探討Piracetam對顱內出血損傷之神經保護機制

中山醫學大學機構典藏 CSMUIR > 醫學院 > 醫學研究所 > 博碩士論文 > Item 310902500/19691

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/19691

Title:	探討Piracetam對顱內出血損傷之神經保護機制 Investigating neuroprotective mechanisms of Piracetam against intracranial hemorrhage-induced damages
Authors:	郭千尹 Kuo, Chein-Yin
Contributors:	中山醫學大學:醫學研究所;林志立;黃建寧
Keywords:	顱內出血;微膠細胞;神經發炎反應;神經保護;Piracetam Intracerebral hemorrhage;Microglia;Neuroinflammation;Neuroprotection;Piracetam
Date:	2018
Issue Date:	2019-01-04T04:45:11Z (UTC)
Abstract:	顱內出血後因血腫的形成，造成局部腦部組織灌流減少，導致局部的原發性腦組織傷害，並且連帶引起一系列瀰漫性的續發損傷，包括血管內皮細胞活化產生活性氧化物質，並因此活化微膠細胞促進發炎因子的釋放。其結果造成的神經毒性會使神經細胞受損，並再次擴大發炎的規模，而過長時間的發炎反應會演變成慢性的創傷性腦病變，更增加了日後發展成神經退化性疾病的機會。目前在臨床上對於創傷後神經學功能的復原及神經炎症的控制，還沒有一套有效的預防及治療標準，只能針對症狀緩解、復健運動或是透過藥物輔助治療效果。Piracetam是臨床上最廣泛被使用的一種腦循環促進劑，用於皮質性陣發性抽搐輔助療法以及腦血管障礙及老化所引起的智力障礙，並且有文獻透過動物實驗證實，Piracetam能增強認知功能，但藥物的作用機轉目前仍不明確。因此本研究首先透過回溯性病例回顧，收集近年內轉入本院神經外科加護病房共1189位患者，比較顱內出血後有服用Piracetam的34位及未服用藥物的56位兩組成年患者之間，發炎相關指標顯著下降。為了探討Piracetam緩解神經發炎反應的功效，及其分子機轉中和微膠細胞之間的關係，因此我們進一步設計了體外細胞培養實驗，利用LPS(脂多醣)誘導BV2微膠細胞在發炎狀態下，觀察加入Piracetam後的變化，結果發現包括活化型態的BV2細胞數目減少，粒線體功能障礙改善後活性氧化物質堆積減少，以及在NF-κB、JNK等調控發炎因子路徑中相關蛋白表現減少等現象，並透過RT-PCR分析驗證，Piracetam治療下IL-1β、IL-6、TNFα的表現亦受到抑制。綜合以上結果我們發現，Piracetam用於治療顱內出血患者神經炎症的機轉可能與抑制微膠細胞活化有關。 Cerebral hypoperfusion may induce some secondary injuries such as neuroinflammation after hematoma development when intracerebral hemorrhage happens. It stimulates endothelial cell of blood vessel and subsequently causes microglia activation and nerve cell damage by accumulation of reactive oxygen species (ROS). Moreover, neuroinflammation can be prolonged which exaggerates chronic traumatic encephalopathy and contributes to the progression of neurodegenerative diseases. Until now, there is no prevention and guideline for treatment of neuroinflammation after intracerebral hemorrhage. Only symptom relief, rehabilitation and the usage of some medications can be used for assistance in the therapy. To this end, Piracetam is a metabolism enhancer be most widely used. Its indications include involutional syndrome related to aging, epilepsy, stroke, cerebral circulatory insufficiency, and improvement of intellectual performance. However, the precise mechanism of drug action is still unknown. To elucidate the molecular mechanism of Piracetam, our aims are divided into two parts in this research: (i) retrospective study was conducted at a medical center located Taichung. Consecutive patients who were diagnosed and hospital survived with having intracerebral hemorrhage visited NSICU from January 2015 to April 2017. By comparison of blood samples collected from 34 patients with Piracetam treatment and 56 patients without Piracetam treatment, our results showed that inflammation-related makers are significantly decreased in Piracetam groups after intracerebral hemorrhage. (ii) We investigated the effect of Piracetam on BV2 microglia cells with stimulation of lipopolysaccharide (LPS)-induced inflammation. Our results showed that treatment of Piracetam suppresses the activation of LPS-treated BV2 cells. In addition, Piracetam also improved mitochondrial dysfunction and reduced ROS production in activated BV2 cells. This is likely through the inhibition of NF-κB and JNK signaling, and the results form qPCR also confirmed decreased mRNA levels of IL-1β, IL-6, TNFα in LPS-activated BV2 cells. Collectively, our results suggest a putative neuroprotective mechanism of Piracetam against intracranial hemorrhage-induced damages by suppression of inflammatory microglial activation.
URI:	https://ir.csmu.edu.tw:8080/ir/handle/310902500/19691
Appears in Collections:	[醫學研究所] 博碩士論文

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