细胞因子信号转导抑制因子-3与缺血性脑损伤

新近的研究表明,缺血性脑损伤后的炎症反应不仅受促炎因子的影响,而且还与负反馈调节因子的调控密切相关[1].细胞因子信号转导抑制因子-3(suppressors of cytokinesignaling-3,SOCS-3)在缺血性脑损伤发生、发展的病理过程中起重要作用,其机制亟需深入地研究.本文现就其生物学特征及其与缺血性脑损伤的关系做一综述.     

JAK2/STAT3信号转导通路在缺血性脑损伤中作用机制的研究

目的 探讨磷酸化JAK2、磷酸化STAT3蛋白在局灶性脑缺血再灌注损伤后的表达及JAK2-STAT3信号转导通路在缺血性脑损伤中的作用.方法 采用大脑中动脉线栓法制作大鼠局灶性脑缺血再灌注损伤模型,应用Western blotting检测大鼠局灶性脑缺血再灌注损伤后磷酸化JAK2、磷酸化STAT3蛋白表达水平的变化.利用原位缺口末端标记法(TUNEL法)研究神经细胞凋亡的变化.同时应用JAK2特异性抑制剂AG490观察其影响.结果 大鼠局灶性脑缺血再灌注损伤后,再灌注损伤3h P-JAK2、P-STAT3蛋白可见少量表达,12h表达增强,24h达高峰,以后逐渐下降,168h后仍有少量表达.缺血再灌注损伤后凋亡细胞也显著增多,再灌注24～48h达高峰,凋亡细胞的变化与磷酸化JAK2、磷酸化STAT3蛋白表达变化一致.应用JAK2特异性抑制剂AG490不但阻断JAK2的磷酸化、STAT3的酪氨酸磷酸化,而且具有抗细胞凋亡作用.结论 脑缺血再灌注损伤后可引发JAK2、STAT3的活化,JAK2/STAT3信号通路可能参与了脑缺血再灌注损伤机制.     

细胞凋亡与缺血性脑损伤

细胞凋亡与缺血性脑损伤许金明郑惠民作者单位：２００４３３上海第二军医大学长海医院神经内科脑血管病以其高发病率、高死亡率、高致残率而严重危害人类健康，已成为２０世纪９０年代三大死亡原因之一，据全军脑血管病流行病研究协作组１９８６年调查的结果，我国脑血管...     

神经干细胞与缺血性脑损伤

介绍神经干细胞及其在缺血性脑损伤中的作用     

溶血磷脂酸与缺血性脑损伤

溶血磷脂酸 (LPA)是一种细胞间磷脂信使 ,主要产生于血栓形成过程中被激活的血小板 ,可通过G蛋白偶联受体引起多种生物学效应。其中 ,对脂质乙酰化代谢、血液循环及神经细胞损伤的作用亦存在于缺血性卒中发生发展的代谢级联中 ,提示LPA可能在缺血性脑损伤中起重要作用     

信号转导与蛛网膜下腔出血早期脑损伤

蛛网膜下腔出血(subarachnoid hemorrhage,SAH)是一种破坏性脑血管疾病,导致高死亡率和致残率,在临床上,大多数死亡发生在SAH发病后的几个小时以内,并且许多幸存者遗留认知缺陷,永久影响其功能状态和生活质量.     

JAK-STAT信号转导通路与脑卒中关系研究进展

JAK-STAT(Janus激酶-信号转导子和转录激活子)信号通路是近年来新发现的一条起干扰素作用的胞内信号转导通路。尽管对该信号通路的研究尚未十分透彻,但近年来发展却十分迅速,目前已明确其是细胞因子信号转导的重要通路之一,不仅参与炎症反应,同时也与氧化应激、细胞损伤、凋亡等密切相关[1-3]。最近有报道表明,JAK-STAT通路不仅参与了神经细胞的分化、生长发育及衰老等生理过程,而且也参与了一些神经系统疾病的病理过程,尤其与脑缺     

转化生长因子β与缺血性脑损伤

转化生长因子β（ＴＧＦβ）是由１１２个氨基酸残基组成的分了量为２５ＫＤ的双聚体活性多肽,与细胞膜上相应的三种受体结合而发挥作用。脑缺血后ＴＧＦβ表达明显增加,ＴＧＦβ可抵御脑缺血损伤,其作用机制可能与ＴＧＦβ稳定细胞内钙浓度,拮抗兴奋性氨基酸的神经毒性、抗氧化、抗细胞凋亡和促血管增生等方面有关。     

NF-кB与缺血性脑损伤

核因子-kB(nuclear factor-kappa B,NF-kB)是存在于多数细胞中调控许多基因表达的核转录因子之一。NF-kB在中枢神经系统中的神经塑形、神经发育及神经变性过程中具有独特的作用。脑缺血诱导了NF-kB的激活,活化的NF-kB参与了脑缺血损伤后的炎性反应,且可能与神经细胞死亡机制有关。NF-kB将为缺血性脑损伤病理生理机制及治疗药物的研究开辟新途径。     

癫痫与JNK信号转导通路关系

信号通路是目前癫痫研究的主要方向,尤其是丝裂原活化蛋白激酶家族(mitogen activated protein kinases,MAPKs).该家族包括细胞外信号激酶(extraeellular signal-regulated protein kinase,ERK)、c-Jun氨基端激酶(c-Jun N-terminal kinase,JNK)、p38等,其在神经系统中广泛表达,受各种细胞外刺激,影响突触传递、神经重塑、形态分化和存活等,造成神经元的凋亡、苔藓纤维出芽、胶质增生等病理改变.     

缺血性脑损害病理生理过程的炎症反应

缺血性脑损害的病理生理过程分3个时期：急性期、亚急性期及慢性期.在不同的时期,不同的炎症反应及炎症细胞参与缺血性脑损害的时间及作用各异,表现为时间依赖性.识别不同时期炎症反应特点有助于针对不同的靶点采取抗炎治疗,有助于临床更有效地防治和减轻脑缺血再灌注性脑组织损害.     

Anoxic depolarization determines ischemic brain injury

Abstract

To clarify the role of anoxic depolarization (AD) in ischemic brain injury, we examined the correlation between AD and ischemia-induced neuronal injury. Twenty-eight rats underwent transient forebrain ischemia with lowering of blood pressure and bilateral carotid occlusion while direct current shiftslelectrocorticogram, and cortical blood flow (COBF) were epidurally recorded from the right parietal cortex. One week later the right parietal cortex was studied histopathologically. AD appeared 0.5-3.0 min after carotid occlusion in 21 of28 animals. Circulation was reinitiated 75 min afterAD onset in 77 rats (group A) and 10 min after onset in 70 rats (group B). AD did not develop during 20 min of ischemia in 7 rats (group C). All 72 rats (6 from group A and 6 from group B) in which CoBF decreased below 9.5% of control flow exhibited AD. Histopathologic examination disclosed massive neuronal necrosis in 5 of the 6 group A animals with marked flow reduction but in none from group B. CoBF fell between 9.5% and 20% in 74 rats, among these, AD appeared in 9 (5 from group A and 4 from group B) but not in 5 (group C). Massive neuronal necrosis was demonstrated in 3 of5 rats from group A. Ischemic neuronal changes were absent or minimal in only 7/5 ofgroup A animals, a much lower fraction than in group B (4/4, p<0.05) or in group.C (5/5/, p<0.05). When CoBF remained above 20% of control flow during ischemia (2 rats) no AD or irreversible injury occurred. The present study suggests that AD is a more reliable determinant of irreversible brain injury than degree of CBF reduction, and also demonstrates that 75 min is the critical duration of AD for irreversible brain injury at brain temperatures around 37° C. [Neural Res 1998; 20: 343-348]     

缺血性脑损伤诱导大鼠巢蛋白表达的实验研究

目的探讨缺血性脑损伤对内源性神经干细胞增殖、迁移的影响。方法选用健康雄性SD大鼠62只，随机分为正常组（6只）、脑缺血10min再灌流1、3、5、7、10、15、20d组（简称手术组，每时间点6只）、假手术对照组（14只，每时间点2只），参照Pulsinelli—Brierley方法制作短暂性全脑缺血动物模型：用SABC免疫组化法显示巢蛋白（nestin）阳性细胞；光镜下观察nestin阳性细胞的形态学变化并计数，半定量分析脑缺血损伤后内源性神经干细胞增殖、迁移的变化过程。结果手术组的nestin阳性细胞在缺血再灌流24h后表达增多，7～10d到高峰，15d时仍有显著表达；在室管膜下区的nestin阳性细胞有向皮质、海马迁移的迹象。结论缺血性脑损伤能诱导内源性神经干细胞增殖，这可能对脑损伤后的修复发挥作用。     

鼠脑缺血性损伤程度与缺血时间的关系研究

目的 探讨大脑中动脉（ＭＣＡ）闭塞时因侧不同部位的病理演变特。研究一损伤程度与缺血时间的。方法 利用线栓法ＭＣＡ闭塞模型,采用ＨＥ染色,光镜电镜观察ＭＣＡ闭塞不同时相点缺血侧基底节区、皮质和海马的损伤特征,并直接对坏死和暗神经元计数,运用对数方程作出脑损伤程度－缺血时间关系曲线,运算ＥＴ５０值。结果 因３０分钟坏死神经元首先出现在缺血侧基底节区,以后逐渐扩展到皮质,至缺血２４小时后,缺血中心逐步出     

Acupuncture activates signal transduction pathways related to brain-tissue restoration after ischemic injury

A middle cerebral artery occlusion-model was established in rats using the improved thread embolism method.Rats were treated with acupuncture at either Dazhui(DU14),Renzhong(DU26), Baihui(DU20),or a non-meridian point.Detection with protein-chip technology showed that the level of protein phosphorylation in both groups was upregulated or downregulated depending on the signaling pathway compared with the model group that did not receive acupuncture.Analysis of proteins showing downregulated phosphorylation revealed that five signaling pathways were activated in the acupuncture-treatment group,while only two were activated in the acupuncture-control group.In contrast,analysis of proteins showing upregulated phosphorylation revealed only one pathway was activated in the acupuncture-treatment group,whereas four pathways were activated in the acupuncture-control group.Furthermore,the number of activated proteins in the acupuncture-treatment group was not only higher than the acupuncture-control group,but unlike the acupuncture-control group,the majority of activated proteins were key proteins in the signaling pathways.Our findings indicate that acupuncture at specific points can activate multiple signaling pathways to promote the restoration of brain tissue following ischemic injury,and that this is based on a combination of effects resulting from multiple pathways,targets,and means.     

Protein kinase C activation generates superoxide and contributes to impairment of cerebrovasodilation induced by G protein activation after brain injury

Previous studies have observed that activation of protein kinase C (PKC) contributes to generation of superoxide anion (O(-)(2)) after fluid percussion brain injury (FPI). This study was designed to characterize the effects of FPI on the vascular activity of two activators of a pertussis toxin sensitive G protein, mastoparan and mastoparan-7, and the role of PKC dependent O(-)(2) generation in such effects in newborn pigs equipped with a closed cranial window. Mastoparan (10(-8), 10(-6) M) elicited pial artery dilation that was blunted by FPI and partially restored by the PKC inhibitor chelerythrine (10(-7) M) or the O(-)(2) free radical scavengers polyethylene glycol superoxide dismutase and catalase (SODCAT) (9+/-1 and 16+/-1, sham control; 3+/-1 and 5+/-1, FPI; and 7+/-1 and 11+/-1%, FPI SODCAT pretreated). Similar results were observed for mastoparan-7 but the inactive analogue mastoparan-17 had no effect on pial artery diameter. Exposure of the cerebral cortex to a xanthine oxidase O(-)(2) generating system blunted mastoparan induced pial artery dilation similar to FPI (10+/-1 and 17+/-1 vs. 2+/-1 and 3+/-1%). Pertussis toxin (1 microg/ml) exposure blocked mastoparan and mastoparan-7 vasodilation. These data show that pertussis toxin sensitive G protein activation elicits cerebrovasodilation that is blunted following FPI in a PKC dependent manner. These data also show that O(-)(2) generation similarly blunts G protein mediated cerebrovasodilation. These data suggest that PKC dependent O(-)(2) generation contributes to impaired G protein mediated cerebrovasodilation after FPI.     

炎症反应介导缺血性脑损伤的机制研究进展

脑缺血诱导的缺血性脑损伤涉及一系列复杂的病理生理机制,包括兴奋性氨基酸中毒、离子稳态的失衡、梗死周边区去极化、血脑屏障的破坏、自由基损伤、炎症反应、神经元凋亡等,这些不同的病理生理机制在缺血脑组织中呈现时间、空间变化的动态过程[1].     

G蛋白信号传导通路和颅内动脉瘤的关系

目的 采用基因芯片技术探讨G蛋白信号传导通路与颅内动脉瘤的相关性.方法 采集50例颅内动脉瘤患者的外周血.且将10例正常成人作为对照组.分离其血液单核细胞,另外收集6例手术切除的颅内动脉瘤组织标本和3例正常成人的脑动脉血管.提取总RNA,分别与含22 215个人类基因的寡核苷酸基因芯片杂交、洗脱、染色和扫描,分析检测数据.荧光定量RT-PCR法验证芯片检测结果.结果 在检测的22 215个基因中,颅内动脉瘤患者血液中共差异表达的基因有325个,颅内动脉瘤组织中差异表达水平均达2倍以上的基因有571个,生物信息学分析发现多个G蛋白信号传导通路的相关基因存在上调或下调表达.其中3个基因在动脉瘤组织和血液中均有差异表达,即上调表达的RAB31和下调表达的ARHGAP8和CENTG2.结论 G蛋白信号传导通路可能是颅内动脉瘤的一种重要发病机制,RAB31、ARHGAP8和CENTG2与颅内动脉瘤的关系值得进一步研究.     

局灶性脑缺血大鼠脑内mdr1/P-glycoprotein表达的变化

目的观察大鼠局灶性脑缺血损害后脑内mdr1／P—glycoprotein的表达变化。方法大鼠大脑中动脉栓塞法(MCAO法)制作局灶性脑缺血模型,脑切片免疫组织化学染色检测mdr-1／P—glycoprotein在脑内的表达部位及表达时程的变化。结果 mdr-1／P—glycoprootein在缺血侧皮层和纹状体的血管内皮细胞表达增多,并出现在同侧损伤部位的神经元,其在损伤后2h开始出现,6h达到高峰,之后开始下降,到24h不能被检测到。结论大脑中动脉阻塞后可以诱导缺血损伤侧的血管内皮细胞P—glycoprotein过量表达,而同侧的神经元短暂表达P-glyco- protein．