星形胶质细胞激活与创伤性颅脑损伤研究进展

神经胶质细胞作为中枢神经系统中分布最为广泛的一类细胞,对神经元具有支持、保护、营养、形成髓鞘和修复等多种功能。星形胶质细胞作为神经胶质细胞中的一种,已有大量研究证实其在创伤性脑损伤和神经退行性病变中具有重要作用。文中结合相关文献综述介绍创伤性颅脑损伤后星形胶质细胞激活的病理过程及其中潜在的细胞及分子机制     

反应性星形胶质细胞与轴突再生

星形胶质细胞是中枢神经系统中最丰富的胶质细胞类型,中枢神经系统损伤后,星形胶质细胞在形态和分子表达上发生变化形成反应性星形胶质细胞。反应性星形胶质细胞对轴突再生有着双重影响。一方面,反应性星形胶质细胞能分泌神经营养因子,具有神经保护和修复作用;另一方面,反应性星形胶质细胞若过度增殖形成胶质瘢痕,则抑制轴突再生,不利于神经功能恢复。     

反应性星形胶质细胞对脑缺血神经元的保护

近年来研究发现星形胶质细胞在脑缺血后异常活跃。它可通过分泌生长因子、细胞因子、识别分子等修复损伤的神经元,促进轴突再生及诱导再生神经元的迁移。起到恢复神经系统正常功能的作用。现综述如下。1 星形胶质细胞损伤对神经元的影响近10年研究表明神经胶质细胞在神经系统发育、突触传递、神经组织的修复与再生、神经免疫及多种神经疾病的病理机制中都起着十分重要的作用。用选择性胶质毒素Fluorocitrate(FC)注射入无损伤的鼠脑,造成早期胶质细胞功能紊乱,而产生类似缺血半影区的改变,而且发现在缺乏正常胶质细胞时神经元对扩散性…     

反应性星形胶质细胞增生在脑缺血中的作用

星形胶质细胞(AST)是中枢神经系统主要的细胞.当CNS受到损伤时,AST从静止状态下活化,形成反应性星形胶质细胞增生,如损伤严重将形成胶质疤.本文就星形胶质细胞的生理作用,反应性胶质细胞增生的定义、机制、作用以及在脑缺血中的治疗做一综述.     

多发性硬化星形胶质细胞免疫调节作用研究进展

星形胶质细胞(astrocyte,AST)在多环节参与多发性硬化(multiple sclerosis,MS)的发生发展.AST通过表达Toll样受体及dsRNA依赖的蛋白激酶介导中枢神经系统(CNS)固有免疫,并且通过表达组织相容性复合物Ⅱ类分子(major histocompatibility antibody,MHCⅡ),分泌细胞因子参与CNS获得性免疫反应.体内外研究均表明AST表达MHCⅡ类分子受多种因素调控.MHCⅡ反式激活因子(classⅡMHC transacti-vator,CITTA)在AST表达MHCⅡ类分子的信号通路中起重要作用.     

星形胶质细胞在大脑血流量调节中的作用

功能性脑血流量增多以适应神经代谢功能的需要已有大量研究 ,但神经细胞在脑血流量中的调节作用尚有等进一步阐明。目前研究发现由星状胶质细胞衍生的环氧廿烷三烯酸 (epoxyeicosatrienoicacids,EETs)酶有扩张脑血管的作用 ,大脑微循环血管迅速扩张后 ,使血液流向代谢活跃的神经元区 ,以此来调节大脑血流量。现就其可能的调节机理特点作一综述     

中枢神经系统中星形胶质细胞活化机制的研究进展

星形胶质细胞在中枢神经系统(CNS)中含量丰富,对神经元起着支持、营养、修复等多种重要作用.在CNS损伤或外源性物质作用时,星形胶质细胞发生活化.JAK-STAT3、核因子κB(NF-κB)、丝裂原活化蛋白激酶(MAPK)、TGF-β/Smad等多条信号通路共同作用,调节星形胶质细胞内相应基因的转录与表达.探究星形胶质...     

神经系统损伤后星形胶质细胞激活的研究进展

中枢神经系统损伤后星形胶质细胞的反应对创伤愈合具有重要作用。文中就损伤后星形胶质细胞激活、增生和迁移的调控机制及信号通路进行综述。     

星形胶质细胞在颞叶癫痫发病过程中的作用研究进展

<正>癫痫是人类一种慢性脑功能障碍综合征,病因复杂,临床表现多样,发病机制尚未完全阐明,具有三大病理学特征:神经元凋亡,苔藓纤维出芽和胶质增生。一般认为,癫痫的直接原因是大脑神经元的过度兴奋,进而经过大脑扩散导致癫痫发作。颞叶癫痫(temporal lobe epilepsy,TLE)是各种癫痫综合征最常见的类型,严重影响患者正常的生活、工作和学习,是中枢神经系统疾病中的一大顽症。研究TLE     

星形胶质细胞对神经回路形成作用研究进展

星形胶质细胞(astrocytes, Ast)是哺乳动物大脑中含量最多的神经胶质细胞,它在维持血脑屏障、调节局部血流量、抗氧化和代谢支持以及神经回路的形成上起着重要的作用。星形胶质细胞可以通过各种分泌信号控制突触的形成、成熟和修剪。近年来,在突触缺陷所引起的一系列神经精神疾病中也可以发现星形胶质细胞的身影,了解星形胶质细胞在神经回路发育和功能的调控,有助于对这一系列健康疾病问题提供新的治疗手段。神经回路的形成主要包括三个过程,首先,轴突和树突之间形成未成熟突触;其二,突触成熟,沉默突触转化为活性突触;其三,敲除和修剪过量及不合格突触。星形胶质细胞可以控制突触形成、成熟和消除的每个阶段以支持神经回路的发生和维护。现将星形胶质细胞对神经回路形成的调节作用研究进展综述如下。     

Early loss of astrocytes after experimental traumatic brain injury

Neuronal-glial interactions are important for normal brain function and contribute to the maintenance of the brain's extracellular environment. Damage to glial cells following traumatic brain injury (TBI) could therefore be an important contributing factor to brain dysfunction and neuronal injury. We examined the early fate of astrocytes and neurons after TBI in rats. A total of 27 rats were euthanized at 0.5, 1, 2, 4, or 24 h after moderate lateral fluid percussion TBI or after sham TBI. Ipsilateral and contralateral hippocampi were examined in coronal sections from -2.12 to -4.80 mm relative to bregma. Adjacent sections were processed with markers for either astrocytes or degenerating neurons. Astrocytes were visualized using glial fibrillary acidic protein (GFAP) or glutamine synthetase immunohistochemistry. Neuronal degeneration was visualized using Fluoro-Jade (FJ) histofluorescence. At 30 min, there was a significant loss of GFAP immunoreactivity in ipsilateral hippocampal CA3 with some loss of normal astrocyte morphology in the remaining cells. The number of normal staining astrocytes decreased progressively over time with extensive astrocyte loss at 24 h. At 4 h, lightly stained FJ-positive neurons were scattered in the ipsilateral CA3. The intensity and number of FJ-positive neurons progressively increased over time with moderate numbers of degenerating neurons in the ipsilateral hippocampal CA3 evident at 24 h. We conclude that astrocyte loss occurs in the hippocampus early after TBI. The data suggest that loss of supporting glial cell may contribute to subsequent neuronal degeneration.     

大鼠轻型颅脑损伤后星形胶质细胞与神经元的病理改变

目的 探讨轻型颅脑损伤（TBI）后神经元及星形胶质细胞改变的病理生理过程。方法 将24只成年SD大鼠随机分为轻型TBI组（n=18）和假手术组（n=6）,轻型TBI组又分为伤后3 h（n=6）、伤后24 h（n=6）、伤后72 h（n=6）三亚组。采用液压冲击法制作轻型TBI模型。采用胶质纤维酸性蛋白（GFAP）染色检测星形胶质细胞,采用Fluoro-Jade B（FJ-B）荧光染色检测变性神经元。结果 与假手术组相比,轻型TBI后3 h、24 h、72 h邻近顶叶皮质、海马CA2/3区GFAP阳性细胞数量均明显减少（P<0.05）;缺失区周围星形胶质细胞肿胀增生明显。FJ-B阳性神经元在损伤后3 h无明显增加（P>0.05）,伤后24 h皮层区FJ-B阳性神经元显著增加（P<0.05）,伤后72 h海马区FJ-B阳性神经元显著增加（P<0.05）。伤后72 h伤侧皮层区与海马区GFAP阳性细胞数和FJ-B阳性细胞数呈显著负相关（r=-0.8285,P<0.05）。结论 轻型TBI后星形胶质细胞超急性期（3 h）即出现损害和胶质反应,神经元则在急性期（24 h）至亚急性期（72 h）出现明显损害,星形胶质细胞缺失程度可以反应神经元损伤程度。     

Selenoprotein S expression in reactive astrocytes following brain injury

Selenoprotein S (SelS) is an endoplasmic reticulum (ER)-resident protein involved in the unfolded protein response. Besides reducing ER-stress, SelS attenuates inflammation by decreasing pro-inflammatory cytokines. We have recently shown that SelS is responsive to ischemia in cultured astrocytes. To check the possible association of SelS with astrocyte activation, here we investigate the expression of SelS in two models of brain injury: kainic acid (KA) induced excitotoxicity and cortical mechanical lesion. The regulation of SelS and its functional consequences for neuroinflammation, ER-stress, and cell survival were further analyzed using cultured astrocytes from mouse and human. According to our immunofluorescence analysis, SelS expression is prominent in neurons and hardly detectable in astrocytes from control mice. However, brain injury intensely upregulates SelS, specifically in reactive astrocytes. SelS induction by KA was evident at 12 h and faded out after reaching maximum levels at 3-4 days. Analysis of mRNA and protein expression in cultured astrocytes showed SelS upregulation by inflammatory stimuli as well as ER-stress inducers. In turn, siRNA-mediated SelS silencing combined with adenoviral overexpression assays demonstrated that SelS reduces ER-stress markers CHOP and spliced XBP-1, as well as inflammatory cytokines IL-1β and IL-6 in stimulated astrocytes. SelS overexpression increased astrocyte resistance to ER-stress and inflammatory stimuli. Conversely, SelS suppression compromised astrocyte viability. In summary, our results reveal the upregulation of SelS expression in reactive astrocytes, as well as a new protective role for SelS against inflammation and ER-stress that can be relevant to astrocyte function in the context of inflammatory neuropathologies.     

Dementia after traumatic brain injury

Early retrospective studies suggested that individuals with a history of a traumatic brain injury (TBI) had a higher risk for dementia than those without a history of TBI. Two meta-analyses demonstrated that the risk for dementia is higher among men, but not women, with a history of TBI. More recent prospective studies, however, are providing discrepant findings, probably due to important methodological differences. TBI is usually associated with significant neuropsychological deficits, primarily in the domains of attention, executive functioning and memory. These deficits may not improve with time. TBI may also lower the threshold for the clinical expression of dementia among predisposed individuals, and the onset of Alzheimer's disease (AD)-like neuropathological and biochemical changes immediately after severe TBI may play an important role in this mechanism.     

Dose-dependent neuronal injury after traumatic brain injury

The Fluoro-Jade (FJ) stain reliably identifies degenerating neurons after multiple mechanisms of brain injury. We modified the FJ staining protocol to quickly stain frozen hippocampal rat brain sections and to permit systematic counts of stained, injured neurons at 4 and 24 h after mild, moderate or severe fluid percussion traumatic brain injury (TBI). In adjacent sections, laser capture microdissection was used to collect uninjured (FJ negative) CA3 hippocampal neurons to assess the effect of injury severity on mRNA levels of selected genes. Rats were anesthetized, intubated, mechanically ventilated and randomized to sham, mild (1.2 atm), moderate (2.0 atm) or severe (2.3 atm) TBI. Four or 24 h post-TBI, ten frozen sections (10 microm thick, every 15th section) were collected from the hippocampus of each rat, stained with FJ and counterstained with cresyl violet. Fluoro-Jade-positive neurons were counted in hippocampal subfields CA1, CA3 and the dentate gyrus/dentate hilus. At both 4 and 24 h post-TBI, numbers of FJ-positive neurons in all hippocampal regions increased dose-dependently in mildly and moderately injured rats but were not significantly more numerous after severe injury. Although analysis of variance demonstrated no overall difference in expression of mRNA levels for heat shock protein 70, bcl-2, caspase 3, caspase 9 and interleukin-1beta in uninjured CA3 neurons at all injury levels, post hoc analysis suggested that TBI induces increases in neuroprotective gene expression that offset concomitant increases in deleterious gene expression.     

Role of astrocytes in pathogenesis of ischemic brain injury

Astrocytes play an important role in the homeostasis of the CNS both in normal conditions and after ischemic injury. The swelling of astrocytes is observed during and several seconds after brain ischemia. Then ischemia stimulates sequential morphological and biochemical changes in glia and induces its proliferation. Reactive astrocytes demonstrate stellate morphology, increased glial fibrillary acidic protein (GFAP) immunoreactivity, increased number of mitochondria as well as elevated enzymatic and non-enzymatic antioxidant activities. Astrocytes can re-uptake and metabolize glutamate and in this way they control its extracellular concentration. The ability of astrocytes to protect neurons against the toxic action of free radicals depends on their specific energy metabolism, high glutathione level, increased antioxidant enzyme activity (catalase, superoxide dismutase, glutathione peroxidase) and overexpression of antiapoptoticbcl-2 gene. Astrocytes produce cytokines (TNF-±, IL-1, IL-6) involved in the initiation and maintaining of immunological response in the CNS. In astrocytes, like in neurones, ischemia induces the expression of immediate early genes:c-fos, c-jun, fos B, jun B, jun D, Krox-24, NGFI-B and others. The protein products of these genes modulate the expression of different proteins, both destructive ones and those involved in the neuroprotective processes.     

Neuroendocrine disorders after traumatic brain injury

Traumatic brain injury (TBI) is the most common cause of death and disability in young adults living in industrialised countries, in which 180-250 persons per 100 000 per year die or are hospitalised as a result. Neuroendocrine derangements after TBI have received increasing recognition in recent years because of their potential contribution to morbidity, and possibly mortality, after trauma. Marked changes of the hypothalamo-pituitary axis have been documented in the acute phase of TBI, with as many as 80% of patients showing evidence of gonadotropin deficiency, 18% of growth hormone deficiency, 16% of corticotrophin deficiency and 40% of patients demonstrating vasopressin abnormalities leading to diabetes insipidus or the syndrome of inappropriate anti-diuresis. Longitudinal prospective studies have shown that some of the early abnormalities are transient, whereas new endocrine dysfunctions become apparent in the post-acute phase. There remains a high frequency of hypothalamic-pituitary hormone deficiencies among long-term survivors of TBI, with approximately 25% patients showing one or more pituitary hormone deficiencies. This is a higher frequency than previously thought and suggests that most cases of post-traumatic hypopituitarism (PTHP) remain undiagnosed and untreated. PTHP has been associated with adverse outcome both in the acute and chronic phases after injury. These data underscore the need for the identification and appropriate timely management of hormone deficiencies, in order to optimise patient recovery from head trauma, improve quality of life and avoid the long-term adverse consequences of untreated hypopituitarism.     

Bipolar disorder after traumatic brain injury

Objective. We report the case of a 47-year-old man with no psychiatric antecedents who developed manic and depressive symptoms after traumatic brain injury (TBI). Methods and results. Findings on neurobehavioral examination, neuropsychological test battery, electrophysiological and imaging exams suggested the presence of a diffuse cerebral injury with a predominance of left fronto-temporal findings. Conclusions. This case demonstrates that TBI may cause vulnerability to psychiatric disorders, with long latency periods, and that its course may be independent of cognitive impairment and recovery.     

Maraviroc promotes recovery from traumatic brain injury in mice by suppression of neuroinflammation and activation of neurotoxic reactive astrocytes

Neuroinflammation and the NACHT, LRR, and PYD domains-containing protein 3 inflammasome play crucial roles in secondary tissue damage following an initial insult in patients with traumatic brain injury(TBI). Maraviroc, a C-C chemokine receptor type 5 antagonist, has been viewed as a new therapeutic strategy for many neuroinflammatory diseases. We studied the effect of maraviroc on TBI-induced neuroinflammation. A moderate-TBI mouse model was subjected to a controlled cortical impact device. Mara...