本文關鍵詞： 高遷移率族蛋白B1 血—腦脊液屏障 高血糖 腦缺血再灌注損傷　出處：《山東大學》2014年碩士論文　論文類型：學位論文

【摘要】：研究背景：腦卒中是常見病、多發(fā)病,而其中又以大腦中動脈梗塞造成的腦缺血尤為常見。缺血性腦卒中同樣存在著非常高的致死率和致殘率。阻塞血管的再通在缺血性腦卒中的治療中,對于缺血周邊區(qū)域腦組織損傷的修復是非常重要的,但是它帶來的問題——缺血性再灌注損傷,也是目前關注最多的。臨床研究結果發(fā)現(xiàn),缺血性腦卒中的患者當中,有很大一部分患者的血糖增高。引起高血糖原因,目前還沒有完全闡明,大多認為是糖尿病或者是應激性反應的表現(xiàn)。高血糖致使腦卒中患者的死亡率、致殘率增高并且延長神經(jīng)功能恢復時間。因此,高血糖已成為缺血性腦卒中患者預后的一個獨立性預測指標。然而高血糖與缺血性再灌注損傷(CIRI)之間的關系目前尚不清楚,究竟是高血糖本身可誘發(fā)并加重缺血性再灌注損傷(CIRI)呢?還是高血糖僅僅是缺血性腦卒中(ICS)預后差的一個指標,尚需要實驗進一步證實。高血糖加重CIRI的確切機制亦尚未闡明。HMGB1是近年來研究比較多的炎癥因子,有研究表明,HMGB1可以通過破壞BBB參與缺血性腦損傷中,而且應用HMGB1特異性抑制劑則可顯著減輕BBB損傷。HMGB1在正常腦細胞外低表達,但在腦缺血損傷時,細胞外HMGB1迅速升高,胞外的HMGB1可以作為一種重要的炎癥介質(zhì),誘導、維持和延長炎癥過程。隨著神經(jīng)炎癥的發(fā)展,由腦內(nèi)星形膠質(zhì)細胞與血管內(nèi)皮細胞形成的緊密連接所構成的血腦屏障的破壞加劇,引起腦水腫。雖然,目前HMGB1在其他器官的缺血性再灌注損傷中的作用機制的文獻報道比較多,但它在腦缺血再灌注損傷方面研究的不多,特別是在急性高血糖加重缺血性腦損傷中的作用機制方面報道較少。 研究目的：擬建立MCAO模型,探討HMGB1在急性高血糖加重腦缺血再灌注損傷中的作用及其機制。 研究方法：實驗動物wistar大鼠60只,隨機分為假手術(sham)組、正常血糖(NG)組及加HMGB1抑制劑(GL)(NG+GL)組、高血糖(HG)組和加HMGB1抑制劑GL (HG+GL)組,共五組。于缺血90min再灌注后2h、4h用westernblot檢測腦脊液中HMGB1含量、4h時用伊文思藍(Evans blue, EB)檢測血腦屏障的通透性、4h時用westernblot檢測腦組織中HMGB1和occludin含量變化,24h時TTC檢測腦水腫和腦梗死體積,24h時評估神經(jīng)功能缺失。 研究結果：EB外滲率,以及腦梗死范圍和腦水腫均明顯加重(P0.01),神經(jīng)功能評分明顯降低(P0.05),HG組大鼠腦脊液中HMGB1含量顯著提高(P0.01)；腦組織中的Occludin含量明顯降低；采用HMGB1特異性的抑制劑GL治療后,上述指標顯著改善(P0.01)。 結論：在缺血性腦卒中合并高血糖時,可能通過HMGB1釋放增加導致BBB破壞加重,從而加重腦損傷。而HMGB1特異性的抑制劑有保護作用。
[Abstract]:Background: stroke is a common disease. Among them, cerebral ischemia caused by middle cerebral artery infarction is particularly common. Ischemic stroke also has a very high mortality and disability rate. The recanalization of blocked blood vessels is used in the treatment of ischemic stroke. It is very important for the repair of cerebral tissue injury in the ischemic peripheral region, but it brings the problem of ischemic reperfusion injury, which is the most concerned at present. The clinical research results show that among the patients with ischemic stroke, There is a large proportion of patients with hyperglycemia. The causes of hyperglycemia have not been fully elucidated yet, most of them are considered to be signs of diabetes or stress response. Hyperglycemia results in the death rate of stroke patients. As a result, hyperglycemia has become an independent predictor of prognosis in patients with ischemic stroke. However, the relationship between hyperglycemia and ischemic reperfusion injury (CIRI) is unclear. Is it the hyperglycemia itself that induces and exacerbates ischemic reperfusion injury (CIRI)? Whether hyperglycemia is only a poor prognostic indicator of ischemic stroke needs to be further confirmed by experiments. The exact mechanism of hyperglycemia exacerbating CIRI has not been elucidated. HMGB1 is an inflammatory factor which has been studied in recent years. Some studies have shown that HMGB1 can participate in ischemic brain injury by destroying BBB, and the application of HMGB1 specific inhibitor can significantly attenuate the low expression of HMGB1 outside normal brain cells, but during cerebral ischemia injury, extracellular HMGB1 increases rapidly. Extracellular HMGB1 can act as an important inflammatory mediator that induces, maintains, and prolongs the inflammatory process. The destruction of the blood-brain barrier formed by the tight connection between astrocytes and vascular endothelial cells in the brain increases, causing brain edema. At present, there are many reports about the mechanism of HMGB1 in the ischemic reperfusion injury of other organs, but it has not been studied much in the field of cerebral ischemia-reperfusion injury. Especially in the acute hyperglycemia exacerbation of ischemic brain injury in the role of less reported. Objective: to establish MCAO model to investigate the role and mechanism of HMGB1 in acute hyperglycemia exacerbating cerebral ischemia-reperfusion injury. Methods: sixty wistar rats were randomly divided into three groups: sham group, normal blood glucose group, HMGB1 inhibitor GLG group, hyperglycemia group and HMGB1 inhibitor GLG group. The content of HMGB1 in cerebrospinal fluid (CSF) was detected by westernblot at 4 h after ischemia and reperfusion. The permeability of blood-brain barrier was detected by westernblot for 4 h and the contents of HMGB1 and occludin in brain tissue were detected by westernblot. The contents of HMGB1 and occludin in brain tissue were detected by TTC for 24 h. Neurological deficit was evaluated at 24 h after cerebral infarction. Results the percentage of exosmosis, the size of cerebral infarction and cerebral edema were significantly increased in the control group (P 0.01). The neurologic function score significantly decreased the content of HMGB1 in cerebrospinal fluid (CSF) and the content of Occludin in brain tissue (P 0.01) in the HG group. After treatment with GL, a specific inhibitor of HMGB1, the above indexes were significantly improved (P 0.01). Conclusion: in ischemic stroke complicated with hyperglycemia, BBB damage may be aggravated by increasing HMGB1 release, while HMGB1 specific inhibitors have protective effect.
【學位授予單位】：山東大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R743.3

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本文編號：1539344