自发性蛛网膜下腔出血后早期脑损伤机制研究进展

自发性蛛网膜下腔出血（SAH）是高病死率和病残率的三大脑血管疾病之一,影响自发性SAH患者预后的主要因素是早期脑损伤和血管痉挛等并发症。有学者认为早期脑损伤（EBI）是影响自发性SAH患者预后的主要因素。本研究就近年来国内外学者在自发性SAH后EBI病理机制的研究进展作一综述。     

蛛网膜下腔出血后早期脑损伤的研究进展

<正>自发性蛛网膜下腔出血(SAH)是一种常见的危重神经系统血管疾病。随着影像学技术、显微神经外科技术、介入放射技术的提高,其病死率有所下降,但发病率和病死率仍然较高[1]。目前已有多种治疗方法,其中主要针对的是脑血管痉挛(cerebral vasospasm,CVS)和再出血两方面,但患者的不良预后并未得到根本改善[2]。据此推断,CVS并非不良预后的先决条件[3]。近年来,研究人员分析,在CVS     

自噬在蛛网膜下腔出血后早期脑损伤中作用的研究进展

近几年研究发现,蛛网膜下腔出血（SAH）后72 h内即出现的早期脑损伤（early brain injury,EBI）与SAH的不良预后密切相关,成为研究关注的热点.自噬（autophagy）很早就被发现存在于多种组织细胞中,参与降解和回收受损细胞器和大分子物质,出现于多种生理过程和疾病的病理过程中.Lee 等[1]研究发现,SAH后立即可检测到皮质内自噬活性的增强.但自噬在SAH后EBI中的作用及具体机制尚不明确.我们就自噬与EBI的关系综述如下.     

Caspase-3抑制剂对蛛网膜下腔出血后早期脑损伤的作用

目的 探讨Caspase-3抑制剂在蛛网膜下腔出血后早期脑损伤中的作用.方法 颈内动脉穿刺制作大鼠蛛网膜下腔出血模型.将大鼠随机分成3组:实验组(38只)模型制作后腹腔注射Caspase-3抑制剂 Z-VAD-FMK(10 μmol/L,0.3 mL);对照组(38只)注射等体积二甲基亚砜(DMSO);正常组(16只)未进行任何处理.72 h记录死亡率、神经功能评分、脑水肿、血脑屏障通透性等脑损伤指标;TUNEL染色检测神经元细胞凋亡,免疫组化、Western Blot检测Caspase-3表达.结果 Caspase-3抑制剂可降低大鼠死亡率(47.4%vs28.9%,P<0.05),减轻脑水肿,保护血脑屏障,减少Caspase-3蛋白表达及神经元细胞凋亡(P<0.05),但对神经功能评分无明显影响(P>0.05).结论 细胞凋亡在SAH后早期脑损伤中起重要作用,可减轻SAH后早期脑损伤.     

脑红蛋白对蛛网膜下腔出血大鼠早期脑损伤的保护作用

目的探讨脑红蛋白（NGB）对蛛网膜下腔出血（SAH）大鼠早期脑损伤的保护作用。方法将60只清洁级sD大鼠随机分为4组：正常组、假手术组、SAH组、治疗组（SAH＋腹腔注射氯化血红素）组。除SAH组30只外,其余每组10只大鼠。采用枕大池单次注血法建立大鼠SAH模型。采用免疫组化法和图像分析技术观测SAH后,不同时间大脑皮质颞叶的NGB免疫组化反应及平均吸光度A值;采用干湿法测量脑含水量,原位细胞凋亡检测法（TUNEL）检测颞叶神经元凋亡情况。结果①正常组和SAH后24h组平均吸光度4值分别是0．133±0．021和0．236±0．028：②sAH后颞叶皮质NGB阳性反应细胞迅速增加,24h达高峰,随后逐渐减少;③SAH组脑含水量为（77．5±0．4）％,治疗组脑含水量为（76．5±0．6）％,治疗组脑含水量较SAH组减少,差异有统计学意义（P〈0．05）;④治疗组和SAH组脑颞叶神经元凋亡程度为（9．8±2．4）％、（18．5±2．3）％。治疗组脑皮质神经元凋亡程度较SAH组降低（P〈0．05）。结论SAH后大鼠大脑皮质NGB阳性反应细胞呈动态变化。早期给予NGB能减少大鼠SAH模型的皮质神经元凋亡,降低脑水肿程度,具有明显的脑保护作用。     

内质网应激在蛛网膜下腔出血后早期脑损伤中的作用

自发性蛛网膜下腔出血(subarachnoid hemorrhage,SAH)是临床上的一种急性脑血管病,致残率和病死率均很高.最近的研究显示,SAH发病后72 h内即会出现早期脑损伤(early braininjury,EBI),并与SAH患者转归不良密切相关.导致EBI的可能机制有许多,例如炎症、自噬、细胞凋亡等,这些损伤机制均与内质网应激有关.文章就内质网应激在SAH后EBI中的作用进行了综述.     

蛛网膜下腔出血所致脑血管痉挛的发生机制

蛛网膜下腔出血所致脑血管痉挛的发生机制众说纷纭,文章从分子生物学角度重点阐述了与之相关的血管活性物质、微循环以及某些相关基因的研究进展。     

早期持续腰池引流对蛛网膜下腔出血动脉瘤介入填塞术后继发性脑损伤的研究

目的探讨早期持续腰池引流对动脉瘤性蛛网膜下腔出血(aneurysmal subarachnoid hemorrhage,a SAH)动脉瘤介入栓塞术后继发性脑损伤的研究。方法将100例a SAH患者分为置换组50例和引流组50例,两组均给予颅内动脉瘤介入栓塞治疗及脑保护,防止血管痉挛等常规治疗,引流组在动脉瘤填塞术后立即行腰池引流治疗,置换组在动脉瘤填塞术后立即行脑脊液置换治疗,每日一次。结束引流或置换的标准:头颅CT显示蛛网膜下腔积血消失或脑脊液变清亮、压力正常,一般引流或置换7~10d。发病2周内,通过临床表现及TCD诊断脑血管痉挛(cerebral vasospasm,CVS),CT或MRI诊断脑梗死及脑积水并进行比较。比较两组患者头痛缓解时间、蛛网膜下腔积血的清除时间、脑脊液压力恢复正常时间。评价治疗后7d、14d、28d神经功能缺损NIHSS评分,同时检测血清白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、丙二醛(MDA)及超氧化物歧化酶(SOD)水平。结果动脉瘤介入栓塞术后,患者头痛缓解时间、蛛网膜下腔积血清除时间、脑脊液压力正常时间、脑脊液常规、生化恢复正常时间、CVS、脑梗死及脑积水的发生率,引流组均少于置换组(P0.05)。引流组7d、14d、28d神经功能缺损NIHSS评分明显改善(P0.05),7d、14d、28d血液中IL-6和TNF-α含量均明显减低,SOD活性升高和MDA含量降低(P0.05)。结论 a SAH患者动脉瘤介入栓塞术后早期采用腰池引流治疗,能降低脑梗死、脑积水及CVS的发生率,减轻继发性脑损伤,改善神经功能,其机制可能与该措施减轻蛛网膜下腔出血后炎性反应、抑制氧化应激反应有关。     

Melatonin alleviates secondary brain damage and neurobehavioral dysfunction after experimental subarachnoid hemorrhage: possible involvement of TLR4‐mediated inflammatory pathway

Previous studies proved that melatonin protected against secondary brain damage by modulating oxidative stress after experimental subarachnoid hemorrhage (SAH), but it has not been evaluated yet about its effects on inflammatory pathway and secondary cognitive dysfunction in SAH model. This study was undertaken to evaluate the influence of melatonin on toll‐like receptor 4 (TLR4) signaling pathway and neurobehavioral tests after SAH. Adult SD rats were divided into four groups: control group (n = 20), SAH group (n = 20), SAH+vehicle group (n = 20), and SAH+melatonin group (n = 20). The rat SAH model was induced by injection of 0.3 mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20 s. In SAH+melatonin group, melatonin was administered i.p. at 150 mg/kg at 2 and 24 hr after the induction of SAH. Cognitive and memory changes were investigated in the Morris water maze. Treatment with melatonin markedly decreased the expressions of TLR4 pathway‐related agents, such as high‐mobility group box 1 (HMGB1), TLR4, nuclear factor‐κB (NF‐κB), myeloid differentiation factor 88 (MyD88), interleukin‐1β (IL‐1β), tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), and inducible nitric oxide synthase (iNOS). Administration of melatonin following SAH significantly ameliorated spatial learning and memory deficits in this prechiasmatic blood injection model. Staining of apoptosis and necrosis indicated that fewer positive cells appeared in melatonin‐treated group than SAH+vehicle group. In conclusion, melatonin may attenuate neurobehavioral dysfunction in this SAH model, and melatonin exhibits neuroprotection possibly not only through anti‐oxidative pathway but also anti‐inflammatory signaling after experimental SAH.     

蛛网膜下腔出血后脑脊液中的致痉原与脑血管痉挛

脑血管痉挛是自发性蛛网膜下腔出血患者发生脑梗死和迟发性缺血性神经功能缺损的主要原因.对脑血管痉挛的研究目前相对集中于血性腩脊液中的致痉原方面.文章对蛛网膜下腔出血后血性脑脊液中的主要致痉原诱发脑血管痉挛的机制进行了综述.     

Melatonin‐enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage

Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase‐3 activity and the number of TUNEL‐positive cells, while the treatment increased the LC3‐II/LC3‐I, an autophagy marker, which indicated that melatonin‐enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.     

Melatonin activates the Nrf2-ARE pathway when it protects against early brain injury in a subarachnoid hemorrhage model

Melatonin has beneficial effects against early brain injury (EBI) by modulating cerebral oxidative stress after experimental subarachnoid hemorrhage (SAH); however, few investigations relate to the precise underlying molecular mechanisms. To date, the relation between melatonin and nuclear factor erythroid 2-related factor 2 and antioxidant responsive element (Nrf2-ARE) pathway has not been studied in SAH models. This study was undertaken to evaluate the influence of melatonin on Nrf2-ARE pathway in rats after SAH. Adult male SD rats were divided into four groups: (i) control group (n=18); (ii) SAH group (n=18); (iii) SAH+vehicle group (n=18); and (iv) SAH+melatonin group (n=18). The rat SAH model was induced by injection of 0.3mL fresh arterial, nonheparinized blood into the prechiasmatic cistern in 20s. In SAH+melatonin group, melatonin was administered i.p. at 150mg/kg at 2 and 24hr after the induction of SAH. Brain samples were extracted at 48hr after SAH. Treatment with melatonin markedly increased the expressions of Nrf2-ARE pathway-related agents, such as Nrf2, heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutathione S-transferase α-1. Administration of melatonin following SAH significantly ameliorated EBI, including brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and neurological deficits. In conclusion, post-SAH melatonin administration may attenuate EBI in this SAH model, possibly through activating Nrf2-ARE pathway and modulating cerebral oxidative stress by inducing antioxidant and detoxifying enzymes.     

Melatonin attenuates inflammatory response‐induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro‐inflammatory cytokines

Melatonin is a strong anti‐oxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes the reduction of both mortality and neurological deficits. The molecular mechanisms underlying these clinical effects in the SAH model have not been clearly identified. This study examined the influence of melatonin on brain edema secondary to disruption of the blood–brain barrier (BBB) and the relationship between these effects and pro‐inflammatory cytokines in EBI following SAH using the filament perforation model of SAH in male Sprague–Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. Melatonin treatment markedly attenuated brain edema secondary to BBB dysfunctions by preventing the disruption of tight junction protein expression (ZO‐1, occludin, and claudin‐5). Melatonin treatment also repressed cortical levels of pro‐inflammatory cytokines (IL‐1β, IL‐6, and TNF‐α), which were increased in EBI 24 hr after SAH. To further identify the mechanism of this protection, we demonstrated that administration of melatonin attenuated matrix metallopeptidase 9 expression/activity and vascular endothelial growth factor expression, which are related to the inflammatory response and BBB disruption in EBI after SAH. Taken together, this report shows that melatonin prevents disruption of tight junction proteins which might play a role in attenuating brain edema secondary to BBB dysfunctions by repressing the inflammatory response in EBI after SAH, possibly associated with regulation of pro‐inflammatory cytokines.     

Melatonin decreases mortality following severe subarachnoid hemorrhage

Abstract:  Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood–brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague–Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.     

脑出血后血肿周围组织损伤的机制

脑出血(intracerebral hemorrhage,ICH)发病率和病死率均很高.ICH后脑损伤涉及许多机制,包括脑血肿形成过程中的机械力对血肿周围脑组织的直接破坏,血块衍生因子(凝血酶、血红蛋白降解产物)的释放、炎症反应和补体级联反应等.     

Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling

Subarachnoid hemorrhage (SAH) is a devastating condition with high morbidity and mortality rates due to the lack of effective therapy. Nucleotide‐binding oligomerization domain‐like receptor family pyrin domain‐containing 3 (NLRP3) inflammasome activation associated with the upregulation of apoptotic signaling pathway has been implicated in various inflammatory diseases including hemorrhagic insults. Melatonin is reported to possess substantial anti‐inflammatory properties, which is beneficial for early brain injury (EBI) after SAH. However, the molecular mechanisms have not been clearly identified. This study was designed to investigate the protective effects of melatonin against EBI induced by SAH and to elucidate the potential mechanisms. The adult mice were subjected to SAH. Melatonin or vehicle was injected intraperitoneally 2 hr after SAH. Melatonin was neuroprotective, as shown by increased survival rate, as well as elevated neurological score, greater survival of neurons, preserved brain glutathione levels, and reduced brain edema, malondialdehyde concentrations, apoptotic ratio, and blood–brain barrier (BBB) disruption. Melatonin also attenuated the expressions of NLRP3, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), cleaved caspase‐1, interleukin‐1β (IL‐1β), and interleukin‐6 (IL‐6); these changes were also associated with an increase in the anti‐apoptotic factor (Bcl2) and reduction in the pro‐apoptotic factor (Bim). In summary, our results demonstrate that melatonin treatment attenuates the EBI following SAH by inhibiting NLRP3 inflammasome‐associated apoptosis.     

铁超载与脑出血后脑损伤

脑出血(intracerebral hemorrhage,ICH)是一种常见神经系统疾病,其死亡率和致残率均很高,但目前对ICH后脑损伤的机制尚未完全阐明.最新的研究表明,铁超载在ICH后脑损伤中起着重要作用.文章对脑铁分布和功能、ICH后铁超载引起脑损伤的机制以及铁螯合剂应用等方面的研究进展进行了综述.     

蛛网膜下腔出血后的早期心脏异常

约50%～70%的患者在蛛网膜下腔出血后会继发心脏异常,而心脏异常又会加重脑组织缺血缺氧,可能还会促进迟发性缺血缺氧性脑病的发生.很多研究人员借助心电图、心脏彩超和血清心肌酶检测来观察这种变化的临床特征、持续时间及其与预后的关系.文章就蛛网膜下腔出血早期心脏异常的原因以及心电图、心脏彩超和心肌酶谱改变的临床特征方面的研究进展做一综述.