摘要
研究背景：
急性脑血管病是人类三大致死性疾病之一,其中蛛网膜下腔出血(subarachnoid hemorrhage, SAH)的发病率仅次于脑梗塞和脑出血,位居第三位。绝大多数SAH系脑动脉瘤破裂所致,其病死率高达25%以上,存活下来的患者约1/3因神经功能缺损而需依赖他人生活,给社会和家庭带来沉重负担。再出血和继发脑缺血是导致SAH患者严重预后的两个主要并发症。目前对脑动脉瘤的闭塞术和血管内栓塞术取得了很大的进步,SAH后再出血率已显著降低,但其总体预后并没有显著改善。因此,深入探讨SAH后继发脑缺血损伤的机制,寻找有效防治措施是改善SAH预后的关键环节,具有十分重要的现实意义。
数十年来,SAH后脑部主要动脉血管发生的痉挛和管腔狭窄,即所谓脑血管痉挛(cerebral vasospasm, CVS)一直是研究的焦点问题。近年来发现SAH后CVS出现的时程和严重程度与继发性脑缺血损伤并不呈完全平行的关系,除CVS外,SAH后脑微血管痉挛和微循环调节功能异常等因素也与继发性脑缺血的发生有关。神经元的死亡可通过坏死(necrosis)和凋亡(apoptosis)两种不同形式发生。哺乳动物细胞凋亡是受Bcl-2蛋白家族、凋亡蛋白活化因子1(apoptosis protein activating factor, Apaf-1)、caspase(胱冬肽酶)蛋白家族等调控的。caspase家族成员归居于不同的凋亡通路,其中caspase-3与凋亡密切相关。在线粒体对细胞凋亡的调控中,Bcl-2家族的蛋白质对线粒体内一些促凋亡因子的释放具有调控功能,因此在决定细胞生死中也具有十分重要的作用。
通过大分子物质示踪等技术在不同种属动物包括人类的研究已经证实,脑内和蛛网膜下腔中的大分子物质可以被引流入颅外淋巴管和淋巴结。吡哆醇为维生素B族化合物,是机体内一种重要辅酶,它以5′-磷酸吡哆醛的形式参与了氨基酸、脂类等代谢和免疫反应等过程。临床上对淋巴滞留性脑病患者采用大剂量吡哆醇或泛酸治疗能明显减轻患者症状,说明吡哆醇能够改善大分子物质引流,但其机理不清。SAH继发脑缺血发生后,大量血浆蛋白等大分子物质可通过受损的血脑屏障进入脑组织中；由细胞受损而产生的细胞裂解产物和缺血代谢瀑布产生的大量肽类等大分子物质在脑组织中急剧增加。上述大分子物质在脑组织中的积聚直接使神经细胞进一步受损,或通过脑组织渗透压升高而引起脑水肿甚至脑疝,导致患者神经功能缺损乃至死亡。这些在蛛网膜下腔和脑组织内积聚的大分子物质被清除的程度如何,将对SAH的最终结局产生极为重要的影响。然而,目前国内外其他学者对SAH继发脑缺血损伤的研究尚没有涉及大分子物质清除这一重要问题。
研究目的：
1、进一步阐明脑淋巴引流途径在病理条件下脑组织大分子物质引流和维持脑组织内环境稳定中的重要作用。
2、明确SAH后脑淋巴引流途径变化特征,阐明脑淋巴引流途径在SAH继发脑缺血损伤中起到的内源性保护作用。
3、从改善脑内物质的淋巴引流角度寻找有效防治SAH继发脑缺血损伤的药物。
研究方法：
1、选用健康成年Wistar大鼠,雌雄不拘,随机分为正常对照组、SAH组、SAH+CLB组、SAH+CLB+吡哆醇组、SAH+CLB+生理盐水组。采用颈淋巴管结扎和淋巴结摘除法制作大鼠脑淋巴引流阻滞(CLB)模型,应用枕大池二次注血法建立大鼠SAH模型。于模型制作结束后12h内,监测有关生理指标等变化。于第二次注血后48h在体观察基底动脉(BA)管径变化,测定BA对乙酰胆碱(Ach)的反应性,同时行组织病理学观察基底动脉形态和管径,并对脑膜微循环的动态变化进行观察。
2、对上述分组动物,于术后48h,HE染色观察大脑皮层和海马的形态结构变化；PI染色观察大脑皮层和海马细胞核的形态结构变化,采用TUNEL荧光标记法检测大脑皮层和海马原位凋亡。取新鲜大脑皮层和海马,采用SABC免疫荧光技术检测caspase-3和Bcl-2的蛋白表达；利用RT-PCR技术检测caspase-3和Bcl-2的mRNA表达。
研究结果：
1、脑池注血的动物除血压一过性升高外,动脉血气等生理指标维持在正常范围内；SAH组、SAH+CLB组、SAH+CLB+生理盐水组出现ICP升高和脑灌注压(CPP)下降；BA管腔明显痉挛缩窄,管壁增厚,且对Ach反应性降低；脑膜微动、静脉明显痉挛,血流多呈泥沙样流动,甚至可见血流郁滞、摆动等明显异常,以SAH+CLB组、SAH+CLB+溶媒组更为严重。吡哆醇可减轻CLB对SAH所致ICP升高、CPP下降、BA痉挛和脑膜微循环异常的变化。
2、(1)HE染色可见SAH组大鼠部分神经元脱失,皱缩,核固缩、深染,SAH+CLB组脑组织及毛细血管壁明显水肿,组织间隙增宽,内含大量水肿液,脑血管壁水肿,神经元分部稀疏,细胞皱缩、变形,核染色质致密浓缩、边集,部分核碎裂,部分神经元周围有空泡形成。吡哆醇组上述表现较SAH+CLB组有一定程度的减轻。(2)PI染色可见SAH组细胞部分凋亡,细胞核呈波纹状或折缝样,部分染色质出现浓缩状态,个别细胞核的染色质高度凝聚、边缘化,皇新月形,SAH+CLB组大鼠有大量细胞凋亡,且多属于凋亡晚期：染色质高度凝聚、边缘化,新月形,核碎裂,产生凋亡小体。吡哆醇组凋亡细胞明显减少。(3)TUNEL法原位细胞凋亡检测显示SAH组散在较多的TUNEL阳性细胞,SAH+CLB组可见大量TUNEL阳性细胞,凋亡细胞多集中在大脑皮层、海马、基底节区、脉络丛、室管膜等部位,而以海马、室管膜更为明显。吡哆醇组可见散在TUNEL阳性细胞。(4)免疫荧光技术检测到SAH组有较多的caspase-3免疫阳性细胞,SAH+CLB组有大量caspase-3免疫阳性细胞分布,吡哆醇组caspase-3免疫阳性细胞表达较SAH+CLB组减少。SAH组可见较多的Bcl-2免疫阳性细胞,SAH+CLB组可见少量Bcl-2免疫阳性细胞分布,吡哆醇组Bcl-2免疫阳性细胞表达较SAH+CLB组明显增多。(5) RT-PCR检测结果显示SAH组大脑皮层和海马caspase-3基因mRNA表达明显高于正常对照组,SAH+CLB组caspase-3基因mRNA表达更高,吡哆醇组caspase-3基因的mRNA表达则较SAH+CLB组明显减少。SAH组Bcl-2基因mRNA表达明显低于正常对照组,SAH+CLB组Bcl-2基因mRNA表达则更低,吡哆醇组caspase-3基因的mRNA表达则较SAH+CLB组明显增高。
研究结论：1、阻断脑淋巴引流途径可加重SAH后脑血管痉挛和基底动脉的病理变化。
2、阻断脑淋巴引流途径可降低SAH后脑部微循环灌流量,加重微血管痉挛,降低脑微血管流速。
3、吡哆醇干预对脑淋巴引流阻断所致的SAH后脑血管痉挛和微循环异常具有一定缓解作用。
4、阻断脑淋巴引流途径将加重SAH所致脑水肿。
5、阻断脑淋巴引流途径可以通过下调Bcl-2表达,上调caspase-3表达来加重SAH继发性脑缺血损伤。
6、吡哆醇干预对脑淋巴引流阻断所致的SAH继发性脑缺血损伤具有一定缓解作用。
BACKGROUD:
Emergent cerebrovascular dissease is one of the three death causes in the world. Among the total, the incidence of subarachnoid hemorrhage is second only than brain infarction and cerebral hemorrhage. Majority of SAH is caused by brain rupture of aneurysm. Case fatality is above of 25%, about of 1/3 survivals's existence depend on other because of neurologic impairment, which bring albatross to family and society rehaemorrhagia and secondary cerebral ischema are the main complications of SAH and contributes to the mal-prognosis. In spite of the fact that there is a drastic drop in rebleeding due to the progress of the surgical management of cerebral aneurism, the outcome of SAH dose not improve because of a concurrent increase in the occurrence of secondary cerebral ischemia. Thus, understanding of the pathogenesis, preventionand management of secondary cerebral ischemia is of great importance in improving the outcome of patients with SAH.
Over the past several decades, the main cerebral arteril spasm, namely cerebral vasospasn(CVS), has become a focus. In recent years, scientists discovered that the time course and severity of CVS are not completely parallel relation with secondary cerebral ischemia. In spite of CVS, the factor (such as cerebral micrangium vasospasm and abnormal regulate function of microcirculation etc.) are concerned with development of secondary cerebral ischemia. Neuronic death include apoptosis and necrosis. Mammalian cell apoptosis is regulated by Bcl-2 and caspase proteins, apoptosis protein activating factor(Apaf-1). The member of caspase family is belong to different apoptosis pathway, of the total, caspase-3 closely related to Apoptosis. In regulation of mitochondria in apoptosis, the protein of Bcl-2 family can regulate, the liberation of some apoptosis factor, thus it's important in determination on life-and-death of cell.
It has been proved that macromolecular substance in brain and subarachnoid space could be drainage into extracranial lymphatic vessels and lymph nodes, by technique of macromolecular substance tracing in any kind of animals including of human. Pyridoxol is chemical compound of B vitamins, and important coenzyme in vivo. It participates in metabolism of amino acid and lipids and immune response. In clinic, the symptoms of the lymphostatic encephalopathy(LE) patients obviously relieved by using of high-dose Pyridoxol or bepanthen, which explain that pyridoxol can improve drainage of macromolecular substance. But the mechanism is unclear. After occurrence of secondary cerebral ischema following SAH, mass macromolecular substance (such as plasma protein etc.) can pass through the impaired blood-brain barrier into brain tissue.
Because of damaged cell or ischemia metabolism fall, mass cell cleaved product and peptides are producd and rapidly increased in brain tissue. Accumulation of above macromolecular substance can damage directly, or induce the brain edema by osmotic pressure of brain tissue rising, even cerebral hernia, which lead to neurologic impairment or die. It's important to final termination that how the macromolecular substance are pellated. Nevertheless, other scholars have not refered to the inportant problem of macromolecular substance cleaning on secondary cerebral ischema following SAH at home and abroad at present.
OBJECTIVE:
Firstly, to investigate the important role of the cerebral lymphatic drainage pathway on the drainage of macromolecular substance and homeostatic equilibrium in brain tissue under pathological conditions.
Sencondly, to determine the variability features of the cerebral lymphatic drainage pathway, and to investigate the endogenous influence of cerebral lymphatic drainage pathway on the development of secondary cerebral ischema following SAH.
Thirdly, to search for the drug to prevent secondary cerebral ischema following SAH effectively, by improving cerebral lymphatic drainage of macromolecular substance in brain.
MOTHODS:
1. The healthy Wister rats were randomly divided into five groups:normal control, SAH group, SAH+CLB group, SAH+CLB+ pyridoxo group, SAH+CLB+ normal sodium group. Rat SAH model was established by the cisteme magna double injection of autologus arterial hemolysates. Rat cervical lymphatic blocked(CLB) model was established by occlusion of cervical lymphatic tubes and removal of lymphatic nodes. Dynamic alteration of physiological parameters, intracranial pressure(ICP), and pial microcirculation were determined within 12 hours. In vivo BA and responsiveness of BA to Ach measurement was performed after 48 hours.
2.48 hours after induction, changes of the structure and form of cerebral cortex and hippocampal were detected by haematine eosin stain and PI stain. Apoptosis and cell injury in the cerebral cortex and hippocampal were detected by TUNEL method. The protein expressions of Bcl-2 and caspase-3 were assessed by SABC immmunohistochemistry. The expression of mRNA was assessed by technic of RT-PCR.
RESULT:
1. The physiological parameters remained within normal range with the exception of a temporary increase in arterial blood pressure(BP). Rats in SAH, SAH+CLB and SAH+CLB+normal sodium groups showed depressed EEG, increased ICP and a drop in cerebral perfusion pressure(CCP) arid rCBF. BA diameters and BA responsiveness to Ach were decreased. Disturbances of pial microcirculation were obviously abnormal, blood flow much presented flow of sediment, even could be found blood flow stasis and movement. Among the total, Rats in SAH+CLB and SAH+CLB+normal sodium groups were more serious. Pyridoxol may relieve the symptom mentioned above of CLB after SAH.
2. (1) By HE stain, the loss of neurons, karyopyknosis in partial neurons and anachromasis were found in SAH group. In SAH+CLB group, the edema of brain tisssue and capillary wall, wider tissue space, edema of vessel wall was found. The number of neurons decreased and the arrangement were out of order. The nuclei were deep stained and in shape of triangle, strip or abnormity, and fartly found nuclear fragmentation. Pyridoxol may relieve the above symptome of CLB after SAH.
(2) By PI stain, some neurons showed apoptotic conformation. Cell nucleus were in shape of ripple or crease, part of caryotins were pyknotic, individual caryotin were high agglutinated, marginalizated, and in crescent-shaped in SAH group. A great of neurons showed apoptotic conformation, and belong to advanced stage:caryotin were high agglutinated, marginalizated, and in crescent-shaped, and found nuclear fragmentation and apoptotic body in SAH+CLB group. Apoptosis were obviously decreased in pyridoxol group.
(3) Scattered apoptotic cells were observed in SAH group, and a devil of apoptotic cells were observed in SAH+CLB group. Apoptotic cells were centralized in cerebral cortex, hippocamp, basal ganglia, choroid plexus and endyma etc. Of the total, hippocamp, endyma were more visible. In pyridoxol group, scattered apoptotic cells were observed.
(4) By immunofluorescence technic, some expression of caspase-3 and Bcl-2 were observed in SAH group.In SAH+CLB group, the expression of caspase-3 was more than SAH group. However, the expression of Bcl-2 was less. In pyridoxol group, the result of expression of caspase-3 and Bcl-2 were opposite to SAH+CLB group.
(5) By RT-PCR, the mRNA expression of caspase-3 in SAH group was more than normal control, and in SAH+CLB group was the most. In pyridoxol group, the mRNA expression of caspase-3 was less than SAH+CLB group. The mRNA expression of Bcl-2 in SAH group was less than normal control, and in SAH+CLB group was the least. In pyridoxol group, the mRNA expression of Bcl-2 was more than SAH+CLB group.
CONCLUSION:
1. Pathological change of CVS after SAH was aggravated by blockage of cervical lymphatic drainage.
2. Blood flow rate of microcirculation was degraded, and capillary vessel vasospasm was aggravated by blockage of cervical lymphatic drainage after SAH.
3. Pyridoxol can partly relieve CVS and abnormality of microcirculation by blockage of cervical lymphatic drainage after SAH.
4. Brain edema after SAH was aggravated by blockage of cervical lymphatic drainage.
5. Blockage of cervical lymphatic drainage can aggravated cerebral ischemic injury following SAH by down-regulation of Bcl-2 and up-regulation caspase-3.
6. Pyridoxol can partly relieve the cerebral ischemic injury following SAH by blockage of cervical lymphatic drainage.
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