缺血性卒中后神经发生的现状与展望

对神经元发生的机制、神经元发生的影响因素、神经干细胞移植和基因治疗等方面的进展作了简要的回顾和展望.     

缺血性卒中神经保护治疗的临床研究现状

文章介绍了钙通道滞剂、兴奋性氨基酸受体拮抗剂、抗氧化剂、自由基清除剂等常用的神经保护药及低温疗法神经保护治疗的最新临床研究进展。     

神经干细胞移植治疗缺血性脑卒中的研究进展

缺血性脑卒中是严重威胁人类健康的常见病和多发病,具有高致残率、致死率。目前常见的临床治疗主要集中在改善脑循环的多种措施,如溶栓、抗血小板聚集、抗凝、降纤、扩容等,其神经元的不可逆性损伤是治疗难以取得满意效果的主要原因。近年来,体外分离、培养具有自我更新、分化潜能的神经干细胞等相关技术逐渐成熟。越来越多的研究证据显示,将神经干细胞移植入缺血性脑卒中动物模型,能够达到有效治疗效果。本文就神经干细胞生物学特性、神经干细胞移植治疗缺血性脑卒中的机制及其进展方面进行综述。     

缺血性卒中神经保护治疗的临床研究现状

文章介绍了钙通道阻滞剂、兴奋性氨基酸受体拮抗剂、抗氧化剂、自由基清除剂等常用的神经保护药及低温疗法神经保护治疗的最新临床研究进展。     

神经干细胞移植治疗缺血性脑卒中研究进展

缺血性脑卒中是严重威胁人类健康的常见病和多发病,虽然目前使用的超早期溶栓和急性期神经元保护疗法取得了重大进展,但这些治疗措施受到很多限制,只有少数患者得益于此治疗,对大多数脑卒中患者而言,神经元死亡已不可避免,如何积极有效地促进神经功能的恢复仍然是,     

神经干细胞移植治疗缺血性脑卒中后遗症的实验研究

目的研究神经干细胞移植对缺血性脑卒中大鼠模型（tM CAO）后遗症的修复作用,并确定移植的最佳时机。方法神经干细胞经抗5-溴脱氧尿核苷标记后,在不同时间采用立体定向移植到大鼠的脑缺血区域,移植后对大鼠的功能恢复进行评价,免疫组织化学方法染色检查存活的细胞。结果术后8周起,移植组大鼠神经损伤严重程度评分（N SS）明显低于对照组。其中早期移植组大鼠的N SS评分低于超早期移植组和晚期移植组（P〈0.05）。结论神经干细胞移植能改善脑缺血后大鼠的神经功能状况,早期移植治疗效果更佳。     

缺血性心脏病细胞移植疗法的理想工具--骨髓基质干细胞

骨髓基质干细胞是一种由骨髓中分离获得的具有多种分化潜能的间质干细胞。在体外培养条件下，它可以分化为成骨细胞、软骨细胞、脂肪细胞、甚至于成肌细胞。因为骨髓基质干细胞具有易于获取、分高方便和良好的分化特性等特点，在细胞移植和基因治疗方面具有非常巨大的应用前景。对于缺血性心脏病而言，骨髓基质干细胞是非常好的细胞移植供体，对于改善心功能帮助巨大。本文献骨髓基质干细胞的生物学特性和在缺血性心脏病治疗中的应用前景进行简要综述。     

神经干细胞移植治疗缺血性脑卒中的研究进展

缺血性脑卒中是严重威胁人类健康的常见病和多发病，虽然目前使用的超早期溶栓和急性期神经元保护疗法取得了重大进展，但这些治疗措施受到很多限制，只有少数患者得益于此治疗，对大多数脑卒中患者而言，神经元死亡已不可避免，如何积极有效地促进神经功能的恢复仍然是目前脑卒中研究的重点。     

神经保护剂治疗急性缺血性卒中临床研究近况

使用神经保护剂是治疗急性缺血性卒中的重要方法之一。文章介绍了近年来神经保护剂临床研究进展。     

骨髓干细胞移植治疗缺血性心脏病的现状与前景

心肌梗死后的瘢痕形成及心室重塑严重影响缺血性心脏病人的预后,而常规治疗手段又往往难以奏效,因此关于干细胞移植等的临床研究越来越多,现就骨髓干细胞的分类、移植方法和遇到的问题、前景等作简要介绍.     

The role of angiogenesis in damage and recovery from ischemic stroke

Opinion statement 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-γ 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 therapeutic applicability in human brain ischemia.     

骨髓基质细胞治疗缺血性卒中的机制

骨髓基质细胞(bone marrow stromal cell,BMSC)是骨髓内的一类非造血干细胞,具有自我复制能力和多向分化潜能,是细胞移植治疗各种疾病的理想细胞来源.大量动物模型实验表明,BMSC移植能通过多种机制促进脑缺血后脑结构和功能的恢复,为脑血管病的治疗提供了新的思路和方法.文章就近年来BMSC治疗缺血性...     

Optogenetic neuronal stimulation promotes functional recovery after stroke

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area’s excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.Stroke is a major acute neurological insult that disrupts brain function and causes neuron death. Functional recovery after stroke has been observed and is currently attributed to both brain remodeling and plasticity (1–4). Structural and functional remodeling of areas next to an infarct or remote regions can alter signaling within bilateral neuronal networks and thus contribute to functional recovery (3–7). Rewiring of neural connections is mediated by electrical activity, which can activate a number of plasticity mechanisms, including the release of activity-dependent neurotrophins such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) (8–10). Both BDNF and NGF have been shown to improve recovery by enhancing axonal and dendritic sprouting (10–12).Tremendous effort has been focused on promoting recovery after stroke, including pharmacological treatment, rehabilitation (e.g., constraint-induced therapy), stem cell transplantation, and brain stimulation (1, 4, 13). Brain stimulation is a promising area of research because it allows direct activation and manipulation of the target area’s excitability (14–16). The primary motor cortex (M1) is a commonly stimulated area as it directly innervates the corticospinal tract to initiate movement (1, 7). Although electrical stimulation and transcranial magnetic stimulation show promise in promoting recovery (17, 18), these techniques are limited by imprecision and indiscriminate activation or inhibition of all cell types near the stimulated site; thus, they can produce undesired effects such as psychiatric and motor/speech problems (19–21). In addition, it has been difficult to elucidate the cell type and mechanisms driving recovery, as multiple cell types such as neurons, astrocytes, and oligodendrocytes have been shown to contribute to remodeling and recovery processes after stroke (5, 22–27).To elucidate whether activation of neurons alone can promote recovery, we used optogenetics to selectively manipulate the excitability of specific cell groups with millisecond-scale temporal precision in a manner more similar to endogenous neuronal firing patterns (21, 28, 29). This technique uses light-activated microbial proteins such as Channelrhodopsin 2 (ChR2), which depolarizes neurons when illuminated with blue light, or Halorhodopsin (NpHR), which hyperpolarizes neurons (21, 28, 29). Optogenetic approaches have been used in rodents to probe neuronal circuits for several neurological/neurodegenerative diseases, including Parkinson disease (30) and epilepsy (31). Recent studies have also used optogenetics to map functional organization after stroke (32–35). The safety and efficacy of using optogenetics in nonhuman primates has also been characterized (29, 36).In this study, we used optogenetics to selectively stimulate neurons in layer V of the ipsilesional primary motor cortex (iM1) and examine the effects of repeated neuronal stimulations in normal and stroke mice. Sensory-motor behavior tests were used to evaluate functional recovery after stroke, and plasticity-associated mechanisms, such as cerebral blood flow (CBF)/neurovascular coupling responses and activity-dependent neurotrophin expression, were investigated.     

Mobilization,endothelial differentiation and functional capacity of endothelial progenitor cells after ischemic stroke

Endothelial progenitor cells (EPCs) have introduced new possibilities for cell-based vasculogenesis treatment after stroke. In this study we quantified circulating levels of EPCs in stroke patients and in healthy controls, and evaluated the potential of EPCs to induce vasculogenesis in vitro. Blood was drawn from tPA-treated stroke patients and control subjects, and the circulating EPCs levels in each group were quantified by flow cytometry and cell culture assays. Immunophenotyping was performed using multiple markers (UEA-lectin, CD133, vWF and KDR) and tubulogenic function was assessed with the Matrigel® assay. The produced angiogenic factors were quantified by multiple ELISA and RT-PCR. Fluorescence-activated cell sorting (FACS) revealed higher levels of circulating CD133+/CD34+/KDR+/CD45+ cells in the acute strokes as compared to the control subjects (p = 0.02). On the other hand, more EPCs grew in cell culture from subacute strokes (p = 0.016) than from controls. The endothelial and progenitor lineages of the EPCs were confirmed by immunophenotyping. Interestingly, the appearance of outgrowth EPCs (OECs) correlated positively to stroke severity (p = 0.013). Finally, greater capacity to induce vasculogenesis in vitro was found in EPCs from subacute strokes (p = 0.03), which we attribute to a higher expression and secretion of angiogenic factors. Our results suggest an early EPC mobilization but an enhanced angiogenic function in the subacute phase of stroke. Nonetheless, development of cell-based therapy for stroke will require further studies to identify those EPCs with the greatest therapeutic potential.     

吸烟状况与急性缺血性脑卒中后功能结局的关系

吸烟是脑卒中的既定危险因素;然而,脑卒中前吸烟状态是否会影响急性缺血性脑卒中的临床预后尚不确定。该研究旨在阐明吸烟状态与急性缺血性脑卒中后功能预后的关系。研究者获取一项基于日本多中心医院的脑卒中登记资料,调查了2007年7-12月期间住院的10825例急性缺血性脑卒中患者,这些患者在脑卒中发作之前生活能够自理。吸烟状况分为从未吸烟者(不吸烟者),曾经吸烟者和现在吸烟者。临床结局包括3个月时功能转归不良(改良的Rankin量表评分≥2)和功能性依赖(改良的Rankin量表评分2~5)。     

阿尔伯特CT评分预测缺血性脑卒中患者功能恢复的研究

目的探讨阿尔伯特CT评分(the Alberta Stroke Program CT Score,ASPCTS)在预测大脑中动脉梗死患者神经功能恢复中的作用。方法首次大脑中动脉梗死患者70例,根据ASPCTS分为0～2分组(16例)、3～6分组(13例)和7～10分组(41例),同时进行美国国立卫生院脑卒中量表(NIHSS)评分,发病3个月末以改良的Rankin量表(modified rankin scale,MRS)衡量患者神经功能恢复情况。结果 ASPCTS与NIHSS呈显著负相关(r=-0.927,P=0.000)。ASPCTS、年龄和性别与3个月预后相关,OR值分别为0.263、1.069和6.398。0～2分组患者3个月末死亡的可能性最大,3～6分组患者生活依赖的可能性最大,7～10分组患者绝大部分生活独立,其与实际结局的符合率为87%。结论根据ASPCTS可以预测大脑中动脉梗死患者3个月末的结局。     

Association between course of blood pressure within the first 24 hours and functional recovery after acute ischemic stroke

STUDY OBJECTIVE: The relation between course of blood pressure within the first 24 hours after acute stroke and early neurologic outcome remains a matter of dispute. We investigate this relation with adjustment for other influencing variables. METHODS: Three hundred seventy-two patients with the diagnosis of ischemic stroke were included to evaluate the relation between blood pressure course and early neurologic outcome. The following data were collected: age; sex; history of hypertension, diabetes mellitus, hyperlipidemia, coronary heart disease, peripheral vascular disease, and stroke; smoking habits; preadmission blood pressure, blood pressure on admission, and blood pressure 24 hours later; antihypertensive treatment; and stroke localization. We assessed outcome at day 5 after admission as dependent or independent (Rankin Scale score 相似文献   

Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats

We tested the hypothesis that intravenous infusion of human bone marrow stromal cells (hMSCs) promotes vascular endothelial growth factor (VEGF) secretion, VEGF receptor 2 (VEGFR2) expression and angiogenesis in the ischemic boundary zone (IBZ) after stroke. hMSCs (1x10(6)) were intravenously injected into rats 24 hours after middle cerebral artery occlusion (MCAo). Laser scanning confocal microscopy (LSCM), immunohistochemistry and ELISA were performed to assay angiogenesis and levels of human and rat VEGF in the host brain, respectively. In addition, capillary-like tube formation was measured using mouse brain-derived endothelial cells (MBDECs). Morphological and three dimensional image analyses revealed significant (P<0.05) increases in numbers of enlarged and thin walled blood vessels and numbers of newly formed capillaries at the boundary of the ischemic lesion in rats (n=12) treated with hMSCs compared with numbers in rats (n=12) treated with PBS. ELISA measurements showed that treatment with hMSCs significantly (P<0.05) raised endogenous rat VEGF levels in the IBZ from 10.5+/-1.7 ng/mL in the control group to 17.5+/-1.6 ng/mL in the hMSC-treated group. In addition, treatment with hMSCs increased endogenous VEGFR2 immunoreactivity. In vitro, when MBDECs were incubated with the supernatant obtained from cultured hMSCs, capillary-like tube formation was significantly (P<0.01) induced. However, hMSC-induced capillary-like tube formation was significantly (P<0.01) inhibited when the endothelial cells were incubated with the supernatant from hMSCs in the presence of a neutralizing anti-VEGFR2. These data suggest that treatment of stroke with hMSCs enhances angiogenesis in the host brain and hMSC-enhanced angiogenesis is mediated by increases in levels of endogenous rat VEGF and VEGFR2.     

骨髓单个核细胞移植对大鼠脑梗死后影响的初步研究

目的研究骨髓单个核细胞(BMMNC)移植对大鼠脑梗死后损伤的保护作用以及相关机制。方法雄性SD大鼠96只随机分为假手术组、模型组、环氧化酶2(COX-2)抑制剂组(NS398 20mg/kg)和BMMNC组(1×10~7个BMMNC),每组24只。采用改良线栓法制备大脑中动脉永久闭塞模型,分别于模型成功后24、72h和7d取材观察,每个时间点8只。采用Zea-Longa法进行神经功能评分;TTC染色法测脑梗死体积;免疫组织化学染色和Western blot技术检测COX-2、白细胞介素1β(IL-1β)表达。结果 BMMNC组24、72h和7d时脑梗死体积明显低于模型组(P0.05);COX-2蛋白表达[(0.133±0.032)vs(0.342±0.042)、(0.141±0.035)vs(0.362±0.062)、(0.150±0.032)vs(0.330±0.050),P0.05]和IL-1β蛋白表达[(0.213±0.045)vs(0.272±0.055)、(0.231±0.087)vs(0.331±0.105)、(0.134±0.030)vs(0.163±0.053),P0.05]水平明显低于模型组,BMMNC组与COX-2抑制剂组上述指标无显著差异(P0.05)。结论 BMMNC移植可通过抑制脑内免疫炎性反应,显著改善脑梗死大鼠的神经功能,可能与下调COX-2、IL-1β表达有关。