Neuroprotection by human umbilical cord blood-derived progenitors in ischemic brain injuries

Stem cells have an extremely high potential to treat many devastating diseases, including neuronal injuries. Albeit the need for human neuronal stem cells, their quantities are very limited by relying on early human embryos as the main source. Therefore, progenitors of other origins, such as human umbilical cord blood (CB) are being considered. In the last decade, various populations isolated from the CB were reported to differentiate in vitro towards a neural phenotype. The conditions to induce the cell differentiation are not conclusive and may include addition of chemicals, cytokines and growth factors, including the nerve growth factor (NGF). Some CB cells were found to express the TrkANGF receptor, suggesting an endogenous role for this growth factor also in the CB environment. The ability of CB and derived stem cell populations to protect against neurological deficits was shown, both in vitro and in vivo, in models of ischemic brain injuries. In rodent models of stroke, heatstroke, brain trauma and brain damage at birth, CB cells either by intravenous injection or intrastriatal transplantation, were found to reduce the infarct size and the neurological deficits caused by the injury. The restorative effects of CB were suggested to be mediated by mechanisms other than cell replacement. Some of the proposed mechanisms involve reduced inflammation, nerve fiber reorganization by trophic actions, increased cell survival and enhanced angiogenesis. Furthermore, treatment with CB was found to have a therapeutic window of days compared with the present 36 hour window for the treatment of stroke with clinically available tools such as recombinant tissue plasminogen activator. Considering the encouraging results with whole CB and derived cells transplantation in ischemic injury models and since CB is widely available and have been used clinically, they may be an excellent source of cells for treatment of human brain ischemic disorders.     

促红细胞生成素在脑缺血动物模型治疗中的研究进展

促红细胞生成素是一种促进红系造血前体细胞增殖、分化的细胞因子,主要作用为促进红细胞增殖,应用于临床各种贫血治疗。随着研究进展,学者发现促红细胞生成素为一种多功能营养因子及神经保护因子,具有调节中枢神经系统发育、神经营养及神经保护作用。脑缺血性卒中实验研究显示,促红细胞生成素可有效改善中枢神经系统疾病所致的神经功能缺损,本文主要概述促红细胞生成素在脑缺血性卒中动物模型的研究进展,及其发挥神经保护作用所经由的分子机制。相信随着实验研究进展,其在脑缺血性卒中临床治疗方面将拥有更广阔的前景。     

Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats

In traditional Chinese medicine, Ligusticum wallichii Franchat (Chuan Xiong) and its active ingredient tetramethylpyrazine (TMP) have been used to treat cardiovascular diseases and to relieve various neurological symptoms such as ischemic deficits. However, scientific evidence related to their effectiveness or precise modes of neuroprotective action is largely unclear. In the current study, we elicited the neuroprotective mechanisms of TMP after focal cerebral ischemic/reperfusion (I/R) by common carotid arteries and middle cerebral artery occlusion model in rats. TMP was administrated 60 min before occlusion via intraperitoneal injection. TMP concentration-dependently exhibited significant neuroprotective effect against ischemic deficits by reduction of behavioral disturbance. Neuronal loss and brain infarction in the ischemic side of rats were markedly lowered by treatment with TMP. Cerebral I/R-induced internucleosomal DNA fragmentation, caspase-8, caspase-9, and caspase-3 activation, and cytochrome c release were reduced by TMP treatment. Western blot analysis revealed the down-regulation of Bcl-2 and Bcl-xL and the up-regulation of Bax and Bad by cerebral I/R insult. Among them, only the alteration in Bcl-xL expression was reversed by TMP treatment. Moreover, the activation of microglia and/or recruitment of inflammatory cells within the ischemic side and the consequent production of monocyte chemoattractant protein 1 (MCP-1) were suppressed by TMP pre-treatment. Our findings suggest that TMP might provide neuroprotection against ischemic brain injury, in part, through suppression of inflammatory reaction, reduction of neuronal apoptosis, and prevention of neuronal loss.     

Targeting NGF pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases

Inflammation is the first line of defense against injury and infection and works both by controlling the ongoing pathological processes and by promoting neuroprotection and regeneration. When the inflammatory response is hyper activated, it plays a pivotal role in the pathophysiology of many neurological diseases, as it can also be a source of additional injury to host cells. Since neurons lack the ability to divide and recover poorly from injury, they are extremely vulnerable to auto destructive immune and inflammatory processes, and this side effect is fundamental to the outcome of neurological diseases. Inappropriate immune responses are responsible for diseases such as Multiple Sclerosis (MS), Alzheimer's disease (AD) or Parkinson's disease (PD) and for the increased disability after brain trauma or stroke. However, in certain circumstances immune responses in the brain might have a neuroprotective effect, possibly mediated by the release of trophic factors from inflammatory and/or glial cells. The nerve growth factor (NGF) was the first neurotrophin discovered for its stimulatory effect on differentiation, survival, and growth of neurons in peripheral and central nervous system. This factor can protect axons and myelin from inflammatory damage and also can modulate the immune system, reducing the enhanced excitotoxicity during acute inflammatory activation. Therefore, because its neuroprotective activity and immunomodulatory effects, NGF may represent a new therapeutic approach for the treatment of numerous brain disorders.     

Catalpol protects vascular structure and promotes angiogenesis in cerebral ischemic rats by targeting HIF-1α/VEGF

BackgroundThe initial factor in the occurrence, development, and prognosis of cerebral ischemia is vascular dysfunction in the brain, and vascular remodeling of the brain is the key therapeutic target and strategy for ischemic tissue repair. Catalpol is the main active component of the radix of Rehmannia glutinosa Libosch, and it exhibits potential pleiotropic protective effects in many brain-related diseases, including stroke.PurposeThe present study was designed to investigate whether catalpol protects vascular structure and promotes angiogenesis in cerebral ischemic rats and to identify its possible mechanisms in vivo and in vitro.Study designCerebral ischemic rats and oxygen-glucose deprivation-exposed brain microvascular endothelial cells were used to study the therapeutic potential of catalpol in vivo and in vitro.MethodsFirst, neurological deficits, histopathological morphology, infarct volume, vascular morphology, vessel density, and angiogenesis in focal cerebral ischemic rats were observed to test the potential treatment effects of catalpol. Then, oxygen-glucose deprivation-exposed brain microvascular endothelial cells were used to mimic the pathological changes in vessels during ischemia to study the effects and possible mechanisms of catalpol in protecting vascular structure and promoting angiogenesis.ResultsThe in vivo results showed that catalpol reduced neurological deficit scores and infarct volume, protected vascular structure, and promoted angiogenesis in cerebral ischemic rats. The in vitro results showed that catalpol improved oxygen-glucose deprivation-induced damage and promoted proliferation, migration, and in vitro tube formation of brain microvascular endothelial cells. The HIF-1α (hypoxia-inducible factor 1α)/VEGF (vascular endothelial growth factor) pathway was activated by catalpol both in the brains of cerebral ischemic rats and in primary brain microvascular endothelial cells, and the activating effects of catalpol were inhibited by SU1498.ConclusionThe results of both the in vivo and in vitro studies proved that catalpol protects vascular structure and promotes angiogenesis in focal cerebral ischemic rats and that the mechanism is dependent on HIF-1α/VEGF.     

Neuroprotective effects of VEGF administration after focal cerebral ischemia/reperfusion: dose response and time window

Administration of vascular endothelial growth factor (VEGF) has been shown to increase cerebral blood flow and reduce neurological damage after experimental ischemic brain injury. The purpose of this study was to examine the optimal dose and time window for the neuroprotective effect of VEGF when administrated after focal ischemia/reperfusion injury in rabbits. Focal cerebral ischemia/reperfusion was induced by the middle cerebral artery occlusion (MCAO) method. In a dose response experiment, low (1.25 ng/μL), middle (2.5 ng/μL) and high (5.0 ng/μL) doses of VEGF were administered 2h after MCAO by the route of perifocal region. The VEGF at a dose of middle (2.5 ng/μL) displayed excellent effects on neuroprotective efficacy for focal cerebral ischemia/reperfusion injury. In another experiment, 2.5 ng/μL VEGF was administered at times varying from 2 to 8h after MCAO. Infarct volume, water content and neurological deficits were significantly reduced when VEGF was given at 2 and 3h after injury. The protective effect was less when the same dose was given at the later times. Thus, the present findings indicated that VEGF reduced ischemic neuronal danger with a therapeutic time window within the first 3h of transient MCAO and may be useful in the treatment of acute ischemic stroke in humans.     

Macrophage migration inhibitory factor (MIF) acetylation protects neurons from ischemic injury

Ischemia-induced neuronal death leads to serious lifelong neurological deficits in ischemic stroke patients. Histone deacetylase 6 (HDAC6) is a promising target for neuroprotection in many neurological disorders, including ischemic stroke. However, the mechanism by which HDAC6 inhibition protects neurons after ischemic stroke remains unclear. Here, we discovered that genetic ablation or pharmacological inhibition of HDAC6 reduced brain injury after ischemic stroke by increasing macrophage migration inhibitory factor (MIF) acetylation. Mass spectrum analysis and biochemical results revealed that HDAC6 inhibitor or aspirin treatment promoted MIF acetylation on the K78 residue. MIF K78 acetylation suppressed the interaction between MIF and AIF, which impaired MIF translocation to the nucleus in ischemic cortical neurons. Moreover, neuronal DNA fragmentation and neuronal death were impaired in the cortex after ischemia in MIF K78Q mutant mice. Our results indicate that the neuroprotective effect of HDAC6 inhibition and aspirin treatment results from MIF K78 acetylation; thus, MIF K78 acetylation may be a therapeutic target for ischemic stroke and other neurological diseases.Subject terms: Cell death in the nervous system, Stroke     

血管内皮生长因子的脑保护及其机制研究进展

血管内皮生长因子(vascular endothelial growth factor,VEGF)是一种重要的血管发育调节因子,最早发现于肿瘤细胞。上世纪90年代,人们发现VEGF在神经细胞上也有广泛表达,并具有神经细胞保护作用。此外,VEGF显著促进成年哺乳动物结构性神经元再生区(constitutive neurogenic regions)和非神经元再生区(non-neurogenic regions)的神经元再生/更新(neurogenesis/regenera-tion),显示了VEGF在神经损伤性及退行性疾病治疗中的潜在意义。本文着重讨论VEGF在脑缺血损伤中的神经保护(neuroprotection)和神经修复(neural repair)及其细胞和分子机制研究进展。     

Vascular Endothelial Growth Factor Isoform-B Stimulates Neurovascular Repair After Ischemic Stroke by Promoting the Function of Pericytes via Vascular Endothelial Growth Factor Receptor-1

Ischemic stroke triggers endogenous angiogenic mechanisms, which correlates with longer survival in patients. As such, promoting angiogenesis appears to be a promising approach. Experimental studies investigated mostly the potent angiogenic factor vascular endothelial growth factor isoform-A (VEGF-A). However, VEGF-A increases the risk of destabilizing the brain microvasculature, thus hindering the translation of its usage in clinics. An attractive alternative VEGF isoform-B (VEGF-B) was recently reported to act as a survival factor rather than a potent angiogenic factor. In this study, we investigated the therapeutic potential of VEGF-B in ischemic stroke using different in vivo and in vitro approaches. We showed that the delayed intranasal administration of VEGF-B reduced neuronal damage and inflammation. Unexpectedly, VEGF-B stimulated the formation of stable brain microvasculature within the injured region by promoting the interaction between endothelial cells and pericytes. Our data indicate that the effects of VEGF-B were mediated via its specific receptor VEGF receptor-1 (VEGFR-1) that is predominately expressed in brain pericytes. Importantly, VEGF-B promoted the survival of pericytes, and not brain endothelial cells, by inducing expression of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the main protein involved in energy homeostasis AMP-activated protein kinase α (AMPKα). Moreover, we showed that VEGF-B stimulated the pericytic release of factors stimulating a “reparative angiogenesis” that does not compromise microvasculature stability. Our study unraveled hitherto unknown role of VEGF-B/VEGFR-1 signaling in regulating the function of pericytes. Furthermore, our findings suggest that brain microvasculature stabilization via VEGF-B constitutes a safe therapeutic approach for ischemic stroke.     

急性缺血性脑卒中患者入院时血浆BNP水平与梗死部位关系

目的：分析急性缺血性脑卒中患者入院时血浆脑钠肽（BNP）水平与缺血性脑卒中梗死部位的关系。方法：随机入选88例急性缺血性脑卒中患者,按梗死部位,将其分为前循环病灶组（66名）和后循环病灶组（22名）两组进行比较。测定入院时血浆脑钠肽（BNP）水平进行比较。两组脑卒中病人的危险因素血糖、糖化血红蛋白、血脂全套,肝肾功能分析对比,并将急性缺血性脑卒中患者梗死部位相关的多个变量采用单因素logistic回归分析。结果：前循环病灶组血浆脑利钠肽水平的中位数是225.90 pg/mL,四分位数间距为596.00 pg/mL;后循环病灶组的中位数是750.95 pg/mL,四分位数间距为907.00 pg/mL。后循环病灶组血浆脑利钠肽水平要显著高于前循环病灶组血浆脑利钠肽水平,两个部位间入院时的脑利钠肽水平有统计学差异（P=0.004）。通过入院时脑利钠肽水平与缺血性脑卒中梗死部位的关系的ROC曲线,得出截点299.50 pg/mL。入院时血浆脑利钠肽水平≥299.50 pg/mL可以作为后循环病灶组的预测指标,其敏感性72.72%,特异性62.12%。结论：急性缺血性脑卒中患者入院时血浆BNP水平可作为急性期区别前后循环脑梗死的预测因子。     

Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy

Background aimsTransplantation of mesenchymal stromal cells (MSC) derived from bone marrow (BM) or adipose tissue is expected to become a cell therapy for stroke. The present study compared the therapeutic potential of adipose-derived stem cells (ASC) with that of BM-derived stem cells (BMSC) in a murine stroke model.MethodsASC and BMSC were isolated from age-matched C57BL/6J mice. These MSC were analyzed for growth kinetics and their capacity to secrete trophic factors and differentiate toward neural and vascular cell lineages in vitro. For in vivo study, ASC or BMSC were administrated intravenously into recipient mice (1 × 10⁵ cells/mouse) soon after reperfusion following a 90-min middle cerebral artery occlusion. Neurologic deficits, the degree of infarction, expression of factors in the brain, and the fate of the injected cells were observed.ResultsASC showed higher proliferative activity with greater production of vascular endothelial cell growth factor (VEGF) and hepatocyte growth factor (HGF) than BMSC. Furthermore, in vitro conditions allowed ASC to differentiate into neural, glial and vascular endothelial cells. ASC administration showed remarkable attenuation of ischemic damage, although the ASC were not yet fully incorporated into the infarct area. Nonetheless, the expression of HGF and angiopoietin-1 in ischemic brain tissue was significantly increased in ASC-treated mice compared with the BMSC group.ConclusionsCompared with BMSC, ASC have great advantages for cell preparation because of easier and safer access to adipose tissue. Taken together, our findings suggest that ASC would be a more preferable source for cell therapy for brain ischemia than BMSC.     

Models of focal cerebral ischemia in the nonhuman primate

Ischemic stroke is a uniquely human disease syndrome. Models of focal cerebral ischemia developed in nonhuman primates provide clinically relevant platforms for investigating pathophysiological alterations associated with ischemic brain injury, microvascular responses, treatment responses, and clinically relevant outcomes that may be appropriate for ischemic stroke patients. A considerable number of advantages attend the use of nonhuman primate models in cerebral vascular research. Appropriate development of such models requires neurosurgical expertise to produce single or multiple vascular occlusions. A number of experimentally and clinically accessible outcomes can be measured, including neurological deficits, neuron injury, evidence of non-neuronal cell injury, infarction volume, real-time imaging of injury development, vascular responses, regional cerebral blood flow, microvascular events, the relation between neuron and vascular events, and behavioral outcomes. Nonhuman primate models of focal cerebral ischemia provide excellent opportunities for understanding the vascular and cellular pathophysiology of cerebral ischemic injury, which resembles human ischemic stroke, and the appropriate study of pharmacological interventions in a human relevant setting.     

Yangyin Tongnao granules enhance neurogenesis in the peri-infarct area and upregulate brain-derived neurotrophic factor and vascular endothelial growth factor after focal cerebral ischemic infarction in rats

Yangyin Tongnao granules (YYTNG) have been extensively applied in the treatment of brain injury, mainly due to its antioxidant effects, inhibition of apoptosis, and enhancement of blood circulation. To analyze the effect of YYTNG on the recovery of neurological function and neurogenesis in the peri-infarct area after cerebral ischemic infarction in rats and to elucidate its role in the neuroprotective mechanism of stroke, Sprague–Dawley (SD) rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. Rats were randomly divided into five groups: sham, MCAO, and YYTNG-treated rats given doses of 0.83, 1.65, or 3.3 g kg^?1 day^?1. The YYTNG-treated groups (1.65 and 3.3 g kg^?1 day^?1) showed higher neurological scores and a lower infarct volume than the MCAO group on day 3 after MCAO. Furthermore, the YYTNG-treated groups (0.83, 1.65, and 3.3 g kg^?1 day^?1) showed higher neurological scores on day 7 after MCAO. The number of BrdU⁺/nestin⁺, BrdU⁺/NeuN⁺, and BrdU⁺/GFAP⁺ cells in the peri-infarct area 7 days after MCAO was significantly increased in the YYTNG-treated groups in a dose-dependent manner. The protein expression levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) were significantly higher in all three YYTNG-treated groups than in the MCAO group. Based on these results, administration of YYTNG post ischemia could ameliorate neurological function deficits in rats with MCAO. The therapeutic effect of YYTNG may be due to the promotion of neurogenesis in the peri-infarct area and the upregulation of neuroprotective factors BDNF and VEGF in MCAO rats.

     

Immediate remote ischemic postconditioning reduces cerebral damage in ischemic stroke mice by enhancing leptomeningeal collateral circulation

Remote ischemic postconditioning (RIPC) is a promising neuroprotective strategy for ischemic stroke. Here, we employed a focal ischemic stroke mouse model to test the hypothesis that poststroke collateral circulation as a potent mechanism of action underlying the therapeutic effects of immediate RIPC. During reperfusion of cerebral ischemia, the mice were randomly assigned to receive RIPC, granulocyte colony-stimulating factor (G-CSF) as a positive control, or no treatment. At 24 hr, we found RIPC and G-CSF increased monocytes/macrophages in the dorsal brain surface and in the spleen, coupled with enhanced leptomeningeal collateral flow compared with nontreatment group. Blood monocytes depletion by 5-fluorouracil (5-FU) significantly limited the neuroprotection of RIPC or G-CSF treatment. The protein expression of proangiogenic factors such as Ang-2 was increased by ischemia, but treatment with either RIPC or G-CSF showed no further upregulation. Thus, immediate RIPC confers neuroprotection, in part, by enhancing leptomeningeal collateral circulation in a mouse model of ischemic stroke.     

The Contribution of the Blood Glutamate Scavenging Activity of Pyruvate to its Neuroprotective Properties in a Rat Model of Closed Head Injury

The removal of excess glutamate from brain fluids after acute insults such as closed head injury (CHI) and stroke is expected to prevent excitotoxicity and the ensuing long lasting neurological deficits. Since blood glutamate scavenging accelerates the removal of excess glutamate from brain into blood and causes neuroprotection, we have evaluated here whether the neuroprotective properties of pyruvate could be partly accounted to its blood glutamate scavenging activity. The neurological outcome of rats after CHI improved significantly when treated with intravenous pyruvate (0.9 mmoles/100 g) but not with pyruvate administered together with glutamate. Pyruvate, at 5 μmole/100 g rat was neither protective not able to decrease blood glutamate but displayed the latter two properties when combined with 60 μg/100 g of glutamate-pyruvate transaminase. Since the neurological recovery from CHI was correlated with the decrease of blood glutamate levels, we conclude that pyruvate blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms.     

Notoginsenoside R1 intervenes degradation and redistribution of tight junctions to ameliorate blood-brain barrier permeability by Caveolin-1/MMP2/9 pathway after acute ischemic stroke

BackgroundThe leakage of blood-brain barrier (BBB) is main pathophysiological change in acute stage of ischemic stroke, which not only deteriorates neurological function, but also increases the risk of hemorrhagic transformation after thrombolysis.Purpose/Study DesignThis article investigates the efficacy of Notoginsenoside R1, an active ingredient of Panax notoginseng, on BBB permeability and explores related mechanisms after acute ischemic stroke.MethodsIn vivo, male Sprague-Dawley rats (260–280 g) were selected and randomly divided into 6 groups: sham group, model group, low, middle and high doses of Notoginsenoside R1 groups and positive drug Dl-3-n-Butylphthalide group. Except for sham group, rats were performed with permanent middle cerebral artery occlusion model in each group. Twelve hours later, rats were evaluated for Bederson neurological function, and BBB integrity by Evans blue leak imaging; Triphenyltetrazolium chloride staining was used to detect the volume of cerebral infarction. Frozen sections of rats’ brain tissue were prepared for detection of MMPs activity in situ zymography. Peripheral tissue of cerebral infarction was collected and tested the expression of MMP2, 9 and tight junction proteins (zo1, claudin5, occludin) by western blot. In vitro, transwell endothelial barrier model was established by bEnd.3 cells. Oxygen glucose deprivation (OGD) was chosen to simulate the hypoxic environment. Suitable OGD stimulation time as well as Notoginsenoside R1 and Dl-3-n-Butylphthalide optimal dose concentrations were determined through transwell leakage and CCK8 assay. Furthermore, endothelial subcellular component proteins were extracted. The change of zo1, claudin5, occludin and caveolin1 was detected by western blot.ResultsNotoginsenoside R1 treatment significantly reduced BBB leakage and cerebral infarction volume, weakened neurological deficits in post-stroke rats. Moreover, it inhibited the activity of MMPs in infarcted cortex and striatum, down-regulated MMP2, 9 and up-regulated zo1 and claudin5 expressions in penumbra. In vitro, Notoginsenoside R1 treatment decreased OGD-induced endothelial barrier permeability, restored expressions of zo1, claudin5 on cellular membrane and cytoplasm, as well as mediated membrane redistribution of occludin and caveolin1 from actin cytoskeletal fraction.ConclusionsNotoginsenoside R1 treatment attenuates BBB permeability, cerebral infarction volume and neurological impairments in rats with acute cerebral ischemia. The mechanisms might be related to intervening degradation and redistribution of zo1, caludin5 and occludin by caveolin1/ MMP2/9 pathway. More effects and mechanisms of Notoginsenoside R1 on rehabilitation of stroke are worthy to be explored in the future.     

Vascular and neuronal effects of VEGF in the nervous system: implications for neurological disorders

Vascular endothelial growth factor (VEGF) was originally discovered as an endothelial-specific growth factor. While the predominant role of this growth factor in the formation of new blood vessels (angiogenesis) is unquestioned, recent observations indicate that VEGF also has direct effects on neurons and glial cells, and stimulates their growth, survival and axonal outgrowth. Because of these pleiotropic effects, VEGF has now been implicated in several neurological disorders both in the preterm infant (leukomalacia) and the adult (stroke, neurodegeneration, cerebral and spinal trauma, ischemic and diabetic neuropathy, nerve regeneration). A challenge for the future is to unravel to what extent the effect of VEGF in these disorders relates to its angiogenic activity or direct neurotrophic effect.     

Sirt3 Protects Against Ischemic Stroke Injury by Regulating HIF-1α/VEGF Signaling and Blood–Brain Barrier Integrity

Sirtuin 3 (Sirt3) is a member of the Sirtuin family proteins and known to regulate multiple physiological processes such as metabolism and aging. As stroke is an aging-related disease, in this work, we attempt to examine the role and potential mechanism of Sirt3 in regulating ischemic stroke by using a permanent middle cerebral artery occlusion (pMCAO) model in wild type (WT) and Sirt3 knockout (KO) mice, coupled with oxygen glucose deprivation (OGD) experiments in cultured primary astrocytes. Sirt3 deficiency aggravated neuronal cell apoptosis and neurological deficits after brain ischemia. In addition, Sirt3 KO mice showed more severe blood–brain barrier (BBB) disruption and inflammatory responses compared with WT group in the acute phase. Furthermore, specific overexpression of Sirt3 in astrocytes by injecting glial fibrillary acidic protein (GFAP)::Sirt3 virus in ischemic region showed protective effect against stroke-induced damage. Mechanistically, Sirt3 could regulate vascular endothelial growth factor (VEGF) expression by inhibiting hypoxia inducible factor-1α (HIF-1α) signaling after ischemia (OGD). Our results have shown that Sirt3 plays a protective role in ischemic stroke via regulating HIF-1α/VEGF signaling in astrocytes, and reversal of the Sirt3 expression at the acute phase could be a worthy direction for stroke therapy.