Neuroprotective effects of valproic acid following transient global ischemia in rats

AimsA growing number of studies demonstrate that valproic acid (VPA), an anti-convulsant and mood-stabilizing drug, is neuroprotective against various insults. This study investigated whether treatment of ischemic stroke with VPA ameliorated hippocampal cell death and cognitive deficits. Possible mechanisms of action were also investigated.Main methodsGlobal cerebral ischemia was induced to mimic ischemia/reperfusion (I/R) damage. The pyramidal cells within the CA1 field were stained with cresyl violet. Cognitive ability was measured 7 days after I/R using a Morris water maze. The anti-inflammatory effects of VPA on microglia were also investigated by immunohistochemistry. Pro-inflammatory cytokine production was determined using enzyme-linked immunosorbent assays (ELISA). Western blot analysis was performed to determine the levels of acetylated H3, H4 and heat shock protein 70 (HSP70) in extracts from the ischemic hippocampus.Key findingsVPA significantly increased the density of neurons that survived in the CA1 region of the hippocampus on the 7th day after transient global ischemia. VPA ameliorated severe deficiencies in spatial cognitive performance induced by transient global ischemia. Post-insult treatment with VPA also dramatically suppressed the activation of microglia but not astrocytes, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. VPA treatment resulted in a significant increase in levels of acetylated histones H3 and H4 as well as HSP70 in the hippocampus.SignificanceOur results indicated that VPA protected against hippocampal cell loss and cognitive deficits. Treatment with VPA following cerebral ischemia probably involves multiple mechanisms of action, including inhibition of ischemia-induced cerebral inflammation, inhibition of histone deacetylase (HDAC) and induction of HSP.     

Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation

Neuroprotective properties of the mood stabilizer valproic acid (VPA) are implicated in its therapeutic efficacy. Heat-shock protein 70 (HSP70) is a molecular chaperone, neuroprotective and anti-inflammatory agent. This study aimed to investigate underlying mechanisms and functional significance of HSP70 induction by VPA in rat cortical neurons. VPA treatment markedly up-regulated HSP70 protein levels, and this was accompanied by increased HSP70 mRNA levels and promoter hyperacetylation and activity. Other HDAC inhibitors – sodium butyrate, trichostatin A, and Class I HDAC-specific inhibitors MS-275 and apicidin, – all mimicked the ability of VPA to induce HSP70. Pre-treatment with phosphatidylinositol 3-kinase inhibitors or an Akt inhibitor attenuated HSP70 induction by VPA and other HDAC inhibitors. VPA treatment increased Sp1 acetylation, and a Sp1 inhibitor, mithramycin, abolished the induction of HSP70 by HDAC inhibitors. Moreover, VPA promoted the association of Sp1 with the histone acetyltransferases p300 and recruitment of p300 to the HSP70 promoter. Further, VPA-induced neuroprotection against glutamate excitotoxicity was prevented by blocking HSP70 induction. Taken together, the data suggest that the phosphatidylinositol 3-kinase/Akt pathway and Sp1 are likely involved in HSP70 induction by HDAC inhibitors, and induction of HSP70 by VPA in cortical neurons may contribute to its neuroprotective and therapeutic effects.     

Transient focal cerebral ischemia down-regulates glutamate transporters GLT-1 and EAAC1 expression in rat brain

Transient focal cerebral ischemia leads to extensive excitotoxic neuronal damage in rat cerebral cortex. Efficient reuptake of the released glutamate is essential for preventing glutamate receptor over-stimulation and neuronal death. Present study evaluated the expression of the glial (GLT-1 and GLAST) and neuronal (EAAC1) subtypes of glutamate transporters after transient middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. Between 24h to 72h of reperfusion after transient MCAO, GLT-1 and EAAC1 protein levels decreased significantly (by 36% to 56%, p < 0.05) in the ipsilateral cortex compared with the contralateral cortex or sham control. GLT-1 and EAAC1 mRNA expression also decreased in the ipsilateral cortex of ischemic rats at both 24h and 72h of reperfusion, compared with the contralateral cortex or sham control. Glutamate transporter down-regulation may disrupt the normal clearance of the synaptically-released glutamate and may contribute to the ischemic neuronal death.     

Effects of MK-801 on nitrite and cGMP levels during focal cerebral ischemia in rats.

Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and initiates the events leading to ischemic brain damage. Glutamate receptor antagonists are being used to reduce neuronal damage observed after hypoxia and ischemia. The glutamate receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)-cyclohepten-5,10-imine maleate (MK-801) crosses the blood-brain barrier readily and produces a non-competitive use-dependent blockade of the N-methyl-D-aspartate subtype of glutamate receptor. The aim of this study was to investigate effects of MK-801 administered before and just after the onset of ischemia in rats on nitrite and cyclic guanosine monophosphate (cGMP) levels. Focal cerebral ischemia in rats was produced by permanent occlusion of right middle cerebral artery (MCAO). Nitrite and cGMP levels were measured in both cortex and cerebellum at 0, 10, and 60 min following MCAO. The same parameters were measured in rats treated with MK-801 (0.5 mg/kg, i.p.) 30 min before or just after MCAO. Ipsilateral cortical nitrite levels were increased relative to contralateral cortex after MCAO. No significant changes were observed in cerebellum. The cGMP concentrations in both sides of the cortex and cerebellum were increased at 10 and 60 min compared with 0 min values. cGMP level in the ipsilateral cortex was higher than contralateral cortex, whereas the opposite was found for the cerebellum. MK-801 treatment before or just after MCAO decreased significantly nitrite and cGMP production. Our data indicate that MK-801 treatment before or just after focal ischemia prevents the increase in NO and cGMP production.     

雌激素在脑缺血诱导的大鼠齿状回神经再生中的作用

为研究雌激素对成年动物局灶性脑缺血诱导成年动物海马齿状回神经元再生的影响,将雄性SD大鼠分为假手术 雌激素组(SE)、假手术 生理盐水替代组(SN)、缺血 雌激素组(ME)和缺血 生理盐水替代组(MN),右侧大脑中动脉闭塞(MCAO)建立脑缺血模型。在缺血90min后恢复供血再灌注,分别于再灌注后1、3、12、24和28h处死老鼠并检测各组大鼠脑梗死体积、细胞凋亡以及脑缺血诱导的成年动物海马齿状回神经元再生的情况。在5个时间点的检测中,ME组脑梗死体积显著小于SE组(P<0.05);在MCAO大鼠中,海马齿状回区域并未发现有神经元丢失及凋亡的现象。同时,MN组与SN组相比较,损伤侧齿状回新生神经元数目明显增多(P<0.05),说明这种缺血诱导的神经元再生并不依赖于齿状回区域神经细胞的死亡;ME组与MN组相比较,损伤侧新生神经元数目显著增多(P<0.05);SE与SN组相比较,手术侧和对侧的新生神经元数目都显著增加(P<0.05)。结果提示雌激素对局灶性脑缺血后海马齿状回神经元再生具有促进作用,且这种促进作用与海马缺血损伤程度无关。     

Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats

Free radical induced neuronal damage is implicated in cerebral ischemia reperfusion (IR) injury and antioxidants are reported to have neuroprotective activity. Several in vitro and in vivo studies have proved the antioxidant potential of curcumin and its metabolites. Hence, in the present study the neuroprotective potential of curcumin was investigated in middle cerebral artery occlusion (MCAO) induced focal cerebral IR injury. 2 h of MCAO and 22 h of reperfusion resulted in the infarct volume of 210.39 +/- 31.25 mm3. Administration of curcumin 100 and 300 mg/kg, i.p. 30 min. after MCAO produced 37.23 +/- 5.10% and 46.39 +/- 10.23% (p < 0.05) reduction in infarct volume, respectively. Ischemia induced cerebral edema was reduced in a dose dependent manner. Curcumin at 300 mg/kg, i.p. produced 50.96 +/- 6.04% reduction in edema (p < 0.05) volume. Increase in lipid peroxidation after MCAO in ipsilateral and contralateral hemisphere of brain was observed, which was reduced by curcumin (300 mg/kg, i.p.)-treatment. Decrease in superoxide dismutase and glutathione peroxidase activity was observed in ipsilateral hemisphere of MCAO animal. Curcumin-treatment (300 mg/kg, i.p.) prevented IR injury mediated fall in glutathione peroxide activity. Peroxynitrite measured using rhodamine123 fluorescence and anti-nitrotyrosine immunofluorescence indicated increased peroxynitrite formation after IR insult. Curcumin-treatment reduced peroxynitrite formation and hence the extent of tyrosine nitration in the cytosolic proteins. These results suggest the neuroprotective potential of curcumin in cerebral ischemia and is mediated through its antioxidant activity.     

A novel cell-permeable antioxidant peptide, SS31, attenuates ischemic brain injury by down-regulating CD36

Oxidative stress is implicated in the pathogenesis of ischemia/reperfusion injury. Recently, we demonstrated that activation of CD36, a class B scavenger receptor, mediates free radical production and tissue injury in cerebral ischemia (1). Oxidized low density lipoproteins (oxLDL) are among the ligands that bind to CD36 and are elevated in acute cerebral infarction. SS31 is a cell-permeable antioxidant peptide that reduces intracellular free radicals and inhibits LDL oxidation/lipid peroxidation (2). The current study was designed to investigate whether treatment with SS31 normalizes ischemia-induced redox changes and attenuates CD36-mediated tissue injury. C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO). Redox status and infarct volume were measured in animals treated with either saline or SS31. Oxidative stress induced by ischemia/reperfusion profoundly depleted glutathione (GSH) concentrations in the ipsilateral cortex and striatum. Treating mice with SS31 immediately after reperfusion significantly attenuated ischemia-induced GSH depletion in the cortex and reduced infarct size. By contrast, the protective effect of SS31 was absent in CD36 knock-out mice, indicating that SS31 is acting through inhibition of CD36. Treating C57BL/6 mice with SS31 reduced CD36 expression in postischemic brain and mouse peritoneal macrophages (MPM). Further in vitro studies revealed that SS31 attenuated oxLDL-induced CD36 expression and foam cell formation in MPM. These in vivo and in vitro studies indicate that the down-regulation of CD36 by novel class antioxidant peptides may be a useful strategy to treat ischemic stroke victims.     

Inhibition of Ischemia-Induced Fodrin Breakdown by a Novel Phenylpyrimidine Derivative NS-7: An Implication for Its Neuroprotective Action in Rats with Middle Cerebral Artery Occlusion

Abstract: The effect of a novel neuroprotective compound, NS-7[4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy)pyrimidine hydrochloride], on ischemia-induced fodrin breakdown was examined both in vitro and in vivo. The fodrin breakdown was measured by western blot followed by a densitometric analysis. In slices of the rat cerebral cortex, a pronounced fodrin breakdown was observed under hypoxic and hypoglycemic conditions. The enhancement of fodrin breakdown was completely blocked by omission of extracellular Ca²⁺ and significantly inhibited by calpain inhibitors such as E-64 and calpain inhibitor-I, thereby suggesting that the fodrin breakdown induced by hypoxia/hypoglycemia is due to the activation of Ca²⁺-stimulated neutral protease calpain. NS-7 (1–30 µ M ) produced a concentration-dependent inhibition of hypoxia/hypoglycemia-induced fodrin breakdown. In rats with unilateral middle cerebral artery occlusion (MCAO), a pronounced fodrin breakdown was observed in the cerebral cortex and striatum, although the time course for the development of the fodrin breakdown was much slower in the cerebral cortex than in the striatum. NS-7 (0.5 mg/kg i.v.), when injected immediately after MCAO, suppressed not only the fodrin breakdown but also the infarction in the cerebral cortex. From these results it is suggested that inhibition of calpain activation is implicated in the neuroprotective action of NS-7.     

局灶性脑缺血再灌损伤时神经细胞内Ca~(2+)时空动态变化的实验研究

本文用插线法制作局灶性脑缺血／再灌损伤模型,利用激光共聚焦扫描显微镜观察活体脑片细胞内Ｃａ２＋的分布及动态变化,结果表明：（１）缺血／再灌时间不同,梗塞面积不同,缺血４小时梗塞面积占同侧半球的１６．３％,缺血４小时再灌２０小时梗塞面积增加到２５．９％,缺血２４小时梗塞面积占同侧半球的６０．４％。（２）本文首次观察到在缺血４小时纹状体区域的Ｃａ２＋变化明显高于皮层,并且再灌后皮层及纹状体区域Ｃａ２＋的含量明显增加     

Decreased expression of vesicular GABA transporter, but not vesicular glutamate, acetylcholine and monoamine transporters in rat brain following focal ischemia

In nerve terminals, vesicular transporters pack neurotransmitters into synaptic vesicles, which is an essential prerequisite for transmitter release. To date, three distinct families of vesicular transporters have been identified which are specific for (a) excitatory amino acids (glutamate and aspartate), (b) inhibitory amino acids (GABA and glycine) and (c) acetylcholine and monoamines. The present study evaluated the effect of transient focal cerebral ischemia on the expression of these vesicular transporters in adult rat brain. Ischemia was induced by a 1 h transient middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats. At various reperfusion periods (3-72 h), mRNA levels of the vesicular transporters were estimated in the contralateral and the ipsilateral cerebral cortex by real-time PCR analysis. Following transient focal ischemia, mRNA expression of the vesicular GABA transporter (VGAT) decreased significantly by 3 h of reperfusion and remained at a significantly lower level than sham until at least 72 h of reperfusion. Western blotting showed a significant decrease in the VGAT immunoreactive protein levels in the ipsilateral cortex of rats subjected to focal ischemia and 24 h reperfusion. Immunohistochemistry demonstrated many VGAT immunopositive puncta in the contralateral cortex, which were significantly decreased in the ipsilateral cortex at 24 h reperfusion. Focal ischemia had no effect on the mRNA levels of the vesicular transporters specific for glutamate/aspartate, acetylcholine and monoamines at either 6 h or 24 h of reperfusion.     

Role of ERK signaling in the neuroprotective efficacy of magnesium sulfate treatment during focal cerebral ischemia in the gerbil cortex

Magnesium sulfate (MgSO4) ameliorates focal ischemia-induced neuronal death in the rat and gerbil models. However, the molecular mechanisms for this neuroprotection are not known. Focal cerebral ischemia was produced by unilateral occlusion of the right common carotid artery and the right middle cerebral artery (CCAO + MCAO) for 30 min or 60 min. Treatment with MgSO4 significantly increased the level of mitogen-activated protein kinase/extra-cellular signal-regulated kinase kinase 1/2 (MEK1/2), extra-cellular signal-regulated kinase 1/2 (ERK1/2), cyclic-AMP response element binding protein (CREB) phosphorylation and the anti-apoptotic protein Bcl-2 both in the non-ischemic (contralateral) and ischemic (ipsilateral) cortex. However, these effects were reversed by administration of U0126, a MEK kinase inhibitor. In the ipsilateral cortex, a significant increase in the level of the proapoptotic proteins Bax, Bad, BNIP3 and activated caspase 3 were detected at the end of focal ischemia compared to the non-ischemic cortex. Treatment of MgSO4 prevented these ischemia-induced activations of the death cascade. Collectively, these data indicate that the ERK-CREB-Bcl-2 signaling pathway might be involved in MgSO4-induced neuroprotection following focal ischemia. Moreover, MgSO4 treatment also resulted in a reduction in pro-apoptotic proteins. These results enhance our understanding on the role of MgSO4 in treating cerebral ischemia.     

Hepcidin is involved in iron regulation in the ischemic brain

Oxidative stress plays an important role in neuronal injuries caused by cerebral ischemia. It is well established that free iron increases significantly during ischemia and is responsible for oxidative damage in the brain. However, the mechanism of this ischemia-induced increase in iron is not completely understood. In this report, the middle cerebral artery occlusion (MCAO) rat model was performed and the mechanism of iron accumulation in cerebral ischemia-reperfusion was studied. The expression of L-ferritin was significantly increased in the cerebral cortex, hippocampus, and striatum on the ischemic side, whereas H-ferritin was reduced in the striatum and increased in the cerebral cortex and hippocampus. The expression level of the iron-export protein ferroportin1 (FPN1) significantly decreased, while the expression of transferrin receptor 1 (TfR1) was increased. In order to elucidate the mechanisms of FPN1 regulation, we studied the expression of the key regulator of FPN1, hepcidin. We observed that the hepcidin level was significantly elevated in the ischemic side of the brain. Knockdown hepcidin repressed the increasing of L-ferritin and decreasing of FPN1 invoked by ischemia-reperfusion. The results indicate that hepcidin is an important contributor to iron overload in cerebral ischemia. Furthermore, our results demonstrated that the levels of hypoxia-inducible factor-1α (HIF-1α) were significantly higher in the cerebral cortex, hippocampus and striatum on the ischemic side; therefore, the HIF-1α-mediated TfR1 expression may be another contributor to the iron overload in the ischemia-reperfusion brain.     

Remote Limb Ischemic Preconditioning Protects Rats Against Cerebral Ischemia via HIF-1α/AMPK/HSP70 Pathway

Remote limb ischemic preconditioning (RIPC) is a clinically feasible strategy to protect against ischemia/reperfusion injury, but the knowledge concerning the mechanism underlying RIPC is scarce. This study was performed to examine the effect of RIPC on brain tissue suffering from ischemia challenge and explore its underlying mechanism in a rat model. The animals were divided into four groups: Sham, middle cerebral artery occlusion (MCAO), RIPC, and MCAO+RIPC. We found that previous exposure to RIPC significantly attenuated neurological dysfunction and lessened brain edema in MCAO+RIPC group. Moreover, other important events were observed in MCAO+RIPC group, including substantial decrements in the concentrations of oxidative response indicators [malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), and protein carbonyl], significant reductions in levels of inflammation mediators [myeloperoxidase (MPO), tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β), and IL-6], and significant decline in neuronal apoptosis revealed by a smaller number of TUNEL-positive cells. Interestingly, both MCAO and RIPC groups exhibited meaningful elevations in the levels of HIF-1a, HSP70, and AMP-activated protein kinase (AMPK) compared to Sham group, and previous exposure to RIPC further elevated the levels of HIF-1a, HSP70, and AMPK in MCAO+RIPC group. Furthermore, the administration of YC-1 (HIF-1 inhibitor), 8-bAMP (AMPK inhibitor), and Quercetin (HSP70 inhibitor) to MCAO+RIPC rats demonstrated that HIF-1α/AMPK/HSP70 was involved in RIPC-mediated protection against cerebral ischemia.     

Changes in the Metabolism of Histamine arid Monoamines After Occlusion of the Middle Cerebral Artery in Rats

Changes in the levels of histamine, monoamines, and their metabolites in the cerebral cortex and striatum after occlusion of the middle cerebral artery in rats were examined. The water content of the ipsilateral brain regions gradually increased after occlusion. In the ischemic side, 1 h after occlusion, the cortical norepinephrine and striatal 5-hydroxy-tryptamine levels significantly decreased, and striatal 3,4-dihydroxyphenylacetic acid and homovanillic acid levels markedly increased. In contrast, the levels of histamine and tele-methylhistamine in either brain region gradually increased and the changes became pronounced and statistically significant 6-12 h after induction of ischemia. The striatal histamine and tele-methylhistamine reached levels three- and twofold higher, respectively, than those of the contralateral side. In rats treated with alpha-fluoromethylhistidine 1 h before induction of ischemia, elevation of histamine and tele-methylhistamine was not observed. The elevated histamine level in the ipsilateral straitum at 9 h after occlusion was further significantly increased by the treatment with metoprine, an inhibitor of histamine-N-methyltransferase. These results suggest that the histaminergic activity in the brain is gradually enhanced by cerebral ischemia.     

Folic acid stimulates proliferation of transplanted neural stem cells after focal cerebral ischemia in rats

Folic acid (FA) stimulates neural stem cell (NSC) proliferation in vitro and enhances hippocampal neurogenesis in rats after middle cerebral artery occlusion (MCAO). The effect of FA supplementation on exogenous NSCs transplanted in MCAO rats was observed to determine if FA can stimulate NSC replacement after focal cerebral ischemia. Rats were randomly assigned to 3 groups: MCAO; MCAO and exogenous NSC transplantation (MCAO+NSCs); and MCAO, NSC transplantation and FA (MCAO+NSCs+FA). FA (0.8 mg/kg) or vehicle was administered by gavage daily for 28 days before MCAO and 23 days afterward. NSCs were labeled with superparamagnetic iron oxide (SPIO) and bromodeoxyuridine (BrdU) prior to transplantation into the striatum, contralateral to the ischemic zone, at 2 days post-MCAO. Magnetic resonance imaging tracking and fluorescent immunohistochemistry, as well as measurement of serum folate concentration, were performed at intervals up to 21 days after transplantation. FA supplementation caused sustained increases of 400–600% in serum folate concentration. Magnetic resonance images indicated that SPIO-labeled NSCs were more abundant at the transplantation and ischemic brain sites in MCAO+NSCs+FA rats than in MCAO+NSCs rats. Similarly, immunohistochemistry showed that the numbers of Sox-2/BrdU double positive cells at the transplantation and ischemic sites were higher in the rats that received FA. In conclusion, after focal cerebral ischemia, FA supplementation stimulates transplanted NSCs to proliferate and migrate to ischemic sites.     

大鼠局灶性脑缺血后缺血边缘区NG_2细胞的表达

目的观察局灶性脑缺血后缺血边缘区海马和皮层NG2细胞的动态表达,探讨其在脑缺血神经损伤与修复过程中所起的作用。方法将大鼠随机分为假手术组(sham)和脑缺血再灌注组,脑缺血再灌注组采用线栓法制备大鼠大脑中动脉阻塞再灌流模型(MCAO),假手术组不插入线栓,采用免疫荧光组织化学法结合共聚焦显微镜成像观察sham组及脑缺血后3d,7d,30d不同时间点缺血边缘区的海马CA1区和皮层区NG2的动态表达情况。结果脑缺血再灌注后缺血边缘区海马和皮层NG2胶质细胞表达增加,缺血后7d最明显。结论脑缺血后缺血边缘区存在NG2细胞的增生和形态变化可能与脑缺血后损伤修复密切相关。     

δ-Opioid Receptor Activation Rescues the Functional TrkB Receptor and Protects the Brain from Ischemia-Reperfusion Injury in the Rat

Objectives

δ-opioid receptor (DOR) activation reduced brain ischemic infarction and attenuated neurological deficits, while DOR inhibition aggravated the ischemic damage. The underlying mechanisms are, however, not well understood yet. In this work, we asked if DOR activation protects the brain against ischemic injury through a brain-derived neurotrophic factor (BDNF) -TrkB pathway.

Methods

We exposed adult male Sprague-Dawley rats to focal cerebral ischemia, which was induced by middle cerebral artery occlusion (MCAO). DOR agonist TAN-67 (60 nmol), antagonist Naltrindole (100 nmol) or artificial cerebral spinal fluid was injected into the lateral cerebroventricle 30 min before MCAO. Besides the detection of ischemic injury, the expression of BDNF, full-length and truncated TrkB, total CREB, p-CREB, p-ATF and CD11b was detected by Western blot and fluorescence immunostaining.

Results

DOR activation with TAN-67 significantly reduced the ischemic volume and largely reversed the decrease in full-length TrkB protein expression in the ischemic cortex and striatum without any appreciable change in cerebral blood flow, while the DOR antagonist Naltrindole aggregated the ischemic injury. However, the level of BDNF remained unchanged in the cortex, striatum and hippocampus at 24 hours after MCAO and did not change in response to DOR activation or inhibition. MCAO decreased both total CREB and pCREB in the striatum, but not in the cortex, while DOR inhibition promoted a further decrease in total and phosphorylated CREB in the striatum and decreased pATF-1 expression in the cortex. In addition, MCAO increased C11b expression in the cortex, striatum and hippocampus, and DOR activation specifically attenuated the ischemic increase in the cortex but not in the striatum and hippocampus.

Conclusions

DOR activation rescues TrkB signaling by reversing ischemia/reperfusion induced decrease in the full-length TrkB receptor and reduces brain injury in ischemia/reperfusion     

急性脑缺血诱导的Sirt3蛋白表达下调通过破坏线粒体功能导致神经元损伤

本文旨在观察急性脑缺血对神经元沉默信息调节因子2相关酶类3(silent mating type information regulator 2 homolog 3,Sirt3)蛋白表达水平的影响,并阐明Sirt3在急性脑缺血中的病理意义.建立小鼠大脑中动脉栓塞(middle cerebral artery occlu...     

EGCG Ameliorates the Suppression of Long-Term Potentiation Induced by Ischemia at the Schaffer Collateral-CA1 Synapse in the Rat

The function of Epigallocatechin gallate (EGCG), a main component of green tea, has been widely investigated, amelioration of synaptic transmission and neuroprotective effects against ischemia-induced brain damage among others. However, the mechanism underlying is still unveiled. We investigated the effects of EGCG on high frequency stimulation-induced long-term potentiation (LTP) in the Schaffer collateral-CA1 synapse with or without cerebral ischemia injury induced by middle cerebral artery occlusion (MCAO) in vivo to examine the possible relations between EGCG and synaptic transmission. Application of EGCG modulated synaptic transmission and produced a dose-dependent improvement of the induction of LTP. However, relative high-dose EGCG can block the induction of LTP at the Schaffer collateral-CA1 synapse in normal rat in vivo. In addition, the effects of EGCG were observed on the infarct volume and neurological deficit in rats subjected to MCAO; furthermore, the cell viability of primary cultured rat hippocampal and cortical neurons suffered from oxygen–glucose deprivation were evaluated with MTT and LDH assay, which showed significant neuroprotective properties in vitro. Surprisingly, the contents of the glutamate (Glu), glycine (Gly), and gamma-aminobutyric acid amino acids were totally disequilibrated before and after cerebral ischemia injury and could be rebalanced to original level by application of EGCG. Our results suggest that EGCG is able to improve the efficiency of synaptic transmission in cerebral ischemia injury with attenuated effect related to the neuroprotection of EGCG through regulating excitatory and inhibitory amino acid balance.