, Scott E; Saver, Jeffrey; Remmel, Kerri S; Jauch, Edward C

2009-01-01

One of the significant limitations in the evaluation and management of patients with suspected acute cerebral ischemia is the absence of a widely available, rapid, and sensitive diagnostic test. The objective of the current study was to assess whether a test using a panel of biomarkers might provide useful diagnostic information in the early evaluation of stroke by differentiating patients with cerebral ischemia from other causes of acute neurological deficit. A total of 1146 patients presenting with neurological symptoms consistent with possible stroke were prospectively enrolled at 17 different sites. Timed blood samples were assayed for matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and protein S100beta. A separate cohort of 343 patients was independently enrolled to validate the multiple biomarker model approach. A diagnostic tool incorporating the values of matrix metalloproteinase 9, brain natriuretic factor, d-dimer, and S-100beta into a composite score was sensitive for acute cerebral ischemia. The multivariate model demonstrated modest discriminative capabilities with an area under the receiver operating characteristic curve of 0.76 for hemorrhagic stroke and 0.69 for all stroke (likelihood test P<0.001). When the threshold for the logistic model was set at the first quartile, this resulted in a sensitivity of 86% for detecting all stroke and a sensitivity of 94% for detecting hemorrhagic stroke. Moreover, results were reproducible in a separate cohort tested on a point-of-care platform. These results suggest that a biomarker panel may add valuable and time-sensitive diagnostic information in the early evaluation of stroke. Such an approach is feasible on a point-of-care platform. The rapid identification of patients with suspected stroke would expand the availability of time-limited treatment strategies. Although the diagnostic accuracy of the current panel is clearly imperfect, this study demonstrates the feasibility of incorporating a

Collateral blood flow in different cerebrovascular hierarchy provides endogenous protection in cerebral ischemia.

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Luo, Chuanming; Liang, Fengyin; Ren, Huixia; Yao, Xiaoli; Liu, Qiang; Li, Mingyue; Qin, Dajiang; Yuan, Ti-Fei; Pei, Zhong; Su, Huanxing

2017-11-01

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. © 2016 International Society of

Modulation of key biochemical markers relevant to stroke by Antiaris ...

African Journals Online (AJOL)

Modulation of key biochemical markers relevant to stroke by Antiaris africana leaf extract following cerebral ischemia/reperfusion injury. Omotayo B. Ilesanmi, Afolabi C. Akinmoladun, Olanrewaju Sam Olayeriju, Ibrahim Olabayode Saliu, M. Tolulope Olaleye, Afolabi A. Akindahunsi ...

Obstruction of cerebral arteries in childhood stroke

International Nuclear Information System (INIS)

Velkey, I.; Lombay, B.; Panczel, G.

1992-01-01

Middle cerebral artery obstruction in children is reviewed by our two cases. Ischemic childhood stroke was caused by moyamoya disease in the first, and by fibromuscular dysplasia in the second patient. In both cases transcranial Doppler sonography and cranial CT were performed, but the final diagnosis was made by angiography. The importance of angiography in childhood stroke is emphasized. (orig.)

Cerebral ischemic stroke: is gender important?

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Gibson, Claire L

2013-09-01

Cerebral stroke continues to be a major cause of death and the leading cause of long-term disability in developed countries. Evidence reviewed here suggests that gender influences various aspects of the clinical spectrum of ischemic stroke, in terms of influencing how a patients present with ischemic stroke through to how they respond to treatment. In addition, this review focuses on discussing the various pathologic mechanisms of ischemic stroke that may differ according to gender and compares how intrinsic and hormonal mechanisms may account for such gender differences. All clinical trials to date investigating putative neuroprotective treatments for ischemic stroke have failed, and it may be that our understanding of the injury cascade initiated after ischemic injury is incomplete. Revealing aspects of the pathophysiological consequences of ischemic stroke that are gender specific may enable gender relevant and effective neuroprotective strategies to be identified. Thus, it is possible to conclude that gender does, in fact, have an important role in ischemic stroke and must be factored into experimental and clinical investigations of ischemic stroke.

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

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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.

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

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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.

Characteristics and dynamics of cognitive impairment in patients with primary and recurrent cerebral ischemic hemispheric stroke

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A. A. Kozyolkin

2014-08-01

Full Text Available Acute cerebrovascular disease is a global medical and social problem of the modern angioneurology, occupying leading positions in the structure of morbidity and mortality among adult population of the world. Ischemic stroke – is one of the most common pathology. Today this disease took out the world pandemic. More than 16 million new cases of cerebral infarction recorded in the world each year and it “kills” about 7 million of people. About 111,953 cases of cerebral stroke were registered in 2013 in Ukraine. Cognitive impairment, t hat significantly disrupt daily activities and life of the patient, is one of the most significant post-stroke complications that have social, medical and biological significance. Aim. The purpose of this investigation was to study features and dynamics of cognitive impairments in patients with primary and recurrent cerebral hemispheric ischemic stroke (CHIS in the acute stage of the disease. Materials and methods. To achieve the aim, and the decision of tasks in the clinic of nervous diseases Zaporozhye State Medical University (supervisor - Doctor of Medicine, Professor Kozelkin A. based on the department of acute cerebrovascular disease were performed comparative, prospective cohort study, which included comprehensive clinical and paraclinical examinations of 41 patients (26 men and 15 women aged 45 to 85 years (mean age 66,4 ± 1,4 years with acute left-hemispheric (2 patients and right - hemispheric (39 patients CHIS . First up was a group of 28 patients (19 men and 9 women, mean age 65,6 ± 1,6 years, who suffered from primary CHIS. The second group consisted of 13 patients (7 men and 6 women, mean age 68,1 ± 2,5 years with recurrent CHIS. The groups were matched by age, sex, localization of the lesion and the initial level of neurological deficit. All patients underwent physical examination, neurological examination. Dynamic clinical neurological examination assessing the severity of stroke was conducted

TRPV1 receptor-mediated expression of Toll-like receptors 2 and 4 following permanent middle cerebral artery occlusion in rats

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Elham Hakimizadeh

2017-08-01

Full Text Available Objective(s: Stroke is known as a main cause of mortality and prolonged disability in adults. Both transient receptor potential V1 (TRPV1 channels and toll-like receptors (TLRs are involved in mediating the inflammatory responses. In the present study, the effects of TRPV1 receptor activation and blockade on stroke outcome and gene expression of TLR2 and TLR4 were assessed following permanent middle cerebral artery occlusion in rats Materials and Methods: Eighty male Wistar rats were divided into four groups as follows: sham, vehicle, AMG9810 (TRPV1 antagonist -treated and capsaicin (TRPV1 agonist -treated. For Stroke induction, the middle cerebral artery was permanently occluded and then behavioral functions were evaluated 1, 3 and 7 days after stroke. Results: TRPV1 antagonism significantly reduced the infarct volume compared to the stroke group. Also, neurological deficits were decreased by AMG9810 seven days after cerebral ischemia. In the ledged beam-walking test, the slip ratio was enhanced following ischemia. AMG9810 decreased this index in stroke animals. However, capsaicin improved the ratio 3 and 7 days after cerebral ischemia. Compared to the sham group, the mRNA expression of TLR2 and TLR4 was significantly increased in the stroke rats. AMG9810 Administration significantly reduced the mRNA expression of TLR2 and TLR4. However, capsaicin did not significantly affect the gene expression of TLR2 and TLR4. Conclusion: Our results demonstrated that TRPV1 antagonism by AMG9810 attenuates behavioral function and mRNA expression of TLR2 and TLR4. Thus, it might be useful to shed light on future therapeutic strategies for the treatment of ischemic stroke.

Cerebral and extracerebral vasoreactivity in symptomatic lacunar stroke patients: a case-control study.

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Deplanque, Dominique; Lavallee, Philippa C; Labreuche, Julien; Gongora-Rivera, Fernando; Jaramillo, Arturo; Brenner, David; Abboud, Halim; Klein, Isabelle F; Touboul, Pierre-Jean; Vicaut, Eric; Amarenco, Pierre

2013-08-01

Whether cerebral artery endothelial dysfunction is a key factor of symptomatic lacunar stroke and cerebral small vessel disease remains unclear. Cerebral and extracerebral vasoreactivity were measured in 81 patients with recent symptomatic lacunar stroke and in 81 control subjects matched for main vascular risk factors. Cerebral vasoreactivity and carotid endothelial-dependent vasodilation were measured after five-minutes of carbon dioxide-induced hypercapnia. Brachial endothelial-dependent vasodilation was assessed after hyperemia induced by deflating a cuff around the forearm previously inflated to 200 mmHg for four-minutes. Carotid and brachial endothelial-independent vasodilation were measured five-minutes after administration of sublingual nitroglycerin 300 μg. Brain magnetic resonance imaging were analyzed in lacunar stroke patients. One-month after stroke onset, patients had more severely impaired cerebral vasoreactivitys than matched controls (mean ± standard deviation, 14·4 ± 12·1% vs. 19·4 ± 17·4%; P = 0·049). Severe alterations of both carotid and brachial endothelial-dependent and at a lesser degree of carotid and brachial endothelial-independent vasodilation were observed in both groups. After adjustment for confounders, subjects with a cerebral vasoreactivity value in the two lower tertiles (≤19·6%) were more likely to have had a symptomatic lacunar stroke (adjusted odds ratio, 3·78; 95% confidence interval, 1·42 to 10·08; P = 0·008). Only alteration of brachial endothelial-independent vasodilation correlated with parenchymal abnormalities, namely microbleeds and leukoaraiosis. While abnormalities in extracerebral vasoreactivity seem related to vascular risk factors, the severity of endothelial dysfunction in cerebral arteries may be determinant in the occurrence of symptomatic lacunar stroke in patients with small vessel disease. © 2012 The Authors. International Journal of Stroke © 2012 World Stroke

Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury.

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Cao, Wei; Li, Aiqing; Li, Jiawen; Wu, Chunyi; Cui, Shuang; Zhou, Zhanmei; Liu, Youhua; Wilcox, Christopher S; Hou, Fan Fan

2017-09-01

A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury. Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p renal damage and dysfunction persisted after controlling blood pressure with hydralazine. This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

Spreading depression and focal venous cerebral ischemia enhance cortical neurogenesis

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Ryo Tamaki

2017-01-01

Full Text Available 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.

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

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

2014-01-01

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

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein

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Rui-Xin Yang

2017-06-01

Full Text Available Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB, against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro. SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Pretreatment with Sodium Phenylbutyrate Alleviates Cerebral Ischemia/Reperfusion Injury by Upregulating DJ-1 Protein.

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Yang, Rui-Xin; Lei, Jie; Wang, Bo-Dong; Feng, Da-Yun; Huang, Lu; Li, Yu-Qian; Li, Tao; Zhu, Gang; Li, Chen; Lu, Fang-Fang; Nie, Tie-Jian; Gao, Guo-Dong; Gao, Li

2017-01-01

Oxidative stress and mitochondrial dysfunction play critical roles in ischemia/reperfusion (I/R) injury. DJ-1 is an endogenous antioxidant that attenuates oxidative stress and maintains mitochondrial function, likely acting as a protector of I/R injury. In the present study, we explored the protective effect of a possible DJ-1 agonist, sodium phenylbutyrate (SPB), against I/R injury by protecting mitochondrial dysfunction via the upregulation of DJ-1 protein. Pretreatment with SPB upregulated the DJ-1 protein level and rescued the I/R injury-induced DJ-1 decrease about 50% both in vivo and in vitro . SPB also improved cellular viability and mitochondrial function and alleviated neuronal apoptosis both in cell and animal models; these effects of SPB were abolished by DJ-1 knockdown with siRNA. Furthermore, SPB improved the survival rate about 20% and neurological functions, as well as reduced about 50% of the infarct volume and brain edema, of middle cerebral artery occlusion mice 23 h after reperfusion. Therefore, our findings demonstrate that preconditioning of SPB possesses a neuroprotective effect against cerebral I/R injury by protecting mitochondrial function dependent on the DJ-1 upregulation, suggesting that DJ-1 is a potential therapeutic target for clinical ischemic stroke.

Fas/CD95 regulatory protein Faim2 is neuroprotective after transient brain ischemia.

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Reich, Arno; Spering, Christopher; Gertz, Karen; Harms, Christoph; Gerhardt, Ellen; Kronenberg, Golo; Nave, Klaus A; Schwab, Markus; Tauber, Simone C; Drinkut, Anja; Harms, Kristian; Beier, Chrstioph P; Voigt, Aaron; Göbbels, Sandra; Endres, Matthias; Schulz, Jörg B

2011-01-05

Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities. Fas apoptotic inhibitory molecule 2 (Faim2) is an evolutionary conserved, neuron-specific inhibitor of Fas/CD95-mediated apoptosis. To investigate its role during development and in disease models, we generated Faim2-deficient mice. The ubiquitous null mutation displayed a viable and fertile phenotype without overt deficiencies. However, lack of Faim2 caused an increase in susceptibility to combined oxygen-glucose deprivation in primary neurons in vitro as well as in caspase-associated cell death, stroke volume, and neurological impairment after cerebral ischemia in vivo. These processes were rescued by lentiviral Faim2 gene transfer. In summary, we provide evidence that Faim2 is a novel neuroprotective molecule in the context of cerebral ischemia.

Electro-acupuncture exerts beneficial effects against cerebral ischemia and promotes the proliferation of neural progenitor cells in the cortical peri-infarct area through the Wnt/β-catenin signaling pathway

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CHEN, BIN; TAO, JING; LIN, YUKUN; LIN, RUHUI; LIU, WEILIN; CHEN, LIDIAN

2015-01-01

Electro-acupuncture (EA) is a novel therapy based on combining traditional acupuncture with modern electrotherapy, and it is currently being investigated as a treatment for ischemic stroke. In the present study, we aimed to investigate the mechanisms through which EA regulates the proliferation of neural progenitor cells (NPCs) in the cortical peri-infarct area after stroke. The neuroprotective effects of EA on ischemic rats were evaluated by determining the neurological deficit scores and cerebral infarct volumes. The proliferation of the NPCs and the activation of the Wnt/β-catenin signaling pathway in the cortical peri-infarct area were examined. Our results revealed that EA significantly alleviated neurological deficits, reduced the infarct volume and enhanced NPC proliferation [nestin/glial fibrillary acidic protein (GFAP)-double positive] in the cortex of rats subjected to middle cerebral artery occlusion (MCAO). Moreover, the Wnt1 and β-catenin mRNA and protein levels were increased, while glycogen synthase kinase-3 (GSK3) transcription was suppressed by EA. These results suggest that the upregulatory effects of EA on the Wnt/β-catenin signaling pathway may promote NPC proliferation in the cortical peri-infarct area after stroke, consequently providing a therapeutic effect against cerebral ischemia. PMID:26329606

Role of phosphoinositide 3-kinase in ischemic postconditioning-induced attenuation of cerebral ischemia-evoked behavioral deficits in mice.

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Rehni, Ashish K; Singh, Nirmal

2007-01-01

The present study has been designed to pharmacologically investigate the role of phosphoinositide 3-kinase in ischemic postconditioning-induced reversal of global cerebral ischemia and reperfusion-induced behavioral dysfunction in mice. Bilateral carotid artery occlusion for 10 min followed by reperfusion for 24 h was employed in the present study to produce ischemia and reperfusion-induced cerebral injury in mice. Short-term memory was evaluated using the elevated plus maze test. The inclined beam walking test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced impaired short-term memory, motor co-ordination and lateral push response. Three episodes of carotid artery occlusion for a period of 10 s and reperfusion of 10 s (ischemic postconditioning) significantly prevented ischemia-reperfusion-induced behavioral deficit measured in terms of loss of short-term memory, motor coordination and lateral push response. Wortmannin (2 mg/kg, iv), a phosphoinositide 3-kinase inhibitor given 10 min before ischemia attenuated the beneficial effects of ischemic postconditioning. It may be concluded that beneficial effects of ischemic postconditioning on global cerebral ischemia and reperfusion-induced behavioral deficits may involve activation of phosphoinositide 3-kinase-linked pathway.

Effects of hypoxic preconditioning on the changes of expression of neuroglobin mRNA and labeled positive cells following cerebral ischemia in gerbils

Institute of Scientific and Technical Information of China (English)

Yong Zhang; Yanqun Chang; Zhenfang Liu; Qingxi Fu; Xiao Zhang

2006-01-01

BACKGROUND: Neuroglobin (NGB), as newly discovered the third member of the globin family binding oxygen, mainly exists in brain of human beings and vertebrates, and it is closely correlated with the oxygen supply in brain.OBJECTIVE : To observe the changes of the expression of neuroglobin and number of positive cells labeled immunohistochemically following cerebral ischemia in gerbils after hypoxic preconditioning. DESIGN: A complete randomized grouping design and controlled experiment. SETTING: Department of Neurology, Department of Anesthesia, Shandong Provincial Hospital, Shandong University.MATERIALS: Sixty-six adult male Mongolian gerbils of clean degree, about 50-65 g, at an average of 57.5 g were provided by the Experimental Animal Center of Capital Medical University [certificate number of animal quality:SCXK(Beijing)2000-0012]. TRNzil (Tianwei Shidai Company, Beijing), polymerase chain reaction (PCR) primers (synthetized by Invitrogen Company, Shanghai); reverse transcription-PCR (RT-PCR) one-step kit (Toyobo Company); PCR instrument (GeneAmp PCR System 240); mice brain NGB monoclonal antibody (Academy of Military Medical Sciences); DAB (Zhongshan Company, Beijing). METHEDS: The study was completed from December 2004 to June 2005 in Shandong Provincial Hospital. ① The 66 gerbils were randomly divided into sham-operated group (n =6), cerebral ischemia group (n =30) and hypoxic preconditioning group (n =30). The gerbils in the hypoxic preconditioning group were put in the environment which contained O2 (0.08 in volume fraction) and N2 (0.92 in volume fraction) at temperature of 25 ℃ for 2 hours. After 5 hours, the gerbils in the hypoxic preconditioning group and cerebral ischemia group were anesthetized, then bilateral common carotid arteries were ligated. In the sham-operated group, bilateral common carotid arteries were only isolated without ligation and hypoxic preconditioning. ②2 At 1, 5, 10, 30 and 60 minutes after cerebral ischemia, the

Basic principles of magnetic resonance imaging in cerebral ischemia and initial clinical experience

International Nuclear Information System (INIS)

Brant-Zawadzki, M.; Solomon, M.; Newton, T.H.; Weinstein, P.; Schmidley, J.; Norman, D.

1985-01-01

The basic principles of magnetic resonance imaging are described and their use in the investigation of cerebral ischemia outlined. A brief account is given of the clinical results of investigation to date

Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat

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Maddahi Aida

2009-06-01

Full Text Available Abstract Background Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression of metalloproteinase-9 (MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1. Results Here, we found an infarct volume of 24.8 ± 2% and a reduced neurological function after two hours of middle cerebral artery occlusion (MCAO, followed by 48 hours of recirculation in rat. Immunocytochemistry and confocal microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume significantly (11.8 ± 2% and 14.6 ± 3%, respectively; P Conclusion These data are the first to show that the elevated vascular expression of MMP-9 and TIMP-1, associated with breakdown of the blood-brain barrier following focal ischemia, are transcriptionally regulated via the MEK/ERK pathway.

ASSESSMENT OF EFFICACY OF SURGICAL CEREBRAL REVASCULARIZATION IN PATIENTS WITH LARGE POST-STROKE CYSTS

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R. N. Lar'kov

2015-01-01

Full Text Available Background: At present, efficacy of carotid endarterectomy for prevention of cerebrovascular accidents has been convincingly proven. Its results in patients with a history of an ischemic stroke depend on multiple factors.Aim: To study results of reconstructive interventions on internal carotid arteries in patients with post-stroke cerebral cysts.Materials and methods: We analyzed data from 210 patients who had undergone an intervention (159 men and 51 women, aged 61 ± 2.7 years with occluding lesions of the internal carotid artery and a history of an ischemic stroke. Depending on the size of a post-stroke lesion, patients were divided into 5 groups: patients from group 1 had a lesion of more than 5 cm in diameter, from group 2, from 2 to 5 cm, from group 3, ≤ 2 cm, patients from group 4 had a lacunar cysts and patients from group 5 had no focal lesions.Results: A clear positive correlation between the size of a post-stroke cyst and the degree of hemodynamic abnormalities in internal carotid arteries was found. The most prominent asymmetry of blood flow in the middle cerebral artery (on average, 34.1% was seen in patients from the group 1. Patients from the group 1 more often had low and critical brain tolerance to ischemia (42.9%. In patients with large post-stroke cysts (group 1 mean Barthell index was 69 ± 8.1, and NIHSS score 8.2 ± 1.6. In patients from other groups neurological deficiency was less pronounced: 80 ± 6.8 and 7.6 ± 1.9 in the group 2, 82 ± 5.7 and 4.1 ± 1.3 in the group 3, 94 ± 4.6 and 3.2 ± 1 in the groups 4 and 5. The differences between groups in the rates of postoperative complications were not statistically significant (p > 0.5. However, signs of hyperperfusion without any clinical manifestations were more often observed in patients from the group 1 (19%. Assessment of changes in neurological status at 1 year after the intervention, depending on the size of post-stroke lesions, showed that in patients with large

Interstitial pO2 in ischemic penumbra and core are differentially affected following transient focal cerebral ischemia in rats.

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Liu, Shimin; Shi, Honglian; Liu, Wenlan; Furuichi, Takamitsu; Timmins, Graham S; Liu, Ke Jian

2004-03-01

Stroke causes heterogeneous changes in tissue oxygenation, with a region of decreased blood flow, the penumbra, surrounding a severely damaged ischemic core. Treatment of acute ischemic stroke aims to save this penumbra before its irreversible damage by continued ischemia. However, effective treatment remains elusive due to incomplete understanding of processes leading to penumbral death. While oxygenation is central in ischemic neuronal death, it is unclear exactly what actual changes occur in interstitial oxygen tension (pO2) in ischemic regions during stroke, particularly the penumbra. Using the unique capability of in vivo electron paramagnetic resonance (EPR) oximetry to measure localized interstitial pO2, we measured both absolute values, and temporal changes of pO2 in ischemic penumbra and core during ischemia and reperfusion in a rat model. Ischemia rapidly decreased interstitial pO2 to 32% +/- 7.6% and 4% +/- 0.6% of pre-ischemic values in penumbra and core, respectively 1 hour after ischemia. Importantly, whilst reperfusion restored core pO2 close to its pre-ischemic value, penumbral pO2 only partially recovered. Hyperoxic treatment significantly increased penumbral pO2 during ischemia, but not in the core, and also increased penumbral pO2 during reperfusion. These divergent, important changes in pO2 in penumbra and core were explained by combined differences in cellular oxygen consumption rates and microcirculation conditions. We therefore demonstrate that interstitial pO2 in penumbra and core is differentially affected during ischemia and reperfusion, providing new insights to the pathophysiology of stroke. The results support normobaric hyperoxia as a potential early intervention to save penumbral tissue in acute ischemic stroke.

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

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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.

Diffusion-weighted magnetic resonance imaging reflects activation of signal transducer and activator of transcription 3 during focal cerebral ischemia/reperfusion

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Wen-juan Wu

2017-01-01

Full Text Available Signal transducer and activator of transcription (STAT is a unique protein family that binds to DNA, coupled with tyrosine phosphorylation signaling pathways, acting as a transcriptional regulator to mediate a variety of biological effects. Cerebral ischemia and reperfusion can activate STATs signaling pathway, but no studies have confirmed whether STAT activation can be verified by diffusion-weighted magnetic resonance imaging (DWI in rats after cerebral ischemia/reperfusion. Here, we established a rat model of focal cerebral ischemia injury using the modified Longa method. DWI revealed hyperintensity in parts of the left hemisphere before reperfusion and a low apparent diffusion coefficient. STAT3 protein expression showed no significant change after reperfusion, but phosphorylated STAT3 expression began to increase after 30 minutes of reperfusion and peaked at 24 hours. Pearson correlation analysis showed that STAT3 activation was correlated positively with the relative apparent diffusion coefficient and negatively with the DWI abnormal signal area. These results indicate that DWI is a reliable representation of the infarct area and reflects STAT phosphorylation in rat brain following focal cerebral ischemia/reperfusion.

Histopathology of motor cortex in an experimental focal ischemic stroke in mouse model.

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de Oliveira, Juçara Loli; Crispin, Pedro di Tárique Barreto; Duarte, Elisa Cristiana Winkelmann; Marloch, Gilberto Domingos; Gargioni, Rogério; Trentin, Andréa Gonçalves; Alvarez-Silva, Marcio

2014-05-01

Experimental ischemia results in cortical brain lesion followed by ischemic stroke. In this study, focal cerebral ischemia was induced in mice by occlusion of the middle cerebral artery. We studied cortical layers I, II/III, V and VI in the caudal forelimb area (CFA) and medial agranular cortex (AGm) from control and C57BL/6 mice induced with ischemic stroke. Based on our analysis of CFA and AGm motor cortex, significant differences were observed in the numbers of neurons, astrocytes and microglia in the superficial II/III and deep V cortical layers. Cellular changes were more prominent in layer V of the CFA with nuclear pyknosis, chromatin fragmentation, necrosis and degeneration, as well as, morphological evidence of apoptosis, mainly in neurons. As result, the CFA was more severely impaired than the AGm in this focal cerebral ischemic model, as evidenced by the proliferation of astrocytes, potentially resulting in neuroinflammation by microglia-like cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Neuroprotective capabilities of TSA against cerebral ischemia/reperfusion injury via PI3K/Akt signaling pathway in rats.

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Ma, Xiao-Hui; Gao, Qiang; Jia, Zhen; Zhang, Ze-Wei

2015-02-01

Hundreds of previous studies demonstrated the cytoprotective effect of trichostatin-A (TSA), a kind of histone deacetylases inhibitors (HDACIs), against cerebral ischemia/reperfusion insult. Meanwhile, phosphatidylinositol-3 kinase/Akt (PI3K/Akt) is a well-known, important signaling pathway that mediates neuroprotection. However, it should be remains unclear whether the neuroprotective capabilities of TSA against cerebral ischemia/reperfusion is mediated by activation of the PI3K/Akt signaling pathway. Five groups rats (n = 12 each), with middle cerebral artery occlusion (MCAO) except sham group, were used to investigate the neuroprotective effect of certain concentration (0.05 mg/kg) of TSA, and whether the neuroprotective effect of TSA is associated with activation of the PI3K/Akt signaling pathway through using of wortmannin (0.25 mg/kg). TSA significantly increased the expression of p-Akt protein, reduced infarct volume, and attenuated neurological deficit in rats with transient MCAO, wortmannin weakened such effect of TSA dramatically. TSA could significantly decrease the neurological deficit scores and reduce the cerebral infarct volume during cerebral ischemia/reperfusion injury, which was achieved partly by activation of the PI3K/Akt signaling pathway via upgrading of p-Akt protein.

Cotard and Capgras syndrome after ischemic stroke.

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Sottile, Fabrizio; Bonanno, Lilla; Finzi, Giuseppina; Ascenti, Giorgio; Marino, Silvia; Bramanti, Placido; Corallo, Francesco

2015-04-01

Capgras and Cotard are delusional misidentification syndromes characterized by delusions about oneself, others, places, and objects. To date, there are few cases of comorbidity of both syndromes. We describe a case of aphasic stroke patient affected by cerebral ischemia localized in right temporoparietal region. The patient showed a typical clinical picture of delusional disorder attributable, through psychological assessment, to comorbidity of both Capgras and Cotard syndromes. Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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

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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.

Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage

NARCIS (Netherlands)

Hijdra, A.; van Gijn, J.; Nagelkerke, N. J.; Vermeulen, M.; van Crevel, H.

1988-01-01

Using logistic regression, we analyzed the predictive value of a number of entry variables with respect to the outcome variables delayed cerebral ischemia, rebleeding, and poor outcome (death or severe disability) in patients with aneurysmal subarachnoid hemorrhage. The entry variables were clinical

Fatty acid methyl esters and Solutol HS 15 confer neuroprotection after focal and global cerebral ischemia.

Science.gov (United States)

Lin, Hung Wen; Saul, Isabel; Gresia, Victoria L; Neumann, Jake T; Dave, Kunjan R; Perez-Pinzon, Miguel A

2014-02-01

We previously showed that palmitic acid methyl ester (PAME) and stearic acid methyl ester (SAME) are simultaneously released from the sympathetic ganglion and PAME possesses potent vasodilatory properties which may be important in cerebral ischemia. Since PAME is a potent vasodilator simultaneously released with SAME, our hypothesis was that PAME/SAME confers neuroprotection in rat models of focal/global cerebral ischemia. We also examined the neuroprotective properties of Solutol HS15, a clinically approved excipient because it possesses similar fatty acid compositions as PAME/SAME. Asphyxial cardiac arrest (ACA, 6 min) was performed 30 min after PAME/SAME treatment (0.02 mg/kg, IV). Solutol HS15 (2 ml/kg, IP) was injected chronically for 14 days (once daily). Histopathology of hippocampal CA1 neurons was assessed 7 days after ACA. For focal ischemia experiments, PAME, SAME, or Solutol HS15 was administered following reperfusion after 2 h of middle cerebral artery occlusion (MCAO). 2,3,5-Triphenyltetrazolium staining of the brain was performed 24 h after MCAO and the infarct volume was quantified. Following ACA, the number of surviving hippocampal neurons was enhanced by PAME-treated (68%), SAME-treated (69%), and Solutol-treated HS15 (68%) rats as compared to ACA only-treated groups. Infarct volume was decreased by PAME (83%), SAME (68%), and Solutol HS15 (78%) as compared to saline (vehicle) in MCAO-treated animals. PAME, SAME, and Solutol HS15 provide robust neuroprotection in both paradigms of ischemia. This may prove therapeutically beneficial since Solutol HS15 is already administered as a solublizing agent to patients. With proper timing and dosage, administration of Solutol HS15 and PAME/SAME can be an effective therapy against cerebral ischemia.

Time Is Brain: The Stroke Theory of Relativity.

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Gomez, Camilo R

2018-04-25

Since the introduction of the philosophical tenet "Time is Brain!," multiple lines of research have demonstrated that other factors contribute to the degree of ischemic injury at any one point in time, and it is now clear that the therapeutic window of acute ischemic stroke is more protracted than it was first suspected. To define a more realistic relationship between time and the ischemic process, we used computational modeling to assess how these 2 variables are affected by collateral circulatory competence. Starting from the premise that the expression "Time=Brain" is mathematically false, we reviewed the existing literature on the attributes of cerebral ischemia over time, with particular attention to relevant clinical parameters, and the effect of different variables, particularly collateral circulation, on the time-ischemia relationship. We used this information to construct a theoretical computational model and applied it to categorically different yet abnormal cerebral perfusion scenarios, allowing comparison of their behavior both overall (i.e., final infarct volume) and in real-time (i.e., instantaneous infarct growth rate). Optimal collateral circulatory competence was predictably associated with slower infarct growth rates and prolongation of therapeutic window. Modeling of identifiable specific types of perfusion maps allows forecasting of the fate of the ischemic process over time. Distinct cerebral perfusion map patterns can be readily identified in patients with acute ischemic stroke. These patterns have inherently different behaviors relative to the time-ischemia construct, allowing the possibility of improving parsing and treatment allocation. It is clearly evident that the effect of time on the ischemic process is relative. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Preliminary EEG study of protective effects of Tebonin in transient global cerebral ischemia in rats

DEFF Research Database (Denmark)

Zagrean, L; Vatasescu, R; Munteanu, A M

2000-01-01

and metabolism. The objective of this study was to investigate the effects of preventive treatment with Ginkgo biloba extract (EGb 761--Tebonin) in cerebral global ischemia and reperfusion in rats using computerized EEG analysis. Ginkgo biloba extract, known to be, in vitro, a free radicals scavanger and a PAF......--antagonist, was administrated in dose of 100 mg/kg over 24 hours, for 5 days before and 5 days after cerebral ischemia--reperfusion. The apparition of isoelectric EEG (flat-line) following 4-vessel occlusion was observed after a mean time of 25 sec. in Ginkgo biloba treated rats and after 18 sec. in control rats (p

Evaluation of hypoxic tissue dynamics with 18F-FMISO PET in a rat model of permanent cerebral ischemia.

Science.gov (United States)

Rojas, Santiago; Herance, José Raul; Abad, Sergio; Jiménez, Xavier; Pareto, Deborah; Ruiz, Alba; Torrent, Èlia; Figueiras, Francisca P; Popota, Foteini; Fernández-Soriano, Francisco J; Planas, Anna M; Gispert, Juan D

2011-06-01

[¹⁸F]Fluoromisonidazole (¹⁸F-FMISO) is a nitroimidazole derivative that has been proposed as a positron emission tomography (PET) radiotracer to detect hypoxic tissue in vivo. This compound accumulates in hypoxic but viable tissue and may be a good candidate for evaluating the ischemic penumbra. We evaluated the time course of ¹⁸F-FMISO uptake using PET in a rat model of permanent cerebral ischemia and the correlation with histological changes. Rats (n = 14) were subjected to permanent ischemia by intraluminal occlusion of the middle cerebral artery in order to assess by PET the uptake of ¹⁸F-FMISO at various times over 24 h following ischemia. The PET results were compared to histological changes with Nissl and 2,3,5 triphenyltetrazolium chloride staining. Elevated uptake of ¹⁸F-FMISO was detected in the infarcted area up to 8 h after occlusion but was no longer detected at 24 h, a time point coincident with pan necrosis of the tissue. Our findings suggest that salvageable tissue persists for up to 8 h in this rat model of brain ischemia. We propose ¹⁸F-FMISO PET as a tool for evaluating the ischemic penumbra after cerebral ischemia.

Study on diffusion anisotropy of cerebral ischemia using diffusion weighted echo-planar MRI

International Nuclear Information System (INIS)

Kajima, Toshio

1997-01-01

Focal cerebral ischemia was produced by occlusion of the intracranial main cerebral artery with a silicone cylinder in Wistar rats. Diffusion-weighted echo-planar images (DW-EPls) using the motion-probing gradient (MPG) method were acquired at 1-3 hours and 24-48 hours after occlusion. Apparent diffusion coefficients (ADCs) were calculated from these images in ischemic lesions and in normal unoccluded regions. Results were as follows. Ischemic lesions could be detected on the DW-EPIs at 1 hour after occlusion. The ADC of water in the brain tissue was smaller than that of free water as a result of restricted diffusion. Anisotropic diffusion that probably can be attributed to the myelin sheath was observed in the normal white matter. In the ischemic lesions, the ADC decreased rapidly within 1-3 hours after occlusion and then decreased gradually after 24-48 hours. In the ischemic white matter, diffusion anisotropy disappeared at 24-48 hours after occlusion. Diffusion-weighted imaging may have applications in the examination of pathophysiological mechanisms in cerebral ischemia by means of evaluation of ADC and diffusion anisotropy. (author)

Patterns of regional cerebral blood flow in acute stroke

DEFF Research Database (Denmark)

Olsen, T S; Skriver, E B

1981-01-01

In a consecutive group of 56 stroke patients the regional cerebral blood flow was measured within 84 hours after stroke. A 254 multidetector scintillation camera and the intracarotid Xenon-133 injection method was used to study rCBF. Typical rCBF-patterns are described and compared to the findings...

Protective Effects of Sodium (±-5-Bromo-2-(α-Hydroxypentyl Benzoate in a Rodent Model of Global Cerebral Ischemia

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Yuan Gao

2017-09-01

stroke in rat model of global cerebral ischemia. The underlying mechanisms may be related to the inhibition of apoptosis and activation of the survival-signaling-pathway.

Transcranial diffuse optical monitoring of microvascular cerebral hemodynamics after thrombolysis in ischemic stroke

Science.gov (United States)

Zirak, Peyman; Delgado-Mederos, Raquel; Dinia, Lavinia; Carrera, David; Martí-Fàbregas, Joan; Durduran, Turgut

2014-01-01

The ultimate goal of therapeutic strategies for ischemic stroke is to reestablish the blood flow to the ischemic region of the brain. However, currently, the local cerebral hemodynamics (microvascular) is almost entirely inaccessible for stroke clinicians at the patient bed-side, and the recanalization of the major cerebral arteries (macrovascular) is the only available measure to evaluate the therapy, which does not always reflect the local conditions. Here we report the case of an ischemic stroke patient whose microvascular cerebral blood flow and oxygenation were monitored by a compact hybrid diffuse optical monitor during thrombolytic therapy. This monitor combined diffuse correlation spectroscopy and near-infrared spectroscopy. The reperfusion assessed by hybrid diffuse optics temporally correlated with the recanalization of the middle cerebral artery (assessed by transcranial-Doppler) and was in agreement with the patient outcome. This study suggests that upon further investigation, diffuse optics might have a potential for bed-side acute stroke monitoring and therapy guidance by providing hemodynamics information at the microvascular level.

Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat

DEFF Research Database (Denmark)

Maddahi, Aida; Chen, Qingwen; Edvinsson, Lars

2009-01-01

. Immunocytochemistry showed no overlap in expression between MMP-9/TIMP-1 and the astrocyte/glial cell marker GFAP in the vessel walls. CONCLUSION: These data are the first to show that the elevated vascular expression of MMP-9 and TIMP-1, associated with breakdown of the blood-brain barrier following focal ischemia......BACKGROUND: Cerebral ischemia is usually characterized by a reduction in local blood flow and metabolism and by disruption of the blood-brain barrier in the infarct region. The formation of oedema and opening of the blood-brain barrier in stroke is associated with enhanced expression...... microscopy revealed enhanced expression of MMP-9, TIMP-1, and phosphorylated ERK1/2 in the smooth muscle cells of the ischemic MCA and associated intracerebral microvessels. The specific MEK1/2 inhibitor U0126, given intraperitoneal zero or 6 hours after the ischemic event, reduced the infarct volume...

Unruptured Cerebral Aneurysm Detected after Intravenous Tissue Plasminogen Activator for Stroke

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Yukihiro Yoneda

2009-06-01

Full Text Available Therapeutic guidelines of intravenous thrombolysis with tissue plasminogen activator (tPA for hyperacute ischemic stroke are very strict. Because of potential higher risk of bleeding complications, the presence of unruptured cerebral aneurysm is a contraindication for systemic thrombolysis with tPA. According to the standard CT criteria, a 66-year-old woman who suddenly developed aphasia and hemiparesis received intravenous tPA within 3 h after ischemic stroke. Magnetic resonance angiography during tPA infusion was performed and the presence of a small unruptured cerebral aneurysm was suspected at the anterior communicating artery. Delayed cerebral angiography confirmed an aneurysm with a size of 7 mm. The patient did not experience any adverse complications associated with the aneurysm. Clinical experiences of this kind of accidental off-label thrombolysis may contribute to modify the current rigid tPA guidelines for stroke.

Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats.

Science.gov (United States)

Ahmed, Maha A E; El Morsy, Engy M; Ahmed, Amany A E

2014-08-21

Interruption to blood flow causes ischemia and infarction of brain tissues with consequent neuronal damage and brain dysfunction. Pomegranate extract is well tolerated, and safely consumed all over the world. Interestingly, pomegranate extract has shown remarkable antioxidant and anti-inflammatory effects in experimental models. Many investigators consider natural extracts as novel therapies for neurodegenerative disorders. Therefore, this study was carried out to investigate the protective effects of standardized pomegranate extract against cerebral ischemia/reperfusion-induced brain injury in rats. Adult male albino rats were randomly divided into sham-operated control group, ischemia/reperfusion (I/R) group, and two other groups that received standardized pomegranate extract at two dose levels (250, 500 mg/kg) for 15 days prior to ischemia/reperfusion (PMG250+I/R, and PMG500+I/R groups). After I/R or sham operation, all rats were sacrificed and brains were harvested for subsequent biochemical analysis. Results showed reduction in brain contents of MDA (malondialdehyde), and NO (nitric oxide), in addition to enhancement of SOD (superoxide dismutase), GPX (glutathione peroxidase), and GRD (glutathione reductase) activities in rats treated with pomegranate extract prior to cerebral I/R. Moreover, pomegranate extract decreased brain levels of NF-κB p65 (nuclear factor kappa B p65), TNF-α (tumor necrosis factor-alpha), caspase-3 and increased brain levels of IL-10 (interleukin-10), and cerebral ATP (adenosine triphosphate) production. Comet assay showed less brain DNA (deoxyribonucleic acid) damage in rats protected with pomegranate extract. The present study showed, for the first time, that pre-administration of pomegranate extract to rats, can offer a significant dose-dependent neuroprotective activity against cerebral I/R brain injury and DNA damage via antioxidant, anti-inflammatory, anti-apoptotic and ATP-replenishing effects. Copyright © 2014 Elsevier Inc

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1.

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Li, Tao; Qin, Juan-Juan; Yang, Xia; Ji, Yan-Xiao; Guo, Fangliang; Cheng, Wen-Lin; Wu, Xiaolin; Gong, Fu-Han; Hong, Ying; Zhu, Xue-Yong; Gong, Jun; Wang, Zhihua; Huang, Zan; She, Zhi-Gang; Li, Hongliang

2017-12-13

Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury. SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting

Statistical modeling of the mother-baby system in newborn infants with cerebral ischemia

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A. V. Filonenko

2014-01-01

Full Text Available The statistical model could consider the influence of specific maternal psychoemotional and personality factors on a newborn with cerebral ischemia and develop a procedure to prevent negative consequences of postpartum depression in the mother-baby system.

Preliminary evaluation of [1-11C]octanoate as a PET tracer for studying cerebral ischemia. A PET study in rat and canine models of focal cerebral ischemia

International Nuclear Information System (INIS)

Kuge, Yuji; Kawashima, Hidefumi; Hashimoto, Tadatoshi

2000-01-01

Octanoate is taken up into the brain and is converted in astrocytes to glutamine through the tricarboxylic acid (TCA) cycle after β-oxidation. We speculate that [1- 11 C]octanoate may be used as a tracer for astroglial functions and/or fatty acid metabolism in the brain and may be useful for studying cerebral ischemia. In the present study we investigated brain distribution of [1- 11 C]octanoate and compared it with cerebral blood flow (CBF) by using rat and canine models of middle cerebral artery (MCA) occlusion and a high resolution PET. In rats brain distribution of [ 15 O]H 2 O measured 1-2 h and 5-6 h after insult was compared with that of [1- 11 C]octanoate measured 3-4 h after insult. Radioactivity ratios of lesioned to normal hemispheres determined with [ 15 O]H 2 O were lower than those determined with [1- 11 C]octanoate. These results were confirmed by a study on a canine model of MCA-occlusion. Twenty-four hours after insult, CBF decreased in the MCA-territory of the occluded hemisphere, whereas normal or higher accumulation of [1- 11 C]octanoate was observed in the ischemic regions. The uptake of [1- 11 C]octanoate-derived radioactivity therefore increased relative to CBF in the ischemic regions, indicating that [1- 11 C]octanoate provides functional information different from CBF. In conclusion, we found that [1- 11 C]octanoate is a potential radiopharmaceutical for studying the pathophysiology of cerebral ischemia. (author)

Systematic Analysis of RNA Regulatory Network in Rat Brain after Ischemic Stroke

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Juan Liu

2018-01-01

Full Text Available Although extensive studies have identified large number of microRNAs (miRNAs and long noncoding RNAs (lncRNAs in ischemic stroke, the RNA regulation network response to focal ischemia remains poorly understood. In this study, we simultaneously interrogate the expression profiles of lncRNAs, miRNAs, and mRNAs changes during focal ischemia induced by transient middle cerebral artery occlusion. A set of 1924 novel lncRNAs were identified and may involve brain injury and DNA repair as revealed by coexpression network analysis. Furthermore, many short interspersed elements (SINE mediated lncRNA:mRNA duplexes were identified, implying that lncRNAs mediate Staufen1-mediated mRNA decay (SMD which may play a role during focal ischemia. Moreover, based on the competitive endogenous RNA (ceRNA hypothesis, a stroke regulatory ceRNA network which reveals functional lncRNA:miRNA:mRNA interactions was revealed in ischemic stroke. In brief, this work reports a large number of novel lncRNAs responding to focal ischemia and constructs a systematic RNA regulation network which highlighted the role of ncRNAs in ischemic stroke.

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

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Burkhard Gess

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

Protective effect of green tea polyphenol EGCG against neuronal damage and brain edema after unilateral cerebral ischemia in gerbils.

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Lee, Hyung; Bae, Jae Hoon; Lee, Seong-Ryong

2004-09-15

Previous studies have demonstrated that a green tea polyphenol, (-)-epigallocatechine gallate (EGCG), has a potent free radical scavenging and antioxidant effect. Glutamate leads to excitotoxicity and oxidative stress, which are important pathophysiologic responses to cerebral ischemia resulting in brain edema and neuronal damage. We investigated the effect of EGCG on excitotoxic neuronal damage in a culture system and the effect on brain edema formation and lesion after unilateral cerebral ischemia in gerbils. In vitro, excitotoxicity was induced by 24-hr incubation with N-methyl-D-aspartate (NMDA; 10 microM), AMPA (10 microM), or kainate (20 microM). EGCG (5 microM) was added to the culture media alone or with excitotoxins. We examined malondialdehyde (MDA) level and neuronal viability to evaluate the effect of EGCG. In vivo, unilateral cerebral ischemia was induced by occlusion of the right common carotid artery for 30, 60, or 90 min and followed by reperfusion of 24 hr. Brain edema, MDA, and infarction were examined to evaluate the protective effect of EGCG. EGCG (25 or 50 mg/kg, intraperitoneally) was administered twice, at 30 min before and immediately after ischemia. EGCG reduced excitotoxin-induced MDA production and neuronal damage in the culture system. In the in vivo study, treatment of gerbils with the lower EGCG dose failed to show neuroprotective effects; however, the higher EGCG dose attenuated the increase in MDA level caused by cerebral ischemia. EGCG also reduced the formation of postischemic brain edema and infarct volume. These results demonstrate EGCG may have future possibilities as a neuroprotective agent against excitotoxicity-related neurologic disorders such as brain ischemia.

Paradigms and mechanisms of inhalational anesthetics mediated neuroprotection against cerebral ischemic stroke

OpenAIRE

Wang, Hailian; Li, Peiying; Xu, Na; Zhu, Ling; Cai, Mengfei; Yu, Weifeng; Gao, Yanqin

2016-01-01

Cerebral ischemic stroke is a leading cause of serious long-term disability and cognitive dysfunction. The high mortality and disability of cerebral ischemic stroke is urging the health providers, including anesthesiologists and other perioperative professioners, to seek effective protective strategies, which are extremely limited, especially for those perioperative patients. Intriguingly, several commonly used inhalational anesthetics are recently suggested to possess neuroprotective effects...

Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia/reperfusion-induced cerebral microcirculatory disturbances and neuron damage

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Sun, Kai; Fan, Jingyu; Han, Jingyan

2015-01-01

Ischemic stroke and ischemia/reperfusion (I/R) injury induced by thrombolytic therapy are conditions with high mortality and serious long-term physical and cognitive disabilities. They have a major impact on global public health. These disorders are associated with multiple insults to the cerebral microcirculation, including reactive oxygen species (ROS) overproduction, leukocyte adhesion and infiltration, brain blood barrier (BBB) disruption, and capillary hypoperfusion, ultimately resulting in tissue edema, hemorrhage, brain injury and delayed neuron damage. Traditional Chinese medicine (TCM) has been used in China, Korea, Japan and other Asian countries for treatment of a wide range of diseases. In China, the usage of compound TCM preparation to treat cerebrovascular diseases dates back to the Han Dynasty. Even thousands of years earlier, the medical formulary recorded many classical prescriptions for treating cerebral I/R-related diseases. This review summarizes current information and underlying mechanisms regarding the ameliorating effects of compound TCM preparation, Chinese materia medica, and active components on I/R-induced cerebral microcirculatory disturbances, brain injury and neuron damage. PMID:26579420

Hemin offers neuroprotection through inducing exogenous neuroglobin in focal cerebral hypoxic-ischemia in rats

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Song, Xue; Xu, Rui; Xie, Fei; Zhu, Haiyuan; Zhu, Ji; Wang, Xin

2014-01-01

Objective: To investigate the inducible effect of hemin on exogenous neuroglobin (Ngb) in focal cerebral hypoxic-ischemia in rats. Methods: 125 healthy SD rats were randomly divided into five groups: sham-operation control group, operation group, hemin treatment group, exogenous Ngb treatment group, and hemin and exogenous Ngb joint treatment group. Twenty-four hours after focal cerebral hypoxic-ischemia, Ngb expression was evaluated by immunocytochemistry, RT-PCR, and western blot analyses, while the brain water content and infarct volume were examined. Results: Immunocytochemistry, RT-PCR, and western blot analyses showed more pronounced Ngb expression in the hemin and exogenous Ngb joint operation group than in the hemin or exogenous Ngb individual treatment groups, thus producing significant differences in brain water content and infarct volume (p exogenous Ngb. PMID:24966924

Neuroimaging patterns of cerebral hyperperfusion

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Semenov, S.; Portnov, Yu; Semenov, A.; Korotkevich, A.; Kokov, A.

2017-08-01

Cerebral hyperperfusion syndrome (CHS) after revascularization is a rare phenomenon associated with post-ischemic (reactive) hyperemia and acute pathological hyperperfusion. First described on perfusion CT as a very often moderate CBF increase, MTT/TTP decrease within 30% like a temporary effect, according to a short-time deterioration of neurological symptoms (vestibular ataxia - 58%, vegetative dysfunction - 100%, asthenic syndrome - 100%) in early postoperative period in patients with cardiac ischemia who had undergone coronary artery bypass surgery. The acute pathological hyperperfusion carotid revascularization is a casuistic phenomenon with two- or three-fold CBV and MTT/TTP increase and high hemorrhage risk. Besides, we detected similar exchanges via perfusion CT called benign hyperemia, which marks extension of MTT/TTP and an increase of CBV from 27% to 48% (average 30%), but with normal CBF-parameters, indicating that venous stasis in acute venous ischemic stroke due cerebral venous sinus-trombosis (68%), only 6% in cardioembolic stroke and appears never in arterial stroke. Territorial coincidence registered for perifocal of necrosis zones of benign hyperemia and vasogenic edema accompanied on MRI (DWI, ADC). Secondary hemorrhagic transformation registered for primary non-hemorrhagic venous stroke in 27%, only in 9% for arterial stroke and in 60% for cardioembolic stroke. Probably, congestion is an increasingly predisposing factor secondary hemorrhaging than necrosis.

Cerebral ischemia is exacerbated by extracellular nicotinamide phosphoribosyltransferase via a non-enzymatic mechanism.

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Bing Zhao

Full Text Available Intracellular nicotinamide phosphoribosyltransferase (iNAMPT in neuron has been known as a protective factor against cerebral ischemia through its enzymatic activity, but the role of central extracellular NAMPT (eNAMPT is not clear. Here we show that eNAMPT protein level was elevated in the ischemic rat brain after middle-cerebral-artery occlusion (MCAO and reperfusion, which can be traced to at least in part from blood circulation. Administration of recombinant NAMPT protein exacerbated MCAO-induced neuronal injury in rat brain, while exacerbated oxygen-glucose-deprivation (OGD induced neuronal injury only in neuron-glial mixed culture, but not in neuron culture. In the mixed culture, NAMPT protein promoted TNF-α release in a time- and concentration-dependent fashion, while TNF-α neutralizing antibody protected OGD-induced, NAMPT-enhanced neuronal injury. Importantly, H247A mutant of NAMPT with essentially no enzymatic activity exerted similar effects on ischemic neuronal injury and TNF-α release as the wild type protein. Thus, eNAMPT is an injurious and inflammatory factor in cerebral ischemia and aggravates ischemic neuronal injury by triggering TNF-α release from glia cells, via a mechanism not related to NAMPT enzymatic activity.

ABCD2 score and BNP level in patients with TIA and cerebral stroke.

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Mortezabeigi, H R; Taghizadeh, A; Talebi, M; Amini, K; Goldust, M

2013-11-01

Scoring systems have been designed to help physicians in early prediction of cerebral stroke following Transitional Ischemic Attack (TIA). ABCD2 system is one of these scoring systems. Considering increase of brain natriuretic peptide following cerebral ischemic stroke, BNP level may be associated with incidence of ischemic stroke following TIA. The present study evaluates ABCD2 score, BNP level in patients with TIA and incidence of cerebral stroke. This cross sectional-analytical study evaluated 78 patients with TIA. ABCD2 score was calculated for all patients based on some criteria including age, blood pressure, clinical manifestations (speech/motor disorder), symptoms duration and diabetes. BNP level was measured at the reference laboratory when the patient referred to the treatment center. The patients were followed up for 6 months considering incidence of cerebral stroke and TIA. Mean age of the patients was 66.53 +/- 13.08 years and the sample was consisted of 62.8% male and 37.2% female patients. Mean BNP level and mean ABCD2 score was 611.31 +/- 125.61 and 4.61 +/- 10.99 in all patients, respectively. During follow-up period, TIA recurrence and cerebral stroke were, respectively seen in 11.5 and 3.8% of cases. Mortality was reported in 5.1% of the patients. BNP was significantly higher in cases with recursive TIA (p = 0.03). But, there was not any difference considering ABCD2 score (p = 0.38). BNP is capable of predicting TIA recurrence following first TIA and it can be used in this case.

Effect of tetramethylpyrazine on the spatial learning and memory function of rats after focal cerebral ischemia

Institute of Scientific and Technical Information of China (English)

Jianjun Zhao; Yong Liu; Xinlin Chen; Jianxin Liu; Yingfang Tian; Pengbo Zhang; Qianyan Kang; Fen Qiu

2006-01-01

BACKGROUND: Tetramethylpyrazine (TMP) presents the effect of anti-platelet aggregation, reduces arterial resistance, increases cerebral blood flow, and improves microcirculation.OBJECTIVE: To observe the effects of TMP on the learning and memory abilities and the number of neurons in cortex and hippocampus after focal cerebral ischemia in rats DESIGN: A randomized controlled trial.SETTING: Department of Human Anatomy and Histological Embryology, School of Medicine, Xi'an Jiaotong University.MATERIALS: Fifty adult male Sprague-Dawley rats, weighing 250-300 g were supplied by the Experimental Animal Center, School of Medicine, Xi'an Jiaotong University. TMP was purchased from Wuxi Seventh Pharmaceutical Co. Ltd (Lot Number: 2004051106, Specification: 2 mL/piece).METHODS: The experiments were carried out in School of Medicine of Xi'an Jiaotong University from June 2004 to May 2005. The 50 rats were randomly divided into five groups according to the random number table method: sham-operated group, cerebral ischemia control group, Iow-dose TMP group, middle-dose TMP group and high-dose TMP group, 10 rats in each group. Rats in the TMP groups were immediately treated with intraperitoneal injection of TMP of 40, 80 and 120 mg/kg respectively, and those in the sham-operated group and cerebral ischemia control group were injected intraperitoneally by isovolume saline, once a day for 14 days successively. On the 15th day, the spatial learning and memory abilities of the rats were assessed with the Morris water maze test, and then the changes of neuron numbers in cortex and hippocampus were observed by Nissl staining of brain sections.MAIN OUTCOME MEASURES: The results of Morris water maze test and the changes of neuron numbers in cortex and hippocampus by Nissl staining of brain sections were observed,RESULTS : Finally 39 rats were involved in the analysis of results, and the other 11 died of excessive anesthesia or failure in model establishment. ① The rats in the

La atorvastatina protege las neuronas gabérgicas y dopaminérgicas del sistema nigroestriatal en un modelo experimental de isquemia cerebral focal transitoria en ratas

OpenAIRE

Sabogal, Angélica María; Arango, César Augusto; Cardona, Gloria Patricia; Céspedes, Ángel Enrique

2014-01-01

Introduction: Cerebral ischemia is the third leading cause of death and the primary cause of permanent disability worldwide. Atorvastatin is a promising drug with neuroprotective effects that may be useful for the treatment of stroke. However, the effects of atorvastatin on specific neuronal populations within the nigrostriatal system following cerebral ischemia are unknown. Objective: To evaluate the effects of atorvastatin on dopaminergic and GABAergic neuronal populations in exofocal brain...

Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular functions after cerebral ischemia.

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Bandla, Aishwarya; Liao, Lun-De; Chan, Su Jing; Ling, Ji Min; Liu, Yu-Hang; Shih, Yen-Yu Ian; Pan, Han-Chi; Wong, Peter Tsun-Hon; Lai, Hsin-Yi; King, Nicolas Kon Kam; Chen, You-Yin; Ng, Wai Hoe; Thakor, Nitish V

2018-06-01

The advance of thrombolytic therapy has been hampered by the lack of optimization of the therapy during the hyperacute phase of focal ischemia. Here, we investigate neurovascular dynamics using a custom-designed hybrid electrocorticography (ECoG)-functional photoacoustic microscopy (fPAM) imaging system during the hyperacute phase (first 6 h) of photothrombotic ischemia (PTI) in male Wistar rats following recombinant tissue plasminogen activator (rtPA)-mediated thrombolysis. We reported, for the first time, the changes in neural activity and cerebral hemodynamic responses following rtPA infusion at different time points post PTI. Interestingly, very early administration of rtPA ( 4 h post PTI) resulted in the deterioration of neurovascular function. A therapeutic window between 1 and 3 h post PTI was found to improve recovery of neurovascular function (i.e. significant restoration of neural activity to 93 ± 4.2% of baseline and hemodynamics to 81 ± 2.1% of baseline, respectively). The novel combination of fPAM and ECoG enables direct mapping of neurovascular dynamics and serves as a platform to evaluate potential interventions for stroke.

Huang-Lian-Jie-Du-Decotion induced protective autophagy against the injury of cerebral ischemia/reperfusion via MAPK-mTOR signaling pathway.

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Wang, Peng-Ran; Wang, Jun-Song; Zhang, Chao; Song, Xing-Fang; Tian, Na; Kong, Ling-Yi

2013-08-26

Huang-Lian-Jie-Du-Decotion (HLJDD, Hwangryun-Hae-Dok-Decotion in Japan), an ancient antipyretic and detoxifying traditional Chinese medicine formula, was reported to have protective effect on ischemic stroke. To investigate the therapeutic effect of HLJDD on ischemic stroke and explore its mode of action. A model of ischemic stroke in the rat was established after transient middle cerebral artery occlusion (MCAO) followed by reperfusion. Rats were assigned randomly to groups of control, sham, transient ischemia/reperfusion (I/R), and three treatment groups by HLJDD at 2.5, 5.0, 10.0mg/kg. The neurological deficit, the cerebral infarct size, morphology abnormality, biochemical parameters were examined, and the levels of relevant proteins were determined by immunoblotting analysis to evaluate the protective effects of HLJDD on ischemic stroke and explore the underlying mechanism. Compared with I/R group, HLJDD significantly ameliorated neurological deficit and histopathology changes, decreased infarct area, and restored the levels of biochemical indicators including nitric oxide (NO), malondialdehyde (MDA), glutathione (GSH), glutathione disulfide (GSSG), total superoxide dismutase (T-SOD), Cu/Zn-SOD, Mn-SOD and glutathione peroxidase (GSH-PX). HLJDD also notably elevated the levels of microtubule-associated protein 1 light chain 3 (LC3), Beclin-1, and other autophagy related genes (Atgs), promoted the activation of extracellular signal-regulated kinases (ERK), protein kinase B (Akt), 3-phosphoinositide-dependent kinase (PDK1), and inhibited the activation of mammalian target of rapamycin (mTOR), c-Jun N-terminal protein kinases (JNK), p38, phosphatase and tensin homolog (PTEN). HLJDD showed neuroprotective effects on ischemic stroke, at least in part to the induced protective autophagy via the regulation of mitogen-activated protein kinase (MAPK) signals. This Akt-independent protective autophagy is favorable in the treatment of stroke, avoiding unfavorable side

Forced treadmill exercise can induce stress and increase neuronal damage in a mouse model of global cerebral ischemia

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Martina Svensson

2016-12-01

Full Text Available Physical exercise is known to be a beneficial factor by increasing the cellular stress tolerance. In ischemic stroke, physical exercise is suggested to both limit the brain injury and facilitate behavioral recovery. In this study we investigated the effect of physical exercise on brain damage following global cerebral ischemia in mice. We aimed to study the effects of 4.5 weeks of forced treadmill running prior to ischemia on neuronal damage, neuroinflammation and its effect on general stress by measuring corticosterone in feces. We subjected C57bl/6 mice (n = 63 to either treadmill running or a sedentary program prior to induction of global ischemia. Anxious, depressive, and cognitive behaviors were analyzed. Stress levels were analyzed using a corticosterone ELISA. Inflammatory and neurological outcomes were analyzed using immunohistochemistry, multiplex electrochemoluminescence ELISA and Western blot. To our surprise, we found that forced treadmill running induced a stress response, with increased anxiety in the Open Field test and increased levels of corticosterone. In accordance, mice subjected to forced exercise prior to ischemia developed larger neuronal damage in the hippocampus and showed higher cytokine levels in the brain and blood compared to non-exercised mice. The extent of neuronal damage correlated with increased corticosterone levels. To compare forced treadmill with voluntary wheel running, we used a different set of mice that exercised freely on running wheels. These mice did not show any anxiety or increased corticosterone levels. Altogether, our results indicate that exercise pre-conditioning may not be beneficial if the animals are forced to run as it can induce a detrimental stress response.

Chinese herbal formula Tongluo Jiunao injection protects against cerebral ischemia by activating neurotrophin 3/tropomyosin-related kinase C pathway

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Peiman Alesheikh

2015-01-01

Full Text Available The Chinese herbal formula Tongluo Jiunao, containing the active components Panax notoginseng and Gardenia jasminoides, has recently been patented and is in use clinically. It is known to be neuroprotective in cerebral ischemia, but the underlying pathway remains poorly understood. In the present study, we established a rat model of cerebral ischemia by occlusion of the middle cerebral artery, and administered Tongluo Jiunao, a positive control (Xuesai Tong, containing Panax notoginseng or saline intraperitoneally to investigate the pathway involved in the action of Tongluo Jiunao injection. 2,3,5-Triphenyltetrazolium chloride (TTC staining showed that the cerebral infarct area was significantly smaller in model rats that received Tongluo Jiunao than in those that received saline. Enzyme-linked immunosorbent assay revealed significantly greater expression of neurotrophin 3 and growth-associated protein 43 in ischemic cerebral tissue, and serum levels of neurotrophin 3, in the Tongluo Jiunao group than in the saline group. The reverse transcription polymerase chain reaction and immunohistochemical staining showed that after treatment with Tongluo Jiunao or Xuesai Tong, tropomyosin-related kinase C gene expression and immunoreactivity were significantly elevated compared with saline, with the greatest expression observed after Tongluo Jiunao treatment. These findings suggest that Tongluo Jiunao injection exerts a neuroprotective effect in rats with cerebral ischemia by activating the neurotrophin 3/tropomyosin-related kinase C pathway.

Computed tomography perfusion as a diagnostic tool for seizures after ischemic stroke

International Nuclear Information System (INIS)

Koome, Miriam; Thevathasan, Arthur; Yan, Bernard; Churilov, Leonid; Chen, Ziyuan; Chen, Ziyi; Naylor, Jillian; Kwan, Patrick

2016-01-01

Cerebral cortical ischemia is a risk factor for post-stroke seizures. However, the optimal imaging method is unclear. We investigated CT perfusion (CTP) in detecting cortical ischemia and its correlation with post-stroke seizures compared with non-contrast CT (NCCT). We included patients with acute ischemic stroke admitted to the Royal Melbourne Hospital between 2009 and 2014. Post-stroke seizure information was collected. Cortical involvement was determined on acute NCCT and CTP (T max , cerebral blood volume [CBV], and cerebral blood flow [CBF]). The association between cortical involvement detected by different imaging modalities and post-stroke seizures was examined. Three-hundred fifty-two patients were included for analysis. Fifty-nine percent were male, and median age was 73 years (inter-quartile range 61-82). Follow-up was available for 96 %; median follow-up duration was 377 days (inter-quartile range 91-1018 days). Thirteen patients had post-stroke seizures (3.9 %). Cortical involvement was significantly associated with post-stroke seizures across all modalities. CBV had the highest hazard ratio (11.3, 95 % confidence interval (CI) 1.1-41.2), followed by NCCT (5.3, 95 % CI 1.5-18.0) and CBF (4.2, 95 % CI 1.1-15.2). Sensitivity was highest for T max (100 %), followed by CBV and CBF (both 76.9 %) and NCCT (63.6 %). Specificity was highest for CBV (77.8 %), then NCCT (75.6 %), CBF (54.0 %), and T max (29.1 %). Receiver-operating characteristic area under the curve was significantly different between imaging modalities (p < 0.001), CBV 0.77, NCCT 0.70, CBF 0.65, and T max 0.65. CTP may improve sensitivity and specificity of cortical involvement for post-stroke seizures compared to NCCT. (orig.)

Computed tomography perfusion as a diagnostic tool for seizures after ischemic stroke

Energy Technology Data Exchange (ETDEWEB)

Koome, Miriam; Thevathasan, Arthur; Yan, Bernard [The Royal Melbourne Hospital, Melbourne Brain Centre, Parkville, VIC (Australia); Churilov, Leonid [University of Melbourne, Florey Neuroscience Institutes, Austin Health, Melbourne (Australia); Chen, Ziyuan [The Royal Melbourne Hospital, Melbourne Brain Centre, Parkville, VIC (Australia); Tsinghua University, School of Medicine, Beijing (China); Chen, Ziyi [The Royal Melbourne Hospital, Melbourne Brain Centre, Parkville, VIC (Australia); Sun Yat-Sen University, First Affiliated Hospital, Guangdong (China); Naylor, Jillian; Kwan, Patrick [The Royal Melbourne Hospital, Melbourne Brain Centre, Parkville, VIC (Australia); The University of Melbourne, Department of Medicine, Melbourne (Australia)

2016-06-15

Cerebral cortical ischemia is a risk factor for post-stroke seizures. However, the optimal imaging method is unclear. We investigated CT perfusion (CTP) in detecting cortical ischemia and its correlation with post-stroke seizures compared with non-contrast CT (NCCT). We included patients with acute ischemic stroke admitted to the Royal Melbourne Hospital between 2009 and 2014. Post-stroke seizure information was collected. Cortical involvement was determined on acute NCCT and CTP (T{sub max}, cerebral blood volume [CBV], and cerebral blood flow [CBF]). The association between cortical involvement detected by different imaging modalities and post-stroke seizures was examined. Three-hundred fifty-two patients were included for analysis. Fifty-nine percent were male, and median age was 73 years (inter-quartile range 61-82). Follow-up was available for 96 %; median follow-up duration was 377 days (inter-quartile range 91-1018 days). Thirteen patients had post-stroke seizures (3.9 %). Cortical involvement was significantly associated with post-stroke seizures across all modalities. CBV had the highest hazard ratio (11.3, 95 % confidence interval (CI) 1.1-41.2), followed by NCCT (5.3, 95 % CI 1.5-18.0) and CBF (4.2, 95 % CI 1.1-15.2). Sensitivity was highest for T{sub max} (100 %), followed by CBV and CBF (both 76.9 %) and NCCT (63.6 %). Specificity was highest for CBV (77.8 %), then NCCT (75.6 %), CBF (54.0 %), and T{sub max} (29.1 %). Receiver-operating characteristic area under the curve was significantly different between imaging modalities (p < 0.001), CBV 0.77, NCCT 0.70, CBF 0.65, and T{sub max} 0.65. CTP may improve sensitivity and specificity of cortical involvement for post-stroke seizures compared to NCCT. (orig.)

Delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage : the role of coagulation and fibrinolysis

NARCIS (Netherlands)

Vergouwen, M.D.I.

2009-01-01

Patients with aneurysmal subarachnoid hemorrhage (SAH) are at risk to develop complications, especially within the first two weeks after the hemorrhage. Delayed cerebral ischemia (DCI) is a complication which occurs in about 30% of SAH patients, leading to symptoms such as aphasia, hemiparesis, or

Multiplex Brain Proteomic Analysis Revealed the Molecular Therapeutic Effects of Buyang Huanwu Decoction on Cerebral Ischemic Stroke Mice.

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Hong-Jhang Chen

Full Text Available Stroke is the second-leading cause of death worldwide, and tissue plasminogen activator (TPA is the only drug used for a limited group of stroke patients in the acute phase. Buyang Huanwu Decoction (BHD, a traditional Chinese medicine prescription, has long been used for improving neurological functional recovery in stroke. In this study, we characterized the therapeutic effect of TPA and BHD in a cerebral ischemia/reperfusion (CIR injury mouse model using multiplex proteomics approach. After the iTRAQ-based proteomics analysis, 1310 proteins were identified from the mouse brain with <1% false discovery rate. Among them, 877 quantitative proteins, 10.26% (90/877, 1.71% (15/877, and 2.62% (23/877 of the proteins was significantly changed in the CIR, BHD treatment, and TPA treatment, respectively. Functional categorization analysis showed that BHD treatment preserved the integrity of the blood-brain barrier (BBB (Alb, Fga, and Trf, suppressed excitotoxicity (Grm5, Gnai, and Gdi, and enhanced energy metabolism (Bdh, thereby revealing its multiple effects on ischemic stroke mice. Moreover, the neurogenesis marker doublecortin was upregulated, and the activity of glycogen synthase kinase 3 (GSK-3 and Tau was inhibited, which represented the neuroprotective effects. However, TPA treatment deteriorated BBB breakdown. This study highlights the potential of BHD in clinical applications for ischemic stroke.

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

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

2008-06-20

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

Protective effect and its mechanism of curcumin on ischemia-reperfusion injury of cerebral cortex in rats

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Li LIU

2013-03-01

Full Text Available Objective 　To investigate the effect of curcumin pretreatment on the expression of uncoupling protein 2 (UCP2 and mitochondrial transcription factor A (MTFA in rats' cerebral cortex against focal ischemia reperfusion injury. Methods 　Eighty male SD rats weighed 220g–300g were randomly divided into 4 groups: sham-operated group, ischemia/reperfusion (I/R group, curcumine 50mg/kg+I/R (low dose group, and curcumine 100mg/kg+I/R (high dose group. The common carotid artery, external carotid artery and internal carotid artery on the right side were exposed in the sham-operated group. Animals of the other groups were subjected to a 2-hour period of right middle cerebral artery occlusion, followed by 24 hours of reperfusion, and then they were sacrificed. Curcumin was administered (ip in a dose of 50mg/kg (low dose group or 100mg/kg (high dose group for 5 days, respectively, prior to arterial occlusion. The pathological changes in neurons and their mitochondria in the cerebral cortex supplied by middle cerebral artery were observed with Nissl staining and electron microscope, respectively. The expressions of UCP2 and MTFA in corresponding cotex were assessed by immunohistochemistry and RT-PCR. Results 　Compared with sham-operated group, animals in I/R group presented edema of neurons in the corresponding cortex, reduction in the number of Nissl bodies, and swelling of mitochondria with broken, even lysis of cristae. Low dose and high dose of curcumin pretreatment before brain ischemia significantly alleviated the loss of neurons and the damage of mitochondria, accompanied with an increase in the expression of UCP2 and TFAM (P<0.05, and the changes appeared a dose-dependent manner (P<0.05. Conclusions 　Curcumin may prevent neurons from focal cerebral ischemia reperfusion injury by up-regulating UCP2 and MTFA. Regulation of mitochondrial biogenesis may probably be a potential target of curcumin as a neuroprotective drug.

[Effects of combined use of total alkaloids of Uncaria rhynchophylla and Coryadlis ambailis migo on cerebral ischemia-reperfusion injury in rats].

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Hu, Xue-yong; Sun, An-sheng; Sui, Yu-xia

2007-11-01

To study the effects of combined use of total alkaloids (TA) of Uncaria rhynchophylla (UR) and Coryadlis ambailis migo (CAM) on cerebral ischemia/reperfusion injury in rats. Rat model of middle cerebral artery ischemia/reperfusion was established, the changes of neurological state was scored before and after treatment with the two kinds of TA, single or combined, and the changes of cerebral infarcted volume, cerebral water content, activities of NOS and SOD and content of MDA in rats' brain were estimated as well. After being treated with the combination of both TA, the average neurological score, cerebral infracted volume, cerebral water content, activity of NOS and content of MDA in the model rats significantly decreased, and the activity of SOD was significantly increased (all P < 0.05). The effect of combined use of the two TA was higher than that of use TA of UR or CAM alone (P <0.05). Moreover, the central nervous system inhibitory effect induced by combined TA was significantly weaker than that of UR. Combined use of TA of UR and CAM may facilitate the protection against cerebral ischemia/reperfusion damage, the action mechanism might be relevant to reducing the lipid peroxidation injury of brain cells through inhibiting the NOS activity and increasing the SOD activity.

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

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

2009-01-01

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-κB). 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-κB 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-κB activity and phosphorylation of the inhibitor of kappa B (IκBα) increased in ischemic brains, but IRF3, inhibitor of κB kinase complex-ε (IKKε), and TANK-binding kinase1 (TBK1) were not activated after cerebral I/R in wild-type (WT) mice. Interestingly, TRIF deficit did not inhibit NF-κB activity or p-IκBα 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-κB signaling and brain injury after acute cerebral I/R.

Effect of ligustrazine on levels of amino acid neurotransmitters in rat striatum after cerebral ischemia-reperfusion injury.

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Han, Jin; Wan, Hai-Tong; Yang, Jie-Hong; Zhang, Yu-Yan; Ge, Li-Jun; Bie, Xiao-Dong

2014-01-01

This study aimed to evaluate the effect of ligustrazine on levels of amino acid transmitters in the extracellular fluid of striatum following cerebral ischemia/reperfusion (I/R) in male Sprague-Dawley rats. A microdialysis cannula guide was implanted into the right striatum. After recovery, animals underwent a sham operation or middle cerebral artery occlusion (MCAO). Those that developed cerebral ischemia after MCAO were randomized to receive propylene glycol salt water and ligustrazine respectively. Striatal fluid samples were collected from all animals at 15-min intervals after treatment and were subjected to HPLC analysis of aspartic acid, glutamic acid, taurine, and γ-amino butyric acid. Upon the last sample collection, animals were sacrificed and brain tissue specimens were collected for triphenyltetrazolium chloride staining and NeuN staining. Compared with the sham operation, MCAO induced significant neurological deficits and increased striatal concentrations of the four neurotransmitters assessed in a time-dependent manner (P cerebral infarction-protective agent may have potential clinical implications for I/R-related brain damage.

Radiology in cases of cerebral stroke

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Forsting, M.; Reith, W.; Kummer, R. von; Sartor, K.

1993-01-01

Today radiologic methods play an important role in the diagnosis of cerebral stroke. The aim of the radiologist, however, should not only be to classify the stroke into the four main categories (ischemic stroke, intracerebral bleeding, subarachnoid hemorrhage, sinovenous thrombis), but also to interprete the findings with regard to the etiology of the disease. The pattern of lesions gives information about the etiology of ischemic stroke; the correct interpretation of these lesion patterns allows one to optimize therapeutic decisions. This paper additionally focusses on the differential diagnosis of intracerebral hemorrhage and the CT and MR signs of sinovenous thrombosis. New developed concepts in the field of stroke therapy and prophylaxis call for authority and continuous education of the radiolgist on this topic. Pure descriptions of radiologic findings without an understanding of the pathogenesis of the disease will be ignored by the clinician. On the other hand, the radiologist can turn the therapeutic decisions in the right direction by combining morphological descriptions with pathogenetic orientated interpretations. In this way, the radiolgist can contribute to the reduction of costs in the public health system. (orig.) [de

Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning

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Ren, Chuancheng; Gao, Xuwen; Steinberg, Gary K.; Zhao, Heng

2009-01-01

Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 minute occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 minute occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for 2 or 3 cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with 3 cycles of 15 minutes performed immediately before stroke reduced infarct size from 47.7±7.6% of control ischemia to 9.8±8.6%; at 2 cycles of 15 minutes, infarct was reduced to 24.7±7.3%; at 2 cycles of 5 minutes, infarct was not reduced. Delayed preconditioning with 3 cycles of 15 minutes conducted 2 days before stroke also reduced infarct to 23.0 ±10.9%, but with 2 cycles of 15 minutes it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with 3 cycles of 15 minutes performed 12 hours before stroke also reduced infarct to 24.7±4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia. PMID:18201834

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

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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.

In vivo cellular uptake of glutamate is impaired in the rat hippocampus during and after transient cerebral ischemia

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Bruhn, T; Christensen, Thomas; Diemer, Nils Henrik

2001-01-01

Using microdialysis in CA1 of the rat hippocampus, we studied the effect of transient cerebral ischemia on in vivo uptake and on extracellular levels of glutamate during, and at different time points after ischemia. (3)H-D-aspartate (test substance), and (14)C-mannitol (reference substance), were...

Intra-arterial thrombolysis using rt-PA in patients with acute stroke due to vessel occlusion of anterior and/or posterior cerebral circulation

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Tountopoulou, Argyro; Ahl, Bjoern; Weissenborn, Karin [Hannover Medical School, Department of Neurology and Clinical Neurophysiology, Hannover (Germany); Becker, Hartmut; Goetz, Friedrich [Hannover Medical School, Department of Neuroradiology, Hannover (Germany)

2008-01-15

The aim of our study was to evaluate the safety and efficacy of intra-arterial (IA) thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute stroke due to occlusion in the anterior or posterior circulation. We retrospectively analyzed the clinical and radiological data of 88 consecutive patients with acute ischemic stroke who underwent emergency cerebral angiography for the purpose of subsequent IA thrombolysis. The neurological deficit on admission and discharge was graded using the National Institutes of Health Stroke Scale (NIHSS) score. Baseline computer tomography (CT) scans were examined for any signs indicative of cerebral ischemia. The angiographic findings were classified according to the Thrombolysis in Myocardial Infarction (TIMI) score for myocardial infarction. Follow-up CT scans were examined for hemorrhagic complication. Of the 88 patients who underwent IA thrombolysis, 63 presented with complete or partial arterial occlusion in the suspected perfusion area. In these 63 patients, the median NIHSS score dropped from 15 points on admission to 10 points at discharge. The recanalization rate was 52.6% for partial and complete reperfusion. In-hospital mortality was 20.6% (9.1% for carotid, 44.4% for basilar territory occlusion). Intracerebral bleeding (ICB) occurred in 38.6% of the patients with occlusion in the anterior circulation, resulting in these patients presenting a worse clinical outcome than those without ICB. Only minor extracranial bleedings occurred in 20.6% of patients. Patients with ICB had a significantly higher frequency of ischemic signs on the baseline CT scan. Occlusion of a cerebral artery is present in about 75% of the patients eligible for thrombolytic therapy. Intra-arterial thrombolysis using rt-PA in patients with acute ischemic stroke can achieve re-vascularization, although ICB remains the major risk factor affecting its efficacy. (orig.)

Intra-arterial thrombolysis using rt-PA in patients with acute stroke due to vessel occlusion of anterior and/or posterior cerebral circulation

International Nuclear Information System (INIS)

Tountopoulou, Argyro; Ahl, Bjoern; Weissenborn, Karin; Becker, Hartmut; Goetz, Friedrich

2008-01-01

The aim of our study was to evaluate the safety and efficacy of intra-arterial (IA) thrombolysis using recombinant tissue plasminogen activator (rt-PA) in patients with acute stroke due to occlusion in the anterior or posterior circulation. We retrospectively analyzed the clinical and radiological data of 88 consecutive patients with acute ischemic stroke who underwent emergency cerebral angiography for the purpose of subsequent IA thrombolysis. The neurological deficit on admission and discharge was graded using the National Institutes of Health Stroke Scale (NIHSS) score. Baseline computer tomography (CT) scans were examined for any signs indicative of cerebral ischemia. The angiographic findings were classified according to the Thrombolysis in Myocardial Infarction (TIMI) score for myocardial infarction. Follow-up CT scans were examined for hemorrhagic complication. Of the 88 patients who underwent IA thrombolysis, 63 presented with complete or partial arterial occlusion in the suspected perfusion area. In these 63 patients, the median NIHSS score dropped from 15 points on admission to 10 points at discharge. The recanalization rate was 52.6% for partial and complete reperfusion. In-hospital mortality was 20.6% (9.1% for carotid, 44.4% for basilar territory occlusion). Intracerebral bleeding (ICB) occurred in 38.6% of the patients with occlusion in the anterior circulation, resulting in these patients presenting a worse clinical outcome than those without ICB. Only minor extracranial bleedings occurred in 20.6% of patients. Patients with ICB had a significantly higher frequency of ischemic signs on the baseline CT scan. Occlusion of a cerebral artery is present in about 75% of the patients eligible for thrombolytic therapy. Intra-arterial thrombolysis using rt-PA in patients with acute ischemic stroke can achieve re-vascularization, although ICB remains the major risk factor affecting its efficacy. (orig.)

PPARγ agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia

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

2009-01-01

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

Protective effect of tetraethyl pyrazine against focal cerebral ischemia/reperfusion injury in rats: therapeutic time window and its mechanism.

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Jia, Jie; Zhang, Xi; Hu, Yong-Shan; Wu, Yi; Wang, Qing-Zhi; Li, Na-Na; Wu, Cai-Qin; Yu, Hui-Xian; Guo, Qing-Chuan

2009-03-01

Tetramethyl pyrazine has been considered an effective agent in treating neurons ischemia/reperfusion injury, but the mechanism of its therapeutic effect remains unclear. This study was to explore the therapeutic time window and mechanism of tetramethyl pyrazine on temporary focal cerebral ischemia/reperfusion injury. Middle cerebral artery occlusion was conducted in male Sprague-Dawley rats and 20 mg/kg of tetramethyl pyrazine was intraperitoneally injected at different time points. At 72 h after reperfusion, all animals' neurologic deficit scores were evaluated. Cerebrums were removed and cerebral infarction volume was measured. The expression of thioredoxin and thioredoxin reductase mRNA was determined at 6 and 24 h after reperfusion. Cerebral infarction volume and neurological deficit scores were significantly decreased in the group with tetramethyl pyrazine treatment. The expression of thioredoxin-1/thioredoxin-2 and thioredoxin reductase-1/thioredoxin reductase-2 was significantly decreased in rats with ischemia/reperfusion injury, while it was increased by tetramethyl pyrazine administration. Treatment with tetramethyl pyrazine, within 4 h after reperfusion, protects the brain from ischemic reperfusion injury in rats. The neuroprotective mechanism of tetramethyl pyrazine treatment is, in part, mediated through the upregulation of thioredoxin transcription.

The evaluation of cerebral oxygenation by oximetry in patients with ischaemic stroke.

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Demet G

2000-04-01

Full Text Available AIMS: To evaluate the clinical significance of estimation of the regional cerebral oxygen saturation (rSO2 in the patients with ischaemic stroke by the cerebral oximetry during acute, sub-acute and chronic phases. SUBJECTS AND METHODS: In this prospective study, 24 patients with ischaemic stroke in the middle cerebral artery territory were included. A detailed clinical examination and appropriate laboratory investigations were carried out. The rSO2 was determined by oximetery (INVOS 3100-SD bilaterally on the first, third, seventh, and fifteenth days. The blood pressure, the peripheral capillary oxygen saturation and the arterial blood gas values were noted too. the changes were evaluated along with Glasgow coma scale (GCS using unpaired student t-test and one way ANOVA test. RESULTS: There were significant differences between the rSO2 values in acute, subacute and chronic phases on the side of the lesion (p value < 0.05. The values of oxygen saturation gradually increased throughout the chronic phase. These values showed a positive correlation with GCS, but the results were not significant statistically. The rSO2 values were also significantly higher on the non-lesional side than those on the lesion side in the acute phase (p= 0.0034, the discrepancy disappeared during the sub-acute and chronic phases. CONCLUSION: Cerebral oximetry can be used as a measure to evaluate the cerebral oxygenation during the various phases of ischaemic stroke. It has a potential to serve as a useful marker for detection of cerebral oxygenation imbalances, to judge the effectiveness of the management and for the follow-up of patients with ischaemic stroke.

Edaravone, a Free Radical Scavenger, Mitigates Both Gray and White Matter Damages after Global Cerebral Ischemia in Rats

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Kubo, Kozue; Nakao, Shinichi; Jomura, Sachiko; Sakamoto, Sachiyo; Miyamoto, Etsuko; Xu, Yan; Tomimoto, Hidekazu; Inada, Takefumi; Shingu, Koh

2012-01-01

Recent studies have shown that similar to cerebral gray matter (mainly composed of neuronal perikarya), white matter (composed of axons and glias) is vulnerable to ischemia. Edaravone, a free radical scavenger, has neuroprotective effects against focal cerebral ischemia even in humans. In this study, we investigated the time course and the severity of both gray and white matter damage following global cerebral ischemia by cardiac arrest, and examined whether edaravone protected the gray and the white matter. Male Sprague-Dawley rats were used. Global cerebral ischemia was induced by 5 minutes of cardiac arrest and resuscitation (CAR). Edaravone, 3 mg/kg, was administered intravenously either immediately or 60 minutes after CAR. The morphological damage was assessed by cresyl violet staining. The microtubule-associated protein 2 (a maker of neuronal perikarya and dendrites), the β amyloid precursor protein (the accumulation of which is a maker of axonal damage), and the ionized calcium binding adaptor molecule 1 (a marker of microglia) were stained for immunohistochemical analysis. Significant neuronal perikaryal damage and marked microglial activation were observed in the hippocampal CA1 region with little axonal damage one week after CAR. Two weeks after CAR, the perikaryal damage and microglial activation were unchanged, but obvious axonal damage occurred. Administration of edaravone 60 minutes after CAR significantly mitigated the perikaryal damage, the axonal damage, and the microglial activation. Our results show that axonal damage develops slower than perikaryal damage and that edaravone can protect both gray and white matter after CAR in rats. PMID:19410562

Neuroprotective Effect of Matricaria chamomilla Extract on Motor Dysfunction Induced by Transient Global Cerebral Ischemia and Reperfusion in Rat

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Azam Moshfegh

2017-09-01

Full Text Available Background Stroke can cause paralysis, muscle weakness, and loss of balance that may affect walking and routine activities. Objectives The aim of this study was to evaluate the effect of ethyl alcohol extract of Matricaria chamomilla on cerebral ischemia-induced motor dysfunctions in rats. Methods In this experimental study, forty two male Wistar rats were divided into 6 groups consisting of control group, sham group, ischemia/reperfusion group and three treatment groups [treated with 50, 100, and 200 mg/kg doses of M. chamomilla extract and undergoing ischemia/reperfusion(I/R]. Motor coordination and balance were evaluated using Rotarod test. Total antioxidant capacity, malondialdehyde (MDA, and nitric oxide (NO levels of serum and brain were also determined. Results The extract of M. chamomilla significantly improved I/R-induced motor dysfunction. Induction of I/R led to increase serum MDA, while the extract of M, chamomlla significantly reduced it. Administration all doses of M. chamomilla extract to the ischemic rats did not reduce the hippocampus MDA levels (P > 0.05. The extract of M. chamomilla at dose of 200 mg/kg slightly decreased cortex MDA (P > 0.01. It had no significant effects on the total antioxidant capacity of the brain (hippocampus and cortex and serum. Injection of Matricaria chamomilla extract also did not change serum NO level. Conclusions Our findings suggested that the Matricaria chamomilla extract could improve motor dysfunction.

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

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Hua, Fang, E-mail: fhua2@emory.edu [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States); Wang, Jun; Sayeed, Iqbal; Ishrat, Tauheed; Atif, Fahim; Stein, Donald G. [Department of Emergency Medicine, Brain Research Laboratory, Emory University School of Medicine, 1365B Clifton Road, Suite 5100, Atlanta, GA 30322 (United States)

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.

Cerebral blood flow variations in CNS lupus

International Nuclear Information System (INIS)

Kushner, M.J.; Tobin, M.; Fazekas, F.; Chawluk, J.; Jamieson, D.; Freundlich, B.; Grenell, S.; Freemen, L.; Reivich, M.

1990-01-01

We studied the patterns of cerebral blood flow (CBF), over time, in patients with systemic lupus erythematosus and varying neurologic manifestations including headache, stroke, psychosis, and encephalopathy. For 20 paired xenon-133 CBF measurements, CBF was normal during CNS remissions, regardless of the symptoms. CBF was significantly depressed during CNS exacerbations. The magnitude of change in CBF varied with the neurologic syndrome. CBF was least affected in patients with nonspecific symptoms such as headache or malaise, whereas patients with encephalopathy or psychosis exhibited the greatest reductions in CBF. In 1 patient with affective psychosis, without clinical or CT evidence of cerebral ischemia, serial SPECT studies showed resolution of multifocal cerebral perfusion defects which paralleled clinical recovery

Hexane extracts of Polygonum multiflorum improve tissue and functional outcome following focal cerebral ischemia in mice.

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Lee, Soo Vin; Choi, Kyung Ha; Choi, Young Whan; Hong, Jin Woo; Baek, Jin Ung; Choi, Byung Tae; Shin, Hwa Kyoung

2014-04-01

Polygonum multiflorum is a traditional Korean medicine that has been utilized widely in East Asian countries as a longevity agent. Clinical studies have demonstrated that Polygonum multiflorum improves hypercholesterolemia, coronary heart disease, neurosis and other diseases commonly associated with aging. However, scientific evidence defining the protective effects and mechanisms of Polygonum multiflorum against ischemic stroke is incomplete. In the present study, we investigated the cerebrovascular protective effects of Polygonum multiflorum against ischemic brain injury using an in vivo photothrombotic mouse model. To examine the underlying mechanism of action, we utilized an in vitro human brain microvascular endothelial cell (HBMEC) culture system. Hexane extracts (HEPM), ethyl acetate extracts (EAEPM) and methanol extracts (MEPM) of Polygonum multiflorum (100 mg/kg) were administered intraperitoneally 30 min prior to ischemic insult. Focal cerebral ischemia was induced in C57BL/6J mice and endothelial nitric oxide synthase knockout (eNOS KO) mice by photothrombotic cortical occlusion. We evaluated the infarct volume, as well as neurological and motor function, 24 h after ischemic brain injury. Following ischemic insult, HEPM induced a significant reduction in infarct volume and subsequent neurological deficits, compared with EAEPM and MEPM. HEPM significantly decreased infarct size and improved neurological and motor function, which was not observed in eNOS KO mice, suggesting that this cerebroprotective effect is primarily an eNOS-dependent mechanism. In vitro, HEPM effectively promoted NO production, however these effects were inhibited by the NOS inhibitor, L-NAME and the PI3K/Akt inhibitor, LY-294002. Furthermore, HEPM treatment resulted in increased phosphorylation-dependent activation of Akt and eNOS in HBMEC, suggesting that HEPM increased NO production via phosphorylation-dependent activation of Akt and eNOS. In conclusion, HEPM prevents cerebral

Neuroprotective effect of curcumin on transient focal cerebral ischemia in rats.

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Zhao, Jing; Zhao, Yong; Zheng, Weiping; Lu, Yuyu; Feng, Gang; Yu, Shanshan

2008-09-10

Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from the powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. Hence, in the present study the neuroprotective potential of curcumin was investigated in middle cerebral artery occlusion (MCAO) induced focal cerebral IR injury. Administration of curcumin 100 and 300 mg/kg i.p. 60 min after MCAO significantly diminished infarct volume, and improved neurological deficit in a dose-dependent manner. Nissl staining showed that the neuronal injury was significantly improved after being treated with curcumin. Curcumin significantly decreased the expression of caspase-3 protein. A higher number of TUNEL-positive cells were found in the vehicle group, but they were significantly decreased in the treated group. Taken together, these results suggest that the neuroprotective potentials of curcumin against focal cerebral ischemic injury are, at least in part, ascribed to its anti-apoptotic effects.

(1)H NMR-based metabonomics revealed protective effect of Naodesheng bioactive extract on ischemic stroke rats.

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Luo, Lan; Zhen, Lifeng; Xu, Yatao; Yang, Yongxia; Feng, Suxiang; Wang, Shumei; Liang, Shengwang

2016-06-20

Stroke is a leading cause of death and disability in the world. However, current therapies are limited. Naodesheng, a widely used traditional Chinese medicine prescription, has shown a good clinical curative effect on ischemic stroke. Also, Naodesheng has been suggested to have neuroprotective effect on focal cerebral ischemia rats, but the underlying molecular mechanism remains unclear. The present study was designed to evaluate the effect of Naodesheng bioactive extract on the metabolic changes in brain tissue, plasma and urine induced by cerebral ischemia perfusion injury, and explore the possible metabolic mechanisms by using a (1)H NMR-based metabonomics approach. A middle cerebral artery occlusion rat model was established and confirmed by the experiments of neurobehavioral abnormality evaluation, brain tissue TTC staining and pathological examination. The metabolic changes in brain tissue, plasma and urine were then assessed by a (1)H NMR technique combined with multivariate statistical analysis method. These NMR data showed that cerebral ischemia reperfusion induced great metabolic disorders in brain tissue, plasma and urine metabolisms. However, Naodesheng bioactive extract could reverse most of the imbalanced metabolites. Meanwhile, it was found that both the medium and high dosages of Naodesheng bioactive extract were more effective on the metabolic changes than the low dosage, consistent with histopathological assessments. These results revealed that Naodesheng had protective effect on ischemic stroke rats and the underlying mechanisms involved multiple metabolic pathways, including energy metabolism, amino acid metabolism, oxidative stress and inflammatory injury. The present study could provide evidence that metabonomics revealed its capacity to evaluate the holistic efficacy of traditional Chinese medicine and explore the underlying mechanisms. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cerebral hypoxia and ischemia in preterm infants

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Alberto Ravarino

2014-06-01

Full Text Available Premature birth is a major public health issue internationally affecting 13 million babies worldwide. Hypoxia and ischemia is probably the commonest type of acquired brain damage in preterm infants. The clinical manifestations of hypoxic-ischemic injury in survivors of premature birth include a spectrum of cerebral palsy and intellectual disabilities. Until recently, the extensive brain abnormalities in preterm neonates appeared to be related mostly to destructive processes that lead to substantial deletion of neurons, axons, and glia from necrotic lesions in the developing brain. Advances in neonatal care coincide with a growing body of evidence that the preterm gray and white matter frequently sustain less severe insults, where tissue destruction is the minor component. Periventricular leukomalacia (PVL is the major form of white matter injury and consists classically of focal necrotic lesions, with subsequent cyst formation, and a less severe but more diffuse injury to cerebral white mater, with prominent astrogliosis and microgliosis but without overt necrosis. With PVL a concomitant injury occurs to subplate neurons, located in the subcortical white matter. Severe hypoxic-ischemic insults that trigger significant white matter necrosis are accompanied by neuronal degeneration in cerebral gray and white matter. This review aims to illustrate signs of cerebral embryology of the second half of fetal life and correlate hypoxic-ischemic brain injury in the premature infant. This should help us better understand the symptoms early and late and facilitate new therapeutic strategies. Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in problem solving Guest Editors: Gavino Faa, Vassilios Fanos, Peter Van Eyken

Metabolite changes in the ipsilateral and contralateral cerebral hemispheres in rats with middle cerebral artery occlusion

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Lei Ruan

2017-01-01

Full Text Available Cerebral ischemia not only causes pathological changes in the ischemic areas but also induces a series of secondary changes in more distal brain regions (such as the contralateral cerebral hemisphere. The impact of supratentorial lesions, which are the most common type of lesion, on the contralateral cerebellum has been studied in patients by positron emission tomography, single photon emission computed tomography, magnetic resonance imaging and diffusion tensor imaging. In the present study, we investigated metabolite changes in the contralateral cerebral hemisphere after supratentorial unilateral ischemia using nuclear magnetic resonance spectroscopy-based metabonomics. The permanent middle cerebral artery occlusion model of ischemic stroke was established in rats. Rats were randomly divided into the middle cerebral artery occlusion 1-, 3-, 9- and 24-hour groups and the sham group. 1H nuclear magnetic resonance spectroscopy was used to detect metabolites in the left and right cerebral hemispheres. Compared with the sham group, the concentrations of lactate, alanine, γ-aminobutyric acid, choline and glycine in the ischemic cerebral hemisphere were increased in the acute stage, while the concentrations of N-acetyl aspartate, creatinine, glutamate and aspartate were decreased. This demonstrates that there is an upregulation of anaerobic glycolysis (shown by the increase in lactate, a perturbation of choline metabolism (suggested by the increase in choline, neuronal cell damage (shown by the decrease in N-acetyl aspartate and neurotransmitter imbalance (evidenced by the increase in γ-aminobutyric acid and glycine and by the decrease in glutamate and aspartate in the acute stage of cerebral ischemia. In the contralateral hemisphere, the concentrations of lactate, alanine, glycine, choline and aspartate were increased, while the concentrations of γ-aminobutyric acid, glutamate and creatinine were decreased. This suggests that there is a

Individual patient data meta-analysis of antiplatelet regimens after noncardioembolic stroke or TIA : Rationale and design

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Greving, Jacoba P.; Diener, Hans Christoph; Csiba, László; Hacke, Werner; Kappelle, L. Jaap; Koudstaal, Peter J.; Leys, Didier; Mas, Jean Louis; Sacco, Ralph L.; Sivenius, Juhani; Algra, Ale

2015-01-01

Background: The Cerebrovascular Antiplatelet Trialists' Collaborative Group was formed to obtain and analyze individual patient data from the major randomized trials of common antiplatelet regimens after cerebral ischemia. Although the risk of stroke can be reduced by antiplatelet drugs, there

Niosomes of ascorbic acid and α-tocopherol in the cerebral ischemia-reperfusion model in male rats.

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Varshosaz, Jaleh; Taymouri, Somayeh; Pardakhty, Abbas; Asadi-Shekaari, Majid; Babaee, Abodolreza

2014-01-01

The objective of the present study was to prepare a stable iv injectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluated in vitro. For in vivo evaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4-8(°)C. In vivo studies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

Cerebral Vasospasm with Ischemia following a Spontaneous Spinal Subarachnoid Hemorrhage

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Sophia F. Shakur

2013-01-01

Full Text Available Cerebral vasospasm is a well-known consequence of aneurysmal subarachnoid hemorrhage (SAH triggered by blood breakdown products. Here, we present the first case of cerebral vasospasm with ischemia following a spontaneous spinal SAH. A 67-year-old woman, who was on Coumadin for atrial fibrillation, presented with chest pain radiating to the back accompanied by headache and leg paresthesias. The international normalized ratio (INR was 4.5. Ten hours after presentation, she developed loss of movement in both legs and lack of sensation below the umbilicus. Spine MRI showed intradural hemorrhage. Her coagulopathy was reversed, and she underwent T2 to T12 laminectomies. A large subarachnoid hematoma was evacuated. Given her complaint of headache preoperatively and the intraoperative finding of spinal SAH, a head CT was done postoperatively that displayed SAH in peripheral sulci. On postoperative day 5, she became obtunded. Brain MRI demonstrated focal restricted diffusion in the left frontoparietal area. Formal angiography revealed vasospasm in anterior cerebral arteries bilaterally and right middle cerebral artery. Vasospasm was treated, and she returned to baseline within 48 hours. Spontaneous spinal SAH can result in the same sequelae typically associated with aneurysmal SAH, and the clinician must have a degree of suspicion in such patients. The pathophysiological mechanisms underlying cerebral vasospasm may explain this unique case.

Investigation of Epidermal Growth Factor, Tumor Necrosis Factor-alpha and Thioredoxin System in Rats Exposed to Cerebral Ischemia

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Erol-Demirbilek Melike

2016-09-01

Full Text Available Background: Thioredoxin reductase (TrxR, epidermal growth factor (EGF and tumor necrosis factor-α (TNF-α have neuroprotective/neurotoxic effects in cerebral ischemia. We aimed to investigate the TrxR activity, EGF and TNF-α levels in cerebral ischemic, sham-operated and non-ischemic rat brains.

EEG patterns from acute to chronic stroke phases in focal cerebral ischemic rats: correlations with functional recovery.

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Zhang, Shao-jie; Ke, Zheng; Li, Le; Yip, Shea-ping; Tong, Kai-yu

2013-04-01

Monitoring the neural activities from the ischemic penumbra provides critical information on neurological recovery after stroke. The purpose of this study is to evaluate the temporal alterations of neural activities using electroencephalography (EEG) from the acute phase to the chronic phase, and to compare EEG with the degree of post-stroke motor function recovery in a rat model of focal ischemic stroke. Male Sprague-Dawley rats were subjected to 90 min transient middle cerebral artery occlusion surgery followed by reperfusion for seven days (n = 58). The EEG signals were recorded at the pre-stroke phase (0 h), acute phase (3, 6 h), subacute phase (12, 24, 48, 72 h) and chronic phase (96, 120, 144, 168 h) (n = 8). This study analyzed post-stroke seizures and polymorphic delta activities (PDAs) and calculated quantitative EEG parameters such as the alpha-to-delta ratio (ADR). The ADR represented the ratio between alpha power and delta power, which indicated how fast the EEG activities were. Forelimb and hindlimb motor functions were measured by De Ryck's test and the beam walking test, respectively. In the acute phase, delta power increased fourfold with the occurrence of PDAs, and the histological staining showed that the infarct was limited to the striatum and secondary sensory cortex. In the subacute phase, the alpha power reduced to 50% of the baseline, and the infarct progressed to the forelimb cortical region. ADRs reduced from 0.23 ± 0.09 to 0.04 ± 0.01 at 3 h in the acute phase and gradually recovered to 0.22 ± 0.08 at 168 h in the chronic phase. In the comparison of correlations between the EEG parameters and the limb motor function from the acute phase to the chronic phase, ADRs were found to have the highest correlation coefficients with the beam walking test (r = 0.9524, p test (r = 0.8077, p < 0.05). This study measured EEG activities after focal cerebral ischemia and showed that functional recovery was closely correlated with the neural

EEG patterns from acute to chronic stroke phases in focal cerebral ischemic rats: correlations with functional recovery

International Nuclear Information System (INIS)

Zhang, Shao-jie; Ke, Zheng; Tong, Kai-yu; Li, Le; Yip, Shea-ping

2013-01-01

Monitoring the neural activities from the ischemic penumbra provides critical information on neurological recovery after stroke. The purpose of this study is to evaluate the temporal alterations of neural activities using electroencephalography (EEG) from the acute phase to the chronic phase, and to compare EEG with the degree of post-stroke motor function recovery in a rat model of focal ischemic stroke. Male Sprague–Dawley rats were subjected to 90 min transient middle cerebral artery occlusion surgery followed by reperfusion for seven days (n = 58). The EEG signals were recorded at the pre-stroke phase (0 h), acute phase (3, 6 h), subacute phase (12, 24, 48, 72 h) and chronic phase (96, 120, 144, 168 h) (n = 8). This study analyzed post-stroke seizures and polymorphic delta activities (PDAs) and calculated quantitative EEG parameters such as the alpha-to-delta ratio (ADR). The ADR represented the ratio between alpha power and delta power, which indicated how fast the EEG activities were. Forelimb and hindlimb motor functions were measured by De Ryck's test and the beam walking test, respectively. In the acute phase, delta power increased fourfold with the occurrence of PDAs, and the histological staining showed that the infarct was limited to the striatum and secondary sensory cortex. In the subacute phase, the alpha power reduced to 50% of the baseline, and the infarct progressed to the forelimb cortical region. ADRs reduced from 0.23 ± 0.09 to 0.04 ± 0.01 at 3 h in the acute phase and gradually recovered to 0.22 ± 0.08 at 168 h in the chronic phase. In the comparison of correlations between the EEG parameters and the limb motor function from the acute phase to the chronic phase, ADRs were found to have the highest correlation coefficients with the beam walking test (r = 0.9524, p < 0.05) and De Ryck's test (r = 0.8077, p < 0.05). This study measured EEG activities after focal cerebral ischemia and showed that functional recovery was closely

Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty

International Nuclear Information System (INIS)

Song, J.K.; Cacayorin, E.D.; Fisher, S.; Seifert, T.D.; Alexandrov, A.V.; Malkoff, M.D.; Grotta, J.C.; Campbell, M.S.

2004-01-01

Postpartum cerebral angiopathy (PCA) is an uncommon cause of ischemic and hemorrhagic stroke in young women. It is usually clinically benign and not relapsing. We describe a patient with non-hemorrhagic PCA who had an atypical progressive neurological deficit from bilateral hemisphere watershed ischemia despite treatment with aggressive medical therapy and intracranial balloon angioplasty. (orig.)

Postpartum cerebral angiopathy: atypical features and treatment with intracranial balloon angioplasty

Energy Technology Data Exchange (ETDEWEB)

Song, J.K. [Center for Endovascular Surgery, Hyman-Newman Inst. for Neurology and Neurosurgery, New York, NY (United States); Cacayorin, E.D. [Interventional Neuroradiology, Dept. of Radiology, Univ. of Texas Medical School, Houston, TX (United States); Fisher, S.; Seifert, T.D.; Alexandrov, A.V.; Malkoff, M.D.; Grotta, J.C.; Campbell, M.S. [Div. of Stroke Neurology, Dept. of Neurology, Univ. of Texas Medical School, Houston, TX (United States)

2004-12-01

Postpartum cerebral angiopathy (PCA) is an uncommon cause of ischemic and hemorrhagic stroke in young women. It is usually clinically benign and not relapsing. We describe a patient with non-hemorrhagic PCA who had an atypical progressive neurological deficit from bilateral hemisphere watershed ischemia despite treatment with aggressive medical therapy and intracranial balloon angioplasty. (orig.)

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

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Vasilenko Т.М.

2015-09-01

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

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

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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

Diet-Induced Ketosis Protects Against Focal Cerebral Ischemia in Mouse.

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Xu, Kui; Ye, Lena; Sharma, Katyayini; Jin, Yongming; Harrison, Matthew M; Caldwell, Tylor; Berthiaume, Jessica M; Luo, Yu; LaManna, Joseph C; Puchowicz, Michelle A

2017-01-01

Over the past decade we have consistently shown that ketosis is neuroprotective against ischemic insults in rats. We reported that diet-induced ketotic rats had a significant reduction in infarct volume when subjected to middle cerebral artery occlusion (MCAO), and improved survival and recovery after cardiac arrest and resuscitation. The neuroprotective mechanisms of ketosis (via ketogenic diet; KG) include (i) ketones are alternate energy substrates that can restore energy balance when glucose metabolism is deficient and (ii) ketones modulate cell-signalling pathways that are cytoprotective. We investigated the effects of diet-induced ketosis following transient focal cerebral ischemia in mice. The correlation between levels of ketosis and hypoxic inducible factor-1alpha (HIF-1α), AKT (also known as protein kinase B or PKB) and 5' AMP-activated protein kinase (AMPK) were determined. Mice were fed with KG diet or standard lab-chow (STD) diet for 4 weeks. For the MCAO group, mice underwent 60 min of MCAO and total brain infarct volumes were evaluated 48 h after reperfusion. In a separate group of mice, brain tissue metabolites, levels of HIF-1α, phosphorylated AKT (pAKT), and AMPK were measured. After feeding a KG diet, levels of blood ketone bodies (beta-hydroxyburyrate, BHB) were increased. There was a proportional decrease in infarct volumes with increased blood BHB levels (KG vs STD; 4.2 ± 0.6 vs 7.8 ± 2.2 mm 3 , mean ± SEM). A positive correlation was also observed with HIF-1α and pAKT relative to blood BHB levels. Our results showed that chronic ketosis can be induced in mice by KG diet and was neuroprotective against focal cerebral ischemia in a concentration dependent manner. Potential mechanisms include upregulation of cytoprotective pathways such as those associated with HIF-1α, pAKT and AMPK.

Optimized Model of Cerebral Ischemia In situ for the Long-Lasting Assessment of Hippocampal Cell Death

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Oksana Rybachuk

2017-07-01

Full Text Available Among all the brain, the hippocampus is the most susceptible region to ischemic lesion, with the highest vulnerability of CA1 pyramidal neurons to ischemic damage. This damage may cause either prompt neuronal death (within hours or with a delayed appearance (over days, providing a window for applying potential therapies to reduce or prevent ischemic impairments. However, the time course when ischemic damage turns to neuronal death strictly depends on experimental modeling of cerebral ischemia and, up to now, studies were predominantly focused on a short time-window—from hours to up to a few days post-lesion. Using different schemes of oxygen-glucose deprivation (OGD, the conditions taking place upon cerebral ischemia, we optimized a model of mimicking ischemic conditions in organotypical hippocampal slices for the long-lasting assessment of CA1 neuronal death (at least 3 weeks. By combining morphology and electrophysiology, we show that prolonged (30-min duration OGD results in a massive neuronal death and overwhelmed astrogliosis within a week post-OGD whereas OGD of a shorter duration (10-min triggered programmed CA1 neuronal death with a significant delay—within 2 weeks—accompanied with drastically impaired CA1 neuron functions. Our results provide a rationale toward optimized modeling of cerebral ischemia for reliable examination of potential treatments for brain neuroprotection, neuro-regeneration, or testing neuroprotective compounds in situ.

The effects of Mucuna pruriens extract on histopathological and biochemical features in the rat model of ischemia.

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Nayak, Vanishri S; Kumar, Nitesh; D'Souza, Antony S; Nayak, Sunil S; Cheruku, Sri P; Pai, K Sreedhara Ranganath

2017-12-13

Stroke is considered to be one of the most important causes of death worldwide. Global ischemia causes widespread brain injury and infarctions in various regions of the brain. Oxidative stress can be considered an important factor in the development of tissue damage, which is caused because of arterial occlusion with subsequent reperfusion. Kapikacchu or Mucuna pruriens, commonly known as velvet bean, is well known for its aphrodisiac activities. It is also used in the treatment of snakebites, depressive neurosis, and Parkinson's disease. Although this plant has different pharmacological actions, its neuroprotective activity has received minimal attention. Thus, this study was carried out with the aim of evaluating the neuroprotective action of M. pruriens in bilateral carotid artery occlusion-induced global cerebral ischemia in Wistar rats. The carotid arteries of both sides were occluded for 30 min and reperfused to induce global cerebral ischemia. The methanolic plant extract was administered to the study animals for 10 days. The brains of the Wistar rats were isolated by decapitation and observed for histopathological and biochemical changes. Cerebral ischemia resulted in significant neurological damage in the brains of the rats that were not treated by M. pruriens. The group subjected to treatment by the M. pruriens extract showed significant protection against brain damage compared with the negative control group, which indicates the therapeutic potential of this plant in ischemia.

The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response

International Nuclear Information System (INIS)

Xian, Wenjing; Wu, Yan; Xiong, Wei; Li, Longyan; Li, Tong; Pan, Shangwen; Song, Limin; Hu, Lisha; Pei, Lei; Yao, Shanglong

2016-01-01

Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brain tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. - Highlights: • MaR1 significantly protects against ischemia reperfusion injury. • MaR1 inhibits pro-inflammatory cytokines and chemokines and reducing glial activation and neutrophil infiltration. • These effects at least partially occurred via suppression of the NF-κB p65 signalling pathway.

The pro-resolving lipid mediator Maresin 1 protects against cerebral ischemia/reperfusion injury by attenuating the pro-inflammatory response

Energy Technology Data Exchange (ETDEWEB)

Xian, Wenjing [Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Wu, Yan [Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Xiong, Wei [Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Li, Longyan [Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Li, Tong [Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Pan, Shangwen [Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Song, Limin [Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Hu, Lisha [Department of Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Pei, Lei [Department of Neurobiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); Yao, Shanglong, E-mail: ysltian@163.com [Department of Anesthesiology, Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (China); and others

2016-03-25

Inflammation plays a crucial role in acute ischemic stroke pathogenesis. Macrophage-derived Maresin 1 (MaR1) is a newly uncovered mediator with potent anti-inflammatory abilities. Here, we investigated the effect of MaR1 on acute inflammation and neuroprotection in a mouse brain ischemia reperfusion (I/R) model. Male C57 mice were subjected to 1-h middle cerebral artery occlusion (MCAO) and reperfusion. By the methods of 2,3,5-triphenyltetrazolium chloride, haematoxylin and eosin or Fluoro-Jade B staining, neurological deficits scoring, ELISA detection, immunofluorescence assay and western blot analysis, we found that intracerebroventricular injection of MaR1 significantly reduced the infarct volume and neurological defects, essentially protected the brain tissue and neurons from injury, alleviated pro-inflammatory reactions and NF-κB p65 activation and nuclear translocation. Taken together, our results suggest that MaR1 significantly protects against I/R injury probably by inhibiting pro-inflammatory reactions. - Highlights: • MaR1 significantly protects against ischemia reperfusion injury. • MaR1 inhibits pro-inflammatory cytokines and chemokines and reducing glial activation and neutrophil infiltration. • These effects at least partially occurred via suppression of the NF-κB p65 signalling pathway.

Arctigenin attenuates ischemic stroke via SIRT1-dependent inhibition of NLRP3 inflammasome.

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Zhang, Shimeng; Jiang, Liangjun; Che, Fengyuan; Lu, Yucheng; Xie, Zhongxiang; Wang, Hao

2017-11-04

Arctigenin (ARC), a phenylpropanoid dibenzylbutyrolactone lignan derived from Arctium lappa L, has been reported to protect against cerebral ischemia injury in rats, but the underlying mechanism is unclear. In this study, we investigated whether ARC ameliorated ischemic stroke by inhibiting NLRP3 inflammasome-derived neuroinflammation and whether SIRT1 signaling was involved in this process. ARC (20 mg/kg) or vehicle were intraperitoneally injected to Sprague-Dawley rats for 3 days before middle cerebral artery occlusion (MCAO) surgery performed. The infarct volume, neurological score, brain water content, neuroinflammation, NLRP3 inflammasome activation and SIRT1 protein expression were assessed. Furthermore, we also investigated whether ARC protected against cerebral ischemia via SIRT1-dependent inhibition of NLRP3 inflammasome by administrating EX527, a specific SIRT1 inhibitor, under oxygen-glucose deprivation (OGD) condition. We found that ARC pretreatment decreased infarct volume, neurological score and brain water content. Moreover, ARC treatment effectively inhibited cerebral ischemia induced NLRP3 inflammasome activation and IL-1β, IL-18 secretion both in vivo and in vitro. Futhermore, ARC treatment activated Silent information regulator 1 (SIRT1) singnaling in the brain. Importantly, suppress of SIRT1 reversed the inhibitory effect of ARC on NLRP3 inflammasome activation. Taken together our results demonstrated that ARC may confer protection against ischemic stroke by inhibiting NLRP3 inflammasome activation. The activation of SIRT1 signaling pathway may contribute to the neuroprotection of ARC in MCAO. Copyright © 2017 Elsevier Inc. All rights reserved.

Effects of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats

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Mingsan Miao

2017-05-01

Full Text Available The effect of the Rabdosia rubescens total flavonoids on focal cerebral ischemia reperfusion model in rats was observed. The model group, nimodipine group, cerebral collateral group, and large, medium and small dose group of the Rabdosia rubescens total flavonoids were administered with corresponding drugs but sham operation group and model group were administered the same volume of 0.5%CMC, 1 times a day, continuous administration of 7 d. After 1 h at 7 d to medicine, left incision in the middle of the neck of rats after anesthesia, we can firstly expose and isolate the left common carotid artery (CCA, and then expose external carotid artery (ECA and internal carotid artery (ICA. The common carotid artery and the external carotid artery are ligated. Then internal carotid artery with arterial clamp is temporarily clipped. Besides, cut the incision of 0.2 mm from 5 cm of the bifurcation of the common carotid artery. A thread Line bolt is inserted with more than 18–20 mm from bifurcation of CCA into the internal carotid artery until there is resistance. Then the entrance of the middle cerebral artery is blocked and internal carotid artery is ligated (the blank group only exposed the left blood vessel without Plugging wire. Finally it is gently pulled out the plug line after 2 h. Results: Compared with the model mice, Rabdosia rubescens total flavonoids can significantly relieve the injury of brain in hippocampus and cortex nerve cells; experimental rat focal cerebral ischemia was to improve again perfusion model of nerve function defect score mortality; significantly reduce brain homogenate NOS activity and no content, MDA, IL-1, TNF-a, ICAM-1 content; increase in brain homogenate SOD and ATPase activity (P < 0.05, P < 0.01; and reduce the serum S-100β protein content. Each dose group of the Rabdosia rubescens total flavonoids has a better Improvement effect on focal cerebral ischemia reperfusion model in rats.

Dynamics of cognitive disturbances in rats with acute cerebral ischemia on the background of introduction of 0.9 % solution NaCl

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Андрій Ігорович Семененко

2015-06-01

Full Text Available For today there are no clear recommendations on infusion therapy at the disease and injuries of brain, and infusion preparations are commonly used empirically. Within the framework of the complex study of an influence of the different infusion remedies on brain at an experimental ischemia of brain, an aim of this work is to investigate how the 0,9 % solution of NaCl influences on the dynamics of cognitive functions and neurological status of the rats with an acute cerebral ischemia at the course medical introduction into an animal organism.Methods. Experiments were carried out on 60 white rats-males. An acute disturbance of cerebral blood circulation (ADCBC was modeled by means of the two-sided dressing of internal carotid arteries. The 0,9 % solution of NаСІ was injected intravenously in catheterized thigh vein 2,5 ml/kg 2 times/day (5 ml/kg for a day. The first introduction was carried out in 30 minutes after ADCBC and then every day in 12 hours during 7 days. The control groups consist of intact rats that received 0,9 % NаСІ and animals with a model ischemia without treatment.Neurological deficiency in animals was defined on the scale stroke-index McGrow C. P. The dynamics of position-finding activity was assessed in experiment “an open field”. An assessment of animal capacity to training and memorization of an aversive stimulus was studied in the test of conditioned response of passive avoidance. The results were processed using the program StatPlus 2009.Results. The study showed that bilateral carotid occlusion in rats without treatment is followed not only by the high animal lethality but also by the development of a hard neurological symptomatology and then by essential disturbance of mnestic functions in animals that survived during the recovery period of model insult (р<0,01.The study of lethality dynamics, neurological status, behavioral responses in rats with ADCBC on the model of bilateral carotid occlusion showed that the

Cerebral collateral therapeutics in acute ischemic stroke: A randomized preclinical trial of four modulation strategies.

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Beretta, Simone; Versace, Alessandro; Carone, Davide; Riva, Matteo; Dell'Era, Valentina; Cuccione, Elisa; Cai, Ruiyao; Monza, Laura; Pirovano, Silvia; Padovano, Giada; Stiro, Fabio; Presotto, Luca; Paternò, Giovanni; Rossi, Emanuela; Giussani, Carlo; Sganzerla, Erik P; Ferrarese, Carlo

2017-10-01

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm 3 absolute mean difference; p Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

The role of angiogenesis in damage and recovery from ischemic stroke.

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Arenillas, Juan F; Sobrino, Tomás; Castillo, José; Dávalos, Antoni

2007-06-01

Ischemic stroke is burdened with a high morbidity and mortality in our society. However, there are few effective and largely available therapies for this devastating disease. In additon to advancing acute reperfusion therapies, there is a need to develop treatments aimed to promote repair and regeneration of brain tissue damaged by ischemia (neurorecovery). Therapeutic angiogenesis and vasculogenesis represent novel approaches of regenerative medicine that may help in the cure of patients with acute ischemic stroke. Translation of our knowledge about these processes from the bench to bedside is still underway. Although angiogenesis (the sprouting of new blood vessels from pre-existing vascular structures) is likely to contribute to neurorepair, the finality of the angiogenic response in acute ischemic stroke has not been fully elucidated. The first therapeutic approach to angiogenesis after ischemic stroke would be the modulation of the endogenous angiogenic response. In this setting, early instauration of physical activity, statins, and peroxisome proliferator-activated receptor-gamma agonists may enhance angiogenesis and neuroregeneration. Gene therapy with vascular growth factors has been successfully tested in patients affected by chronic myocardial and peripheral ischemia. Regarding brain ischemia, experiments in animal models have shown that the effect of these growth factors is critically affected by the dosage, route of delivery, and time of administration in relation to stroke onset. In addition, the optimal angiogenic substance is unknown. Finally, vectors for gene transfer should be further optimized. Therapeutic vasculogenesis consists of the administration of exogenous endothelial progenitor cells in order to enhance brain repair processes. Endothelial progenitor cells may be recruited in response to cerebral ischemia and participate in reparative vasculogenesis after acute ischemic stroke. Further research is needed to clarify their role and

Stimulation of the sphenopalatine ganglion induces reperfusion and blood-brain barrier protection in the photothrombotic stroke model.

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Haviv Levi

Full Text Available The treatment of stroke remains a challenge. Animal studies showing that electrical stimulation of the sphenopalatine ganglion (SPG exerts beneficial effects in the treatment of stroke have led to the initiation of clinical studies. However, the detailed effects of SPG stimulation on the injured brain are not known.The effect of acute SPG stimulation was studied by direct vascular imaging, fluorescent angiography and laser Doppler flowmetry in the sensory motor cortex of the anaesthetized rat. Focal cerebral ischemia was induced by the rose bengal (RB photothrombosis method. In chronic experiments, SPG stimulation, starting 15 min or 24 h after photothrombosis, was given for 3 h per day on four consecutive days. Structural damage was assessed using histological and immunohistochemical methods. Cortical functions were assessed by quantitative analysis of epidural electro-corticographic (ECoG activity continuously recorded in behaving animals.Stimulation induced intensity- and duration-dependent vasodilation and increased cerebral blood flow in both healthy and photothrombotic brains. In SPG-stimulated rats both blood brain-barrier (BBB opening, pathological brain activity and lesion volume were attenuated compared to untreated stroke animals, with no apparent difference in the glial response surrounding the necrotic lesion.SPG-stimulation in rats induces vasodilation of cortical arterioles, partial reperfusion of the ischemic lesion, and normalization of brain functions with reduced BBB dysfunction and stroke volume. These findings support the potential therapeutic effect of SPG stimulation in focal cerebral ischemia even when applied 24 h after stroke onset and thus may extend the therapeutic window of currently administered stroke medications.

Cryptotanshinone exhibits therapeutical effects on cerebral stroke through the PI3K/AKT‑eNOS signaling pathway.

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Zhu, Weixin; Qiu, Weihong; Lu, Ailan

2017-12-01

Cerebral stroke is a kind of acute cerebrovascular disease with high incidence, morbidity and disability. Treatments against various types of cerebral stroke are limited at preventive measurements due to the lack of effective therapeutic method. The present study aimed to investigate the protective effect of cryptotanshinone (CPT) on cerebral stroke, and investigate the possible mechanism involved in order to develop a novel therapy against stoke. The phosphoinositide 3‑kinase membrane translocation of cerebral stroke rats pretreated with CPT at various concentrations were measured, as well as the phosphorylation of protein kinase B (AKT) and endothelial nitric oxide synthase (eNOS). Additionally, the expression level of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax) and vascular endothelial growth factor were also assessed using western blotting and reverse transcription‑quantitative polymerase chain reaction. Furthermore, biochemical tests were used to measure the activity of superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) in both the cerebral cortex and peripheral blood. As a result, CPT‑pretreated rats presented declined phosphoinositide 3‑kinase (PI3K) and AKT expression levels, indicating that the PI3K/AKT signaling pathway was inhibited. Increased Bcl‑2 and NO levels in both the cerebral cortex and peripheral blood demonstrated the anti‑apoptosis and blood vessel protection effect of CPT. Furthermore, increased SOD activity and declined MDA levels demonstrated suppressed lipid peroxidation. In conclusion, CPT exhibited a protective effect against cerebral stroke through inhibition of the PI3K/AKT‑eNOS signaling pathway. These results suggested the potential of CPT as a promising agent in the treatment of cerebral stroke.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

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Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Cerebral blood flow velocity changes during upright positioning in bed after acute stroke : An observational study

NARCIS (Netherlands)

Aries, Marcel J; Elting, Jan Willem; Stewart, Roy; De Keyser, Jacques; Kremer, Berry; Vroomen, Patrick

2013-01-01

Objectives: National guidelines recommend mobilisation in bed as early as possible after acute stroke. Little is known about the influence of upright positioning on real-time cerebral flow variables in patients with stroke. We aimed to assess whether cerebral blood flow velocity (CBFV) changes

Very Low Cerebral Blood Volume Predicts Parenchymal Hematoma in Acute Ischemic Stroke

DEFF Research Database (Denmark)

Hermitte, Laure; Cho, Tae-Hee; Ozenne, Brice

2013-01-01

BACKGROUND AND PURPOSE: Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective was to exp......BACKGROUND AND PURPOSE: Parenchymal hematoma (PH) may worsen the outcome of patients with stroke. The aim of our study was to confirm the relationship between the volume of very low cerebral blood volume (CBV) and PH using a European multicenter database (I-KNOW). A secondary objective...

Britanin Ameliorates Cerebral Ischemia-Reperfusion Injury by Inducing the Nrf2 Protective Pathway.

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Wu, Guozhen; Zhu, Lili; Yuan, Xing; Chen, Hao; Xiong, Rui; Zhang, Shoude; Cheng, Hao; Shen, Yunheng; An, Huazhang; Li, Tiejun; Li, Honglin; Zhang, Weidong

2017-10-10

Oxidative stress is considered the major cause of tissue injury after cerebral ischemia. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is one of the most important defensive mechanisms against oxidative stresses and has been confirmed as a target for stroke treatment. Thus, we desired to find new Nrf2 activators and test their neuronal protective activity both in vivo and in vitro. The herb-derived compound, Britanin, is a potent inducer of the Nrf2 system. Britanin can induce the expression of protective enzymes and reverse oxygen-glucose deprivation, followed by reperfusion (OGD-R)-induced neuronal injury in primary cortical neurons in vitro. Furthermore, the administration of Britanin significantly ameliorated middle cerebral artery occlusion-reperfusion (MCAO-R) insult in vivo. We report here the crystal structure of the complex of Britanin and the BTB domain of Keap1. Britanin selectively binds to a conserved cysteine residue, cysteine 151, of Keap1 and inhibits Keap1-mediated ubiquitination of Nrf2, leading to induction of the Nrf2 pathway. Britanin is a potent inducer of Nrf2. The complex crystal structure of Britanin and the BTB domain of Keap1 help clarify the mechanism of Nrf2 induction. Britanin was proven to protect primary cortical neurons against OGD-R-induced injury in an Nrf2-dependant way. Additionally, Britanin had excellent cerebroprotective effect in an MCAO-R model. Our results demonstrate that the natural product Britanin with potent Nrf2-activating and neural protective activities both in vitro and in vivo could be developed into a cerebroprotective therapeutic agent. Antioxid. Redox Signal. 27, 754-768.

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

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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 Taurine protected the brain from damage caused by MCAO; this effect may be through down-regulation of 12/15-LOX, p38 MAPK, and cPLA2.

Protective Mechanism of STAT3-siRNA on Cerebral Ischemia Injury

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He, Jinting; Yang, Le; Liang, Wenzhao

2018-01-01

Nerve cells in ischemic brain injury will occur a series of complex signal transduction pathway changes and produce the corresponding biological function, thus affecting the central nervous system functionally different cells in the ischemic brain injury metabolism, division, Differentiation and death process, while changes in signal pathways also play an important role in the repair process of the post-ischemic nervous system. JAK/STAT pathway and vascular lesions have some relevance, but its exact mechanism after cerebral ischemia is not yet fully understood. This study is intended to further explore the JAK / STAT pathway in the functional site of STAT3 in neuronal ischemia Hypoxic injury and related molecular mechanisms, targeting these targets design intervention strategies to block the signal pathway, in order to provide a theoretical basis for the treatment of ischemic brain damage in this pathway.

Chronic photoperiod disruption does not increase vulnerability to focal cerebral ischemia in young normotensive rats.

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Ku Mohd Noor, Ku Mastura; Wyse, Cathy; Roy, Lisa A; Biello, Stephany M; McCabe, Christopher; Dewar, Deborah

2017-11-01

Photoperiod disruption, which occurs during shift work, is associated with changes in metabolism or physiology (e.g. hypertension and hyperglycaemia) that have the potential to adversely affect stroke outcome. We sought to investigate if photoperiod disruption affects vulnerability to stroke by determining the impact of photoperiod disruption on infarct size following permanent middle cerebral artery occlusion. Adult male Wistar rats (210-290 g) were housed singly under two different light/dark cycle conditions ( n = 12 each). Controls were maintained on a standard 12:12 light/dark cycle for nine weeks. For rats exposed to photoperiod disruption, every three days for nine weeks, the lights were switched on 6 h earlier than in the previous photoperiod. T 2 -weighted magnetic resonance imaging was performed at 48 h after middle cerebral artery occlusion. Disruption of photoperiod in young healthy rats for nine weeks did not alter key physiological variables that can impact on ischaemic damage, e.g. blood pressure and blood glucose immediately prior to middle cerebral artery occlusion. There was no effect of photoperiod disruption on infarct size after middle cerebral artery occlusion. We conclude that any potentially adverse effect of photoperiod disruption on stroke outcome may require additional factors such as high fat/high sugar diet or pre-existing co-morbidities.

Niosomes of Ascorbic Acid and α-Tocopherol in the Cerebral Ischemia-Reperfusion Model in Male Rats

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Jaleh Varshosaz

2014-01-01

Full Text Available The objective of the present study was to prepare a stable iv injectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluated in vitro. For in vivo evaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4–8°C. In vivo studies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

Neuroprotective Effect of Curcumin Against Cerebral Ischemia-Reperfusion Via Mediating Autophagy and Inflammation.

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Huang, Lifa; Chen, Chengwei; Zhang, Xin; Li, Xu; Chen, Zupeng; Yang, Chao; Liang, Xiaolong; Zhu, Guochong; Xu, Zhen

2018-01-01

Curcumin, a polyphenolic compound extracted from Curcuma longa, has drawn attention for its effective bioactivities against ischemia-induced injury. This study aimed to evaluate the neuroprotective effect of curcumin and investigate the underlying mechanism that mediates autophagy and inflammation in an animal model of middle cerebral artery occlusion (MCAO) in rats. Curcumin was delivered to Sprague Dawley male rats at a dose of 200 mg/kg curcumin by intraperitoneal injection 30 min after ischemia-reperfusion (I/R). LY294002, a specific inhibitor of the PI3K/Akt/mTOR pathway, as well as anisomycin, an activator of TLR4/p38/MAPK, was administered by ventricle injection 30 min before MCAO. The same volume of saline was given as a control. Brain infarction and neurological function were determined 24 h post-MCAO. Immunoblotting and immunofluorescence were used to detect alterations in autophagy-relevant proteins Akt, p-Akt, mTOR, p-mTOR, LC3-II, and LC3-I, and inflammation-related proteins TLR4, p-38, p-p38, and IL-1 in the ipsilateral hemisphere. Cerebral I/R injury resulted in significant alterations of LC3-II/LC3-I, IL-1, TLR4, and p-p38. Curcumin in MCAO rats significantly improved brain damage and neurological function by upregulating p-Akt and p-mTOR and downregulating LC3-II/LC3-I, IL-1, TLR4, p-38, and p-p38. However, these protective effects against ischemia could be suppressed when LY294002 or anisomycin was included. Curcumin exerts neuroprotective effects by attenuating autophagic activities through mediating the PI3K/Akt/mTOR pathway, while also suppressing an inflammatory reaction by regulating the TLR4/p38/MAPK pathway. Furthermore, this study indicates that curcumin could be an effective therapy for patients afflicted with ischemia.

Reexpression of Prior Stroke Symptoms in Adults: When is a Mimic a Mimic?

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Siegler, James E; George, Alexander J; Martin-Schild, Sheryl

2017-09-01

A "stroke mimic" refers to any clinical condition that causes neurological symptoms clinically indistinguishable from a cerebral lesion that affects a vascular distribution, but is not caused by ischemia. One subtype of stroke mimic, termed stroke reexpression, is a form of mimicry in which previously recovered or improved stroke symptoms recur in the setting of a neurological disturbance (seizure, hypoperfusion state) or a systemic disturbance (toxic, metabolic, infectious). Many reports of stroke reexpression exist in the literature and are well known to clinicians, but there has been no consensus regarding terminology that has been published to date. The purpose of this review is to summarize several examples of stroke reexpression and propose simple, useful criteria for this clinical condition.

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

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Bo Young Choi

2014-10-01

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

A prototypical Sigma-1 receptor antagonist protects against brain ischemia

OpenAIRE

Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

2007-01-01

Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

Hemispheric distribution of middle cerebral artery ischemic strokes in patients admitted to military hospital rawalpindi

International Nuclear Information System (INIS)

Tariq, M.; Ishtiaq, S.; Zulfiqar, S.O.

2016-01-01

Objective: To determine the difference in the frequency of middle cerebral artery (MCA) ischemic strokes between left and right cerebral hemispheres in the adult patients admitted to the Military Hospital (MH) Rawalpindi. Study Design: A descriptive study. Place and Duration of Study: MH Rawalpindi from 01 Dec 2013 to 30 Mar 2014. Patients and Methods: Seventy eight adult patients admitted to MH Rawalpindi with neurologic deficits consistent with MCA strokes and having no evidence of intracerebral haemorrhage on Computed Tomographic (CT) scan of brain. Descriptive Statistics were calculated using SPSS version 17. Results: A total of 78 patients met the inclusion criteria of the study; 35 (45 percent) patients had right MCA stroke while 43 (55 percent) had left MCA stroke. Conclusion: Left MCA ischemic strokes are more common than right MCA ischemic strokes. (author)

The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice

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Gelderblom, Mathias; Leypoldt, Frank; Lewerenz, Jan; Birkenmayer, Gabriel; Orozco, Denise; Ludewig, Peter; Thundyil, John; Arumugam, Thiruma V; Gerloff, Christian; Tolosa, Eva; Maher, Pamela; Magnus, Tim

2012-01-01

The development of the brain tissue damage in ischemic stroke is composed of an immediate component followed by an inflammatory response with secondary tissue damage after reperfusion. Fisetin, a flavonoid, has multiple biological effects, including neuroprotective and antiinflammatory properties. We analyzed the effects of fisetin on infarct size and the inflammatory response in a mouse model of stroke, temporary middle cerebral artery occlusion, and on the activation of immune cells, murine primary and N9 microglial and Raw264.7 macrophage cells and human macrophages, in an in vitro model of inflammatory immune cell activation by lipopolysaccharide (LPS). Fisetin not only protected brain tissue against ischemic reperfusion injury when given before ischemia but also when applied 3 hours after ischemia. Fisetin also prominently inhibited the infiltration of macrophages and dendritic cells into the ischemic hemisphere and suppressed the intracerebral immune cell activation as measured by intracellular tumor necrosis factor α (TNFα) production. Fisetin also inhibited LPS-induced TNFα production and neurotoxicity of macrophages and microglia in vitro by suppressing nuclear factor κB activation and JNK/Jun phosphorylation. Our findings strongly suggest that the fisetin-mediated inhibition of the inflammatory response after stroke is part of the mechanism through which fisetin is neuroprotective in cerebral ischemia. PMID:22234339

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

OpenAIRE

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

2013-01-01

In this study, we hypothesized that total flavonoid of Litsea coreana leve (TFLC) protects against focal cerebral ischemia/reperfusion injury. TFLC (25, 50, 100 mg/kg) was administered orally to a rat model of focal ischemia/reperfusion injury, while the free radical scavenging agent, edaravone, was used as a positive control drug. Results of neurological deficit scoring, 2,3,5-triphenyl tetrazolium chloride staining, hematoxylin-eosin staining and biochemical tests showed that TFLC at differ...

Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats.

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Aparajita Ghosh

Full Text Available Cerebral stroke is the leading cause of death and permanent disability among elderly people. In both humans and animals, cerebral ischemia damages the nerve cells in vulnerable regions of the brain, viz., hippocampus, cerebral cortex, cerebellum, and hypothalamus. The present study was conducted to evaluate the therapeutic efficacy of nanoencapsulated quercetin (QC in combating ischemia-reperfusion-induced neuronal damage in young and aged Swiss Albino rats. Cerebral ischemia was induced by occlusion of the common carotid arteries of both young and aged rats followed by reperfusion. Nanoencapsulated quercetin (2.7 mg/kg b wt was administered to both groups of animals via oral gavage two hours prior to ischemic insults as well as post-operation till day 3. Cerebral ischemia and 30 min consecutive reperfusion caused a substantial increase in lipid peroxidation, decreased antioxidant enzyme activities and tissue osmolality in different brain regions of both groups of animals. It also decreased mitochondrial membrane microviscosity and increased reactive oxygen species (ROS generation in different brain regions of young and aged rats. Among the brain regions studied, the hippocampus appeared to be the worst affected region showing increased upregulation of iNOS and caspase-3 activity with decreased neuronal count in the CA1 and CA3 subfields of both young and aged rats. Furthermore, three days of continuous reperfusion after ischemia caused massive damage to neuronal cells. However, it was observed that oral treatment of nanoencapsulated quercetin (2.7 mg/kg b wt resulted in downregulation of iNOS and caspase-3 activities and improved neuronal count in the hippocampal subfields even 3 days after reperfusion. Moreover, the nanoformulation imparted a significant level of protection in the antioxidant status in different brain regions, thus contributing to a better understanding of the given pathophysiological processes causing ischemic neuronal damage.

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

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Haelewyn Benoit

2011-04-01

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

5-HMF attenuates striatum oxidative damage via Nrf2/ARE signaling pathway following transient global cerebral ischemia.

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Ya, Bai-Liu; Li, Hong-Fang; Wang, Hai-Ying; Wu, Fei; Xin, Qing; Cheng, Hong-Ju; Li, Wen-Juan; Lin, Na; Ba, Zai-Hua; Zhang, Ru-Juan; Liu, Qian; Li, Ya-Nan; Bai, Bo; Ge, Feng

2017-01-01

Recent studies have shown 5-hydroxymethyl-2-furfural (5-HMF) has favorable biological effects, and its neuroprotection in a variety of neurological diseases has been noted. Our previous study showed that treatment of 5-HMF led to protection against permanent global cerebral ischemia. However, the underlying mechanisms in cerebral ischemic injury are not fully understood. This study was conducted to investigate the neuroprotective effect of 5-HMF and elucidate the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway mechanism in the striatum after transient global cerebral ischemia. C57BL/6 mice were subjected to bilateral common carotid artery occlusion for 20 min and sacrificed 24 h after reperfusion. 5-HMF (12 mg/kg) or an equal volume of vehicle was intraperitoneally injected 30 min before ischemia and 5 min after the onset of reperfusion. At 24 h after reperfusion, neurological function was evaluated by neurological disability status scale, locomotor activity test and inclined beam walking test. Histological injury of the striatum was observed by cresyl violet staining and terminal deoxynucleotidyl transferase (TdT)-mediated dNTP nick end labeling (TUNEL) staining. Oxidative stress was evaluated by the carbonyl groups introduced into proteins, and malondialdehyde (MDA) levels. An enzyme-linked immunosorbent assay (ELISA)-based measurement was used to detect Nrf2 DNA binding activity. Nrf2 and its downstream ARE pathway protein expression such as heme oxygenase-1, NAD (P)H:quinone oxidoreductase 1, glutamate-cysteine ligase catalytic subunit and glutamate-cysteine ligase modulatory subunit were detected by western blot. Our results showed that 5-HMF treatment significantly ameliorated neurological deficits, reduced brain water content, attenuated striatum neuronal damage, decreased the carbonyl groups and MDA levels, and activated Nrf2/ARE signaling pathway. Taken together, these results demonstrated that

Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

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Michelle J Porritt

Full Text Available Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2 and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p. after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

Photothrombosis-induced infarction of the mouse cerebral cortex is not affected by the Nrf2-activator sulforaphane.

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Porritt, Michelle J; Andersson, Helene C; Hou, Linda; Nilsson, Åsa; Pekna, Marcela; Pekny, Milos; Nilsson, Michael

2012-01-01

Sulforaphane-induced activation of the transcription factor NF-E2 related factor 2 (Nrf2 or the gene Nfe2l2) and subsequent induction of the phase II antioxidant system has previously been shown to exert neuroprotective action in a transient model of focal cerebral ischemia. However, its ability to attenuate functional and cellular deficits after permanent focal cerebral ischemia is not clear. We assessed the neuroprotective effects of sulforaphane in the photothrombotic model of permanent focal cerebral ischemia. Sulforaphane was administered (5 or 50 mg/kg, i.p.) after ischemic onset either as a single dose or as daily doses for 3 days. Sulforaphane increased transcription of Nrf2, Hmox1, GCLC and GSTA4 mRNA in the brain confirming activation of the Nrf2 system. Single or repeated administration of sulforaphane had no effect on the infarct volume, nor did it reduce the number of activated glial cells or proliferating cells when analyzed 24 and 72 h after stroke. Motor-function as assessed by beam-walking, cylinder-test, and adhesive test, did not improve after sulforaphane treatment. The results show that sulforaphane treatment initiated after photothrombosis-induced permanent cerebral ischemia does not interfere with key cellular mechanisms underlying tissue damage.

New developments in secondary stroke prevention: impact of the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) on clinical management.

Science.gov (United States)

Lutsep, Helmi L

2007-01-01

Secondary stroke prevention is an important goal of poststroke patient treatment. Various pharmacologic approaches have been advocated, but the relative efficacy and safety of these regimens has remained the subject of much debate. Recently released data from the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) indicated that combination therapy with aspirin and extended-release dipyridamole was more effective than aspirin monotherapy, and probably more effective than anticoagulants, for the prevention of cerebrovascular events after a stroke or transient ischemic attack. When viewed in light of results of earlier trials, these findings confirmed that combination aspirin plus extended-release dipyridamole therapy improved outcomes in these patients and is a recommended option for poststroke patient treatment.

Study of cerebral vascular diseases with radioisotopes in cerebral atherosclerotical subjects and/for subjects with sequelae of cerebral stroke, before and after use of the association piracetam-dihydroergotoxine

International Nuclear Information System (INIS)

Lara, P.F.; Ferreira, A.; Paulillo, L.F.; Cukierman, M.

1985-01-01

Twently subjects with cerebral sclerosis and/or sequelas of cerebral stroke were studied, before and after use of piracetam-dihydroergotoxine. We performed the complete hemispheric cerebral blood flow and cerebral scintigraphy, beyond clinical and neurological examination. Scintigraphies were unchanged. Cerebral circulation times, or both hemispheres, diminished. This occurred, probably, in relation with metabolic effects of both pharmaceutical drugs. The alpha sympatolytic and modulatory effects of dihydroergotoxine should be considered. (author) [pt

Hypoxic ischemia encephalopathy leading to external hydrocephalus and the cerebral atrophy: mechanism and differential diagnosis

International Nuclear Information System (INIS)

Huang Zhenglin; Mo Xiaorong

2002-01-01

Objective: It is a study of the mechanism and differential diagnosis of the infant external hydrocephalus and cerebral atrophy. Methods: In total 84 cases of neonatal hypoxic ischemia encephalopathy followed by infant external hydrocephalus were investigated, among which 26 patients gradually were found having developed cerebral atrophy in follow up. Results: Characteristic dilation of the frontal-parietal subarachnoid space and the adjacent cistern was noted on the CT images of the external hydrocephalus. CT revealed the enlarged ventricle besides the dilated subarachnoid space in the cases of cerebral atrophy, while these two entities were indistinguishable on CT in the early stage. Conclusion: Clinical manifestations make a major differential diagnosis of the external hydrocephalus and cerebral atrophy: tic and mild delayed development of locomotion over major presentation of external hydrocephalus, while cerebral atrophy is featured by remarkable dysnoesia and severe delayed development of locomotion. In addition, hemiplegia and increased muscular tension are presented in a few cases of cerebral atrophy

Effect of different component ratio of Astragalus total saponins and Verbena total glycosides on the cerebral infarction area and serum biochemical indicators in the focal cerebral ischemia-reperfusion rat model

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Erping Xu

2017-05-01

Full Text Available Our purpose is to study the effect of different component ratio of Astragalus Total Saponins (ATS and Verbena Total Glycosides (VTG on the cerebral infarction area and the serum biochemical indicators in the focal cerebral ischemia-reperfusion rat model. Compared with the model group, different component ratio of ATS and VTG could significantly improve the neurological deficit scores to the focal cerebral ischemia-reperfusion rat model, and the group of 7:3, 6:4, 5:5 got the best results; it could reduce the mortality of rat model to a certain extent, and the group of 5:5 group got the best results; it can significantly reduce the cerebral infarction area, and the group of 7:3, 5:5, 4:6 got the best results; it could significantly reduce the content of TNF-α, and the group of 8:2, 6:4 got the best results; it could significantly reduce the content of NO, and the group of 7:3, 5:5 got the best results; it could significantly increase the content of SOD, and the group of 6:4, 5:5 got the best results. This indicates that different component ratio of ATS and VTG may protect the damage of focal cerebral ischemia-reperfusion rat model to a certain extent, which are compared using the comprehensive weight method and the ratio of 5:5 was proved to be the optimal active ratio.

Reduced infarct size in neuroglobin-null mice after experimental stroke in vivo

DEFF Research Database (Denmark)

Raida, Zindy; Hundahl, Christian Ansgar; Kelsen, Jesper

2012-01-01

Neuroglobin is considered to be a novel important pharmacological target in combating stroke and neurodegenerative disorders, although the mechanism by which this protection is accomplished remains an enigma. We hypothesized that if neuroglobin is directly involved in neuroprotection, then perman......, then permanent cerebral ischemia would lead to larger infarct volumes in neuroglobin-null mice than in wild-type mice....

Rodent stroke induced by photochemical occlusion of proximal middle cerebral artery: Evolution monitored with MR imaging and histopathology

International Nuclear Information System (INIS)

Chen Feng; Suzuki, Yasuhiro; Nagai, Nobuo; Jin, Lixin; Yu Jie; Wang Huaijun; Marchal, Guy; Ni Yicheng

2007-01-01

Purpose: To longitudinally investigate stroke in rats after photothrombotic occlusion of proximal middle cerebral artery (MCA) with magnetic resonance imaging (MRI) in correlation with histopathology. Materials and methods: Forty-two rats were subjected to photochemical MCA occlusion and MRI at 1.5 T, and sacrificed in seven groups (n = 6 each) at the following time points: 1, 3, 6 and 12 h, and at day 1, 3 and 9. T2-weighted (T2WI) and diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) map was performed in all rats. Contrast-enhanced T1-weighted imaging (CE-T1WI) was compared to intravital staining with Evans blue in one group for assessing blood-brain barrier (BBB) integrity. The brain was stained histochemically with triphenyl tetrazolium chloride (TTC) and processed for pathological assessment. The evolutional changes of relative lesion volume, signal intensity (SI), and the BBB integrity on MRI with corresponding histopathology were evaluated. Results: The ischemic lesion volume reached a maximum around 12 h to day 1 as visualized successively by DWI, ADC map and T2WI, implicating the evolving pathology from cytotoxic edema through vasogenic edema to tissue death. The ADC of brain infarction underwent a significant reversion after 12 h, reflecting the colliquative necrosis. On CE-T1WI, BBB leakage peaked at 6 h and at day 3 with a transitional partial recovery around 24 h. The infarct volume on T2WI, DWI and ADC map matched well with that on TTC staining at 12 h and at day 1 (p > 0.05). Conclusion: The evolution of the present photothrombotic stroke model in rats could be characterized by MRI. The obtained information may help longitudinal studies of cerebral ischemia and anti-stroke agents using the same model

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

Science.gov (United States)

Wang, Yanzhe; He, Zhiyi; Deng, Shumin

2016-01-01

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. 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. 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 (Pprotective 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. UA can act as a PPARγ agonist to improve the metalloprotease/anti-metalloprotease balance, possibly by inhibiting the activation of the MAPK signaling pathway, thereby attenuating cerebral ischemia and reperfusion injury. Therefore, UA may serve as a novel neuroprotective therapeutic agent.

Prognosis of cerebral ischemia, significance of CSF-lactate-level and computerized tomography

International Nuclear Information System (INIS)

Busse, O.

1982-01-01

In patients (n = 120) with supratentorial ischemic cerebral infarction CSF lactate was determined and a CT was carried out on the 1st, 3rd and 7th day after the stroke. On the 3rd and 7th day the comparative investigation revealed a close correlation between the measure of the ischemic edema and the level of CSF-lactate. Thus the lactate-concentration can be regarded as a measure for the spread of the edema after cerebral infarction. Already on the 3rd day CT- and CSF-lactate results allow a relatively reliable prediction for the course of the stroke. An edema grade III in CT and a CSF-lactate concentration more than 4 mmol/l were prognostically critical. On the other hand good chances of survival were indicated by a CSF lactate level under 2.5 mmol/l and an edema grade I. (orig.) [de

Compensatory cerebral motor control following presumed perinatal ischemic stroke

NARCIS (Netherlands)

van der Hoorn, Anouk; Potgieser, Adriaan R E; Brouwer, Oebele F; de Jong, Bauke M

Case: A fifteen year-old left-handed girl presented with right-sided focal motor seizures. Neuroimaging showed a large left hemisphere lesion compatible with a middle cerebral artery stroke of presumed perinatal origin. She was not previously diagnosed with a motor deficit, although neurological

Niosomes of Ascorbic Acid and α-Tocopherol in the Cerebral Ischemia-Reperfusion Model in Male Rats

OpenAIRE

Varshosaz, Jaleh; Taymouri, Somayeh; Pardakhty, Abbas; Asadi-Shekaari, Majid; Babaee, Abodolreza

2014-01-01

The objective of the present study was to prepare a stable iv injectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluated in vitro. For in vivo evaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neur...

Supratentorial dynamic computed tomography for the diagnosis of vertebrobasilar ischemic stroke

International Nuclear Information System (INIS)

Nagahori, Takeshi; Umemura, Kimiko; Hirashima, Yutaka; Kuwayama, Naoya; Kubo, Michiya; Endo, Shunro

2004-01-01

Dynamic computed tomography (CT) is an established method for the evaluation of perfusion in acute ischemic stroke, but is not frequently used to assess infratentorial ischemia. Eleven patients with vertebrobasilar ischemia underwent dynamic CT on admission and/or during the follow-up period. The time of appearance (TA) and time to peak (TTP) were mapped and differences in TA (ΔTA) and TTP (ΔTTP) between the bilateral middle cerebral artery and posterior cerebral artery (PCA) territories were calculated. Conventional angiography and brain imaging including CT and magnetic resonance imaging were also performed. The TA and TTP maps obtained within 48 hours after onset exhibited time delay in eight of nine patients in the bilateral PCA territories. ΔTA and ΔTTP were greater in patients with stenosis or occlusion of the bilateral vertebral arteries or the basilar artery, and in patients without collateral circulation via the posterior communicating arteries than in control subjects. Furthermore, TA and TTP normalized dramatically in patients with recanalization of the arteries. ΔTA and ΔTTP were also normalized. ΔTA and ΔTTP were negatively correlated with the time from onset to examination. Dynamic CT can provide important information in patients with vertebrobasilar ischemic stroke, and may allow the diagnosis of acute ischemia and monitoring of the course. (author)

Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

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Ruo-Bing Guo

Full Text Available Paeoniflorin (PF, the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2 and 5-LOX in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

Paeoniflorin protects against ischemia-induced brain damages in rats via inhibiting MAPKs/NF-κB-mediated inflammatory responses.

Science.gov (United States)

Guo, Ruo-Bing; Wang, Guo-Feng; Zhao, An-Peng; Gu, Jun; Sun, Xiu-Lan; Hu, Gang

2012-01-01

Paeoniflorin (PF), the principal component of Paeoniae Radix prescribed in traditional Chinese medicine, has been reported to exhibit many pharmacological effects including protection against ischemic injury. However, the mechanisms underlying the protective effects of PF on cerebral ischemia are still under investigation. The present study showed that PF treatment for 14 days could significantly inhibit transient middle cerebral artery occlusion (MCAO)-induced over-activation of astrocytes and microglia, and prevented up-regulations of pro-inflamamtory mediators (TNFα, IL-1β, iNOS, COX(2) and 5-LOX) in plasma and brain. Further study demonstrated that chronic treatment with PF suppressed the activations of JNK and p38 MAPK, but enhanced ERK activation. And PF could reverse ischemia-induced activation of NF-κB signaling pathway. Moreover, our in vitro study revealed that PF treatment protected against TNFα-induced cell apoptosis and neuronal loss. Taken together, the present study demonstrates that PF produces a delayed protection in the ischemia-injured rats via inhibiting MAPKs/NF-κB mediated peripheral and cerebral inflammatory response. Our study reveals that PF might be a potential neuroprotective agent for stroke.

Stroke from Vasospasm due to Marijuana Use: Can Cannabis Synergistically with Other Medications Trigger Cerebral Vasospasm?

Science.gov (United States)

Jamil, Marium; Zafar, Atif; Adeel Faizi, Syed; Zawar, Ifrah

2016-01-01

We present a case of imaging proven cerebral vasospasm causing ischemic stroke in a young patient chronically on buprenorphine-naloxone for heroin remission who started smoking cannabis on a daily basis. With cannabis legalization spreading across the states in the USA, it is important for physicians not only to be aware of cannabis reported association with cerebral vasospasm in some patients but also to be on the lookout for possible interacting medications that can synergistically affect cerebral vessels causing debilitating strokes.

Prolonged drug-induced hypothermia in experimental stroke

DEFF Research Database (Denmark)

Johansen, Flemming Fryd; Jørgensen, Henrik Stig; Reith, Jakob

2007-01-01

In experimental and human stroke, hypothermia is strongly related to a favorable outcome. Previous attempts to manipulate the core temperature in focal cerebral ischemia have been based on mechanical cooling. The purpose of the study is to establish a model for long-term drug-induced hypothermia...... in focal ischemia by pharmacological alteration of the central thermoregulatory set-point. We tested the hypothesis that the dopaminergic agonist Talipexole, which induces hypothermia, reduces infarct size. Body temperature was monitored by a radio-pill-implant. Rats had reversible occlusion of the middle...... that the core body temperature was reduced by 1.7 degrees C for 24 hours after MCAO in rats treated with Talipexole. This treatment induced a significant reduction of infarct volume at 7 days after focal ischemia by 47%. We suggest that the reduction in infarct volume is related to drug-induced hypothermia...

Change of blood glucose level and its possible mechanism in patients with cerebral stroke

International Nuclear Information System (INIS)

Chen Weizhen; Zhang Yong; Zhang Zikang; Mo Congjian

2003-01-01

To study the mechanism of the change of blood glucose levels in patients with cerebral stroke, the levels of blood glucose, cortisol, glucogen, insulin, growth hormone, triiodothyronine (T 3 ), thyroxine (T 4 ) and adrenocorticotropic hormone (ACTH) were dynamically measured in 90 patients with cerebral stroke. The circumstances of brain middle line movement, lateral ventricle oppression and entrance brain ventricle of burst hematoma of the patients were examines by CT scan. The total incidence of hyperglycemia in the patients was 42.22%. The blood glucose level was positively related to the cortisol and glucogen levels, and negatively related to the T 3 level. The changed level of blood glucose and its related hormones both returned to normal range in 10 days. Both the ACTH level and the rate of cerebral pathological change in hyperglycemia group were significantly higher than that in normoglycemia and control groups. The rate of cerebral pathological change in elevated ACTH level group was higher than that in normal ACTH level group. The mechanism of hyperglycemia in the patients with cerebral stroke might be related to the stimulation of the hypothalamus, which may induce the discharge of ACTH and glucagon releasing factor, and to that the level of cortisol and glucagon increased, the level of T 3 decreased

Bone marrow mesenchymal stem cell therapy in ischemic stroke: mechanisms of action and treatment optimization strategies

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Guihong Li

2016-01-01

Full Text Available Animal and clinical studies have confirmed the therapeutic effect of bone marrow mesenchymal stem cells on cerebral ischemia, but their mechanisms of action remain poorly understood. Here, we summarize the transplantation approaches, directional migration, differentiation, replacement, neural circuit reconstruction, angiogenesis, neurotrophic factor secretion, apoptosis, immunomodulation, multiple mechanisms of action, and optimization strategies for bone marrow mesenchymal stem cells in the treatment of ischemic stroke. We also explore the safety of bone marrow mesenchymal stem cell transplantation and conclude that bone marrow mesenchymal stem cell transplantation is an important direction for future treatment of cerebral ischemia. Determining the optimal timing and dose for the transplantation are important directions for future research.

The permeability of puerarin loaded poly(butylcyanoacrylate) nanoparticles coated with polysorbate 80 on the blood-brain barrier and its protective effect against cerebral ischemia/reperfusion injury.

Science.gov (United States)

Zhao, Li-xia; Liu, An-chang; Yu, Shu-wen; Wang, Zeng-xin; Lin, Xiao-qian; Zhai, Guang-xi; Zhang, Qing-zhu

2013-01-01

Puerarin (PUE) is a good candidate for treating stroke, but its low concentration in brain after administration limits its curative efficacy. The aim of the present work was to design and characterize PUE loaded poly(butylcyanoacrylate) nanoparticles (PBCN) coated with polysorbate 80 (Ps 80), and to evaluate the effect of PBCN on the permeability of PUE across the blood-brain barrier (BBB) and the effect of PUE loaded PBCN on the cerebral ischemia/reperfusion injury. PUE loaded PBCN were successfully prepared by anionic polymerization method with the mean particle size of 201.2 nm and the zeta potential of -7.72 mV. The in vitro release behavior of PUE from the nanoparticles showed a biphasic profile manner with an initial burst release followed by a sustained release. The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE loaded PBCN were both greater than these for the free drug. Moreover, compared with free drug, the vein injection of PUE loaded PBCN exerted the better neuroprotective effect in rats with focal cerebral ischemic injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, and reducing the infarct volume. The results indicated that this preparation may reduce the total dose required for the stroke therapy with concurrent reduction in dose related toxicity. All these findings suggest that PBCN could enhance the transport of PUE to brain and have a potential as a neuroprotective agent in the focal cerebral ischemic injury.

The synergetic effect of edaravone and borneol in the rat model of ischemic stroke.

Science.gov (United States)

Wu, Hai-Yin; Tang, Ying; Gao, Li-Yan; Sun, Wei-Xiang; Hua, Yao; Yang, Shi-Bao; Zhang, Zheng-Ping; Liao, Gao-Yong; Zhou, Qi-Gang; Luo, Chun-Xia; Zhu, Dong-Ya

2014-10-05

Free radical production contributes to the early ischemic response and the neuroinflammatory response to injury initiates the second wave of cell death following ischemic stroke. Edaravone is a free radical scavenger, and borneol has shown anti-inflammatory effect. We investigated the synergistic effect of these two drugs in the rat model of transient cerebral ischemia. Edaravone scavenged OH, NO and ONOO─ concentration-dependently, and borneol inhibited ischemia/reperfusion-induced tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β) and cyclooxygenase-2 (COX-2) expressions. In the rat model of transient cerebral ischemia and reperfusion, the combination of edaravone and borneol significantly ameliorated ischemic damage with an optimal proportion of 4:1. Emax (% inhibition) of edaravone, borneol and two drugs in combination was 55.7%, 65.8% and 74.3% respectively. ED50 of edaravone and borneol was 7.17 and 0.36 mg/kg respectively. When two drugs in combination, ED50 was 0.484 mg/kg, in which edaravone was 0.387 mg/kg (ineffective dose) and borneol was 0.097 mg/kg (ineffective dose). Combination index (CI)edaravone and borneol. The combination exhibited a therapeutic time window of 6h in ischemia/reperfusion model, and significantly ameliorated damages in permanent ischemia model. Moreover, two drugs in combination promoted long-term effect, including improved elemental vital signs, sensorimotor functions and spatial cognition. Our results suggest that the combination of edaravone and borneol have a synergistic effect for treating ischemic stroke. Copyright © 2014 Elsevier B.V. All rights reserved.

Acupuncture regulates the glucose metabolism in cerebral functional regions in chronic stage ischemic stroke patients---a PET-CT cerebral functional imaging study