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Focal cerebral ischemia was produced by an occlusion of the middle cerebral artery for 1, 3 and 24 hours in gerbils. Infarct volumes were determined by 2,3,5-triphenyltetrazolium chloride (TTC) transcardiac perfusion 24 hours after cerebral ischemia. Significant and consistent infarct sizes were produced in gerbils subjected to 24-hour occlusion of the middle cerebral arterey when compared to the 1 and 3-hour occlusion groups. Long term pretreatment of the 50% ethanol extract of Polygonum multiflorum Thunb. for 2 weeks significantly reduced the infarct volume by 50% as compared to that of the 24-hour occlusion group. The results revealed that long term pretreatment of Polygonum multiflorum Thunb. may protect the brain against focal cerebral ischemia.

The present study was designed to evaluate the neuroprotective effects of Ginkgo biloba leaf extract (EGb761) in male gerbils subjected to focal cerebral ischemia produced by permanent occlusion of the right middle cerebral artery. In this study, gerbils were fed standard chow with or without EGb761 (100 mg/kg/day, i.g.) prior to cerebral ischemia for 1 week. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation. Infarct volume was assessed by TTC (2,3,5-triphenyl-tetrazolium chloride) staining 24 hours after initiation of cerebral ischemia. Results showed that the EGb761 group had significant reduction of infarct volume 4 and 6 mm from the frontal pole by 40% and 30%, respectively when compared to the control group (p < 0.05). Mean locomotor activity of gerbils was reduced 24 hours after the occlusion of the MCA in both groups. However, there was no difference in locomotor activity between groups either 30 minutes before or 24 hours after the occlusion (p < 0.05).

Previously we have reported that Toki-shakuyaku-san (TSS) ameliorated the impairment of spatial memory induced by single cerebral ischemia (1 × 10 minutes) and scopolamine, a muscarinic receptor antagonist. In this experiment, we studied the effect of TSS on repeated cerebral ischemia (2 × 10 minutes, 1-hour interval) induced impairment of spatial memory and neuronal injury in rats. The 8-day post-ischemic treatment with TSS (30–300 mg/kg) was administered p.o. once per day. TSS dose-dependently prevented the impairment of spatial memory, neuronal death and TUNEL positive cells induced by repeated cerebral ischemia. In order to determine the mechanism of TSS, we also studied the effect of TSS on GluR2 mRNA, one of the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor subunits. Repeated cerebral ischemia significantly decreased GluR2 flop mRNA at 1 and 3 days after the occlusion. TSS (300 mg/kg) significantly suppressed the decrease in GluR2 flop at 3 days after repeated cerebral ischemia. These results suggested that the TSS has neuroprotective action which may be indirectly mediated by the AMPA receptor, and TSS may be beneficial for the treatment of cerebrovascular dementia.

Electroacupuncture (EA) is widely used to treat disorders of the nervous system, such as stroke. The aim of the present study was to investigate the effect of EA on cerebral blood flow (CBF) in cerebral ischemic rats. We developed an animal model of cerebral ischemia (CI) by occluding the blood flow of both common carotid arteries in Sprague-Dawley (SD) rats; 2 or 15 Hz EA was applied to both Zusanli acupoints. The levels of nitric oxide (NO) in the peripheral blood and amounts of calcitonin gene-related peptide (CGRP) in the cerebral cortex and thalamus were measured. In addition, L-N (G)-nitro arginine methyl ester (L-NAME) was used to measure the changes in CBF induced by EA in rats with and without CI. The results indicated that both 2 and 15 Hz EA increase the mean CBF in rats with and without CI. However, neither 2 nor 15 Hz EA induced changes in levels of NO in peripheral blood or changes in CGRP levels in cerebral cortex and thalamus. In addition, L-NAME did not change the increase in CBF. We concluded that both 2 and 15 Hz EA at both Zusanli acupoints induced the increase of CBF in rats with and without CI. Whether the effect of EA is related to NO or CGRP will be investigated in a future study.

This study was to investigate the protective effects and possible mechanisms of total flavones of rhododendra (TFR) against cerebral ischemia reperfusion injury in rats and mice. Cerebral ischemia/reperfusion injury was induced by occluding the right middle cerebral artery (MCA). Infarct volume, neurological deficit, brain water content, levels of malondialdehyde (MDA), nitric oxide (NO) contents, lactate dehydrogenase (LDH) activity in plasma and brain, levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and mRNA expression of inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) in brain were evaluated 7 or 10 days after treatment. TFR significantly reduced infarct volume, ameliorated the neurological deficit and reduced the brain water content. The activities of SOD, LDH and GPX in brain were enhanced, while the activity of LDH in plasma and the contents of MDA and NO in plasma and brain were decreased. While, the expression of iNOS and nNOS mRNA in brain were down-regulated, the expression of eNOS mRNA in the brain was up-regulated. These results suggest that TFR has protective effects for cerebral injury in rats and mice, which might be associated with its antioxidant properties and ability to regulate the expression of NOS isoforms.

This study was to observe the neurological protective effects of astragalosides (AST) on focal cerebral ischemia-reperfusion (I/R) injury in rats and to explore its possible mechanism. Male SD rats received right middle cerebral artery occlusion for 120 min and AST (40 mg/kg) was orally administered. The rats were decapitated 1, 3, 7, and 14 days after reperfusion. The neurological deficit score, infarct volume and water content of brain were measured; the activity of superoxide dismutase (SOD), lactate dehydrogenase (LDH) and nitric oxide synthase (NOS), and the content of malondialdehyde (MDA), lactate (LD) and nitric oxide (NO) of brain tissue were detected too. The expression of inducible nitric synthase (iNOS), nerve growth factor (NGF) and tropomyosin receptor kinase A (TrkA) mRNA were measured by RT-PCR or real-time PCR. AST could significantly reduce the neurological deficit score; infract volume and water content, increase SOD and LDH activities, decrease NOS activity and MDA, LD and NO content. AST treatment could down-regulate expression of iNOS mRNA, while, NGF and TrkA mRNA were up-regulated. Our data suggest that AST have the protective effects on focal cerebral ischemia in rats at the different reperfusion time points, the mechanism may be related to the antioxidation, regulated the expressions of iNOS, NGF and TrkA mRNA.

This study evaluated the effects of Angelica sinensis extract [Dang Gui (DG)] administered before 60min of middle cerebral artery occlusion followed by 3d of reperfusion and investigated the involvement of mitogen-activated protein kinase (MAPK)/hypoxia-inducible factor (HIF)-1$\alpha$ signaling in the cortical ischemic penumbra. DG was intraperitoneally administered at a dose of 0.25g/kg (DG-0.25g), 0.5g/kg (DG-0.5g), or 1g/kg (DG-1g) 30min before the onset of cerebral ischemia. Our study results revealed that DG-0.5g and DG-1g pretreatment effectively attenuated cerebral infarct and improved neurological deficits. DG-0.5g and DG-1g pretreatment significantly downregulated glial fibrillary acidic protein (GFAP), cytochrome c, and cleaved caspase-3 expression and upregulated phospho-p38 MAPK (p-p38 MAPK)/p38 MAPK, phospho-cAMP response element-binding protein (p-CREB)/CREB, cytosolic and mitochondrial phospho-Bad (p-Bad)/Bad ratios, and HIF-1$\alpha$, vascular endothelial growth factor-A (VEGF-A), phospho-90 kDa ribosomal S6 kinase (p-p90RSK), and von Willebrand factor (vWF) expression in the cortical ischemic penumbra. Pretreatment with SB203580, a p38 MAPK inhibitor, dramatically abrogated the upregulating effects of DG-1g on p-p38 MAPK/p38 MAPK, p-CREB/CREB, and p-Bad/Bad ratios and HIF-1$\alpha$, VEGF-A, and vWF expression and the downregulating effects of DG-1g on GFAP, cytochrome c, cleaved caspase-3, and cerebral infarction. DG-0.5g and DG-1g pretreatment provided neuroprotective effects against astrocyte-mediated cerebral infarction by activating angiogenic and anti-apoptotic signaling. Moreover, the angiogenic and anti-apoptotic effects of DG pretreatment can be attributed to the activation of p38 MAPK/HIF-1$\alpha$/VEGF-A/vWF signaling and p38 MAPK/HIF-1$\alpha$/VEGF-A/p-Bad-related regulation of cytochrome c/caspase-3 signaling, respectively, in the cortical ischemic penumbra 3d after reperfusion.

This study assessed the anti-apoptotic effects of the administration of ferulic acid (FrA) in rats 30min before middle cerebral artery occlusion (MCAo) followed by 3 d of ischemia and the involvement of 70kDa heat shock protein (HSP70)-mediated signaling in the penumbral cortex. Our results demonstrated that FrA pretreatment at doses of 80mg/kg (FrA-80mg) and 100mg/kg (FrA-100mg) effectively ameliorated neurological functions and reduced the numbers of cytochrome c-, cleaved caspase-3-, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in the penumbral cortex 3 d after ischemia. Moreover, FrA-80mg and FrA-100mg pretreatment markedly upregulated cytosolic HSP70, Beclin-1, microtubule-associated protein 1 light chain 3 (LC3) A/B-II and autophagy-related protein 5 (Atg5) expression; cytosolic and mitochondrial X-linked inhibitor of apoptosis (XIAP) expression and the Bcl-2/Bax ratio. FrA pretreatment downregulated cytosolic cytochrome c, apoptosis-inducing factor (AIF), procathepsin B, and cathepsin B expression and mitochondrial and cytosolic second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein-binding protein with a low isoelectric point (Smac/DIABLO) expression in the penumbral cortex. Pretreatment with VER155008, a HSP70 family inhibitor, significantly inhibited the effects of FrA-100mg on the expression of the aforementioned proteins expression in the penumbral cortex. FrA-80mg and FrA-100mg pretreatment exerts neuroprotective effects against caspase-dependent and -independent apoptosis through activating HSP70/Bcl-2- and HSP70/autophagy-induced signaling pathways. Furthermore, the HSP70/Bcl-2- and HSP70/autophagy-induced anti-apoptotic effects of FrA pretreatment can be attributed to the regulation of Bax/cytochrome c/Smac/DIABLO/XIAP/ caspase-3- (or Bax/AIF-) and Beclin-1/LC3A/B-II/Atg5-mediated signaling, respectively, in the penumbral cortex 3 d after permanent MCAo.

Panax notoginseng is the most widely used Chinese medicinal herb for the prevention and treatment of ischemic diseases. Its main active ingredients are saponins, including ginsenoside Rb1, ginsenoside Rg1, and notoginsenoside R1, among others. This review provides an up-to-date overview on the pharmacological roles of P. notoginseng constituents in cerebral ischemia. The saponins of P. notoginseng induce a variety of pharmacological effects in the multiscale mechanisms of cerebral ischemic pathophysiology, including anti-inflammatory activity, reduction of oxidative stress, anti-apoptosis, inhibition of amino acid excitotoxicity, reduction of intracellular calcium overload, protection of mitochondria, repairing the blood–brain barrier, and facilitation of cell regeneration. Regarding cell regeneration, P. notoginseng not only promotes the proliferation and differentiation of neural stem cells, but also protects neurons, endothelial cells and astrocytes in cerebral ischemia. In conclusion, P. notoginseng may treat cerebrovascular diseases through multiple pharmacological effects, and the most critical ones need further investigation.

Salidroside, an active ingredient in Rhodiola rosea, has potent protective activity against cerebral ischemia. However, the mechanisms underlying its pharmacological actions are poorly understood. In this study, we employed a mouse middle cerebral artery occlusion (MCAO) and cellular oxygen and glucose deprivation (OGD) models to test the hypothesis that salidroside may restore mitochondrial quality control in neurons by modulating the relevant signaling. The results indicated that salidroside mitigated almost 40% the ischemia-induced brain infarct volumes in mice and the OGD-decreased viability of neurons to ameliorate the mitochondrial functions. Furthermore, salidroside treatment alleviated the OGD- or ischemia-induced imbalance of mitochondrial fission and fusion, mitophagy and promoted mitochondrial biogenesis in neurons by attenuating the AMPK activity. Moreover, salidroside alleviated 50% the OGD-promoted mitochondrial calcium fluorescence intensity and 5% mitochondria-associated membrane (MAM) area by down-regulating GRP75 expression independent of the AMPK signaling. Finally, similar findings were achieved in primary mouse neurons. Collectively, these data indicate that salidroside effectively restores the mitochondria dynamics, facilitates mitochondrial biogenesis by attenuating the AMPK signaling, and maintains calcium homeostasis in neurons independent of the AMPK activity.

In this study, numerical simulations are performed to analyze the brain temperature reduction in swine during selective head cooling, whole body cooling or while the animals experience ischemia. Brain temperature is calculated using a time dependent thermal model that incorporates available experimental measurements of the rectal temperature, the cerebral blood flow and the cerebral metabolic rate of oxygen consumption.

The calculated temperature distribution is validated against the in vivo temperature measurements recorded during the different experiments. These comparisons help to better understand the relations between brain temperature, blood flow and metabolic activity, which are essential to successfully apply hypothermia in the treatment of brain injury.

The calculations presented here reproduce the temperature behavior observed in all the experiments considered. It is observed that the arterial temperature and the cerebral metabolic rate are important parameters that affect the deep tissue temperature. It is also concluded that the accurate knowledge of parameters such as the skin and bone thermal conductivity are necessary for effective modeling.

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

The study aimed to examine the behavior capability and morphological structure on neurons in the dentate gyrus of rats with atherosclerosis (AS) after cerebral ischemia reperfusion injury (IRI) and observe the effect of basic fibroblast growth factor (bFGF) on the IRI model rats with AS. Forty Wister rats were randomly divided into the control group, the AS group, the IRI group and the bFGF treatment group. Middle cerebral artery occlusion model rats were established. The bFGF was injected into the abdominal cavity in rats of the bFGF treatment group, and an identical volume physiological saline was given for the other three groups. The colorimetric method was used to detect the levels of superoxide dismutase (SOD) and the malondialdehyde (MDA) content. Western blot was performed for detecting the expression of caspase-3 protein of the rat dentate gyrus. The BrdU-positive cells and ultrastructures of neurons were observed and quantitative analysis was performed. The results indicated that compared with the control group, the behavior capability in the AS group and the IRI group decreased but that of the bFGF treatment group obviously improved (p < 0.05). The content of MDA significantly increased in the AS group and the IRI group (p < 0.05). After treatment with bFGF, the SOD activity of rat brain tissue obviously increased and the content of MDA decreased (p < 0.05), and the number of neurons increased along with Nissl bodies in the cytoplasm. Compared with the control group, expression of caspase-3 protein in the bFGF treatment group obviously decreased (p < 0.05). The quantity of BrdU-positive cells of the rat dentate gyrus in the bFGF treatment group was obviously higher than those of other three groups (p < 0.05). The morphological structure on neurons in the bFGF treatment group was improved compared with the IRI group. bFGF could efficiently improve the behavior ability and decrease the pathological lesion of the rat dentate gyrus of the IRI rats with AS, which might promote the neuroprotective effect in the cerebrovascular disease.