Pathophysiology of Ischemic Damage after SAH (I) Microcirculation Study and the Role of Neuronal Receptor of Advanced Glycation End-Product(RAGE), (II) Role of Neural Stem Cell in the Recovery Stage after SAH

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Project title/計畫英文名

Project Number/計畫編號

MOST103-2314-B002-118-MY2

Translated Name/計畫中文名

蜘蛛膜下腔出血後缺血性神經病變的病態生理---(I)微血流的研究與探討神經細胞的RAGE 接受器在蜘蛛網膜下出血的功能性角色; (II)神經幹細胞在蜘蛛膜下腔出血修復期的角色

Project Principal Investigator/計畫主持人

KUOCHUAN WANG

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

蔡瑞章,蔡力凱,謝松蒼

Start date/計畫起

01-08-2015

Expected Completion/計畫迄

12-07-2016

Description

Abstract

摘要：血管痙攣至今仍為造成腦動脈瘤破裂病人殘障最常見的原因。自2008年以來，我們已經針對蛛網膜下腔出血做了一連串的研究。首先，我們證明了乳酸可有效預測動脈瘤性SAH患者發生長期水腦症。我們還發現腦脊液中的HO1可以有效預測SAH患者的預後。我們假設，大量蛛網膜下腔出血引起的蛛網膜下腔條塊分隔，因此我們在SAH病患從第三天起，經由腰椎引流持續引流出腦脊液。我們的數據顯示，MDA（一種氧化標誌物）與預後相關；另外腰椎引流則可明顯降低MDA的數值。為了可以了解其病態生理學，我們先前的研究引入capillary videoscopy，對於微血流的研究於蜘蛛膜下腔出血動物模式中。結果顯示出血後的腦脊髓液可造成老鼠明顯微血流的病變，且其嚴重度與缺血性病變有明顯關係。我們通過去年度國科會計畫(蜘蛛膜下腔出血後缺血性神經病變的病態生理:微血流的研究與探討神經細胞的RAGE 接受器在蜘蛛網膜下出血的功能性角色NSC 102-2314-B-002-088)。本實驗包含臨床與基礎研究，臨床上的目的在探討動脈瘤破裂病蜘蛛膜下腔出血病患腦脊髓液中HMGB1,sRAGE,及S-100 protein在持續性腰椎引流後的變化與預後的關係。並在動物模式下，訂定微血管變化程度評分標準，前瞻性預測病人延遲性缺血性病變程度及病人預後的相關性。我們將使用腰椎引流第一日與第五日的腦脊髓液進行動物實驗，我們將腦脊髓液加在老鼠腦表面，看其對微血流的影響，藉由我們制訂的微血流評分標準前瞻性的來預測延遲性缺血性神經病變的發生機率與預後。在動物模式上，我們將刺激與燒灼sphenopalatine 神經節觀察副交感神經對於微血流的影響。第二部份我們將蜘蛛膜下腔出血老鼠模式，測量腦脊髓液中sRAGE及HMGB1與缺血性病變的關係，再藉由神經細胞培養與血管內皮細胞培養來研究動脈瘤破裂病蜘蛛膜下腔出血病患造成腦損傷的機制。我們進一步將intra-thecal注射recombinant sRAGE，用以探討sRAGE是否對微血流有改善效果並研究其機制。因時間關係尚需一年才能完成，此即為此計畫的第一部分。本計劃的第二部分是關於神經幹細胞（NSCs ）。最近的研究，我們發現，間質幹細胞靜脈移植可提高中風大鼠功能恢復。內源性神經幹細胞可能成為急性中風治療一個潛在的治療方法。在蛛網膜下腔出血（SAH ），神經幹細胞可能參與，以減輕功能惡化，促進神經功能的恢復。研究神經幹細胞的增殖能力為研究神經系統疾病提供了一個機會，不僅要描繪的疾病的發病機制，而且要找出未來的潛在治療。在計畫第二部分，我們使用從先前的研究SAH患者收集到的腦脊液。將從胚胎Wistar大鼠前腦得到神經幹細胞。將CSF加入NSC培養基後，測量幹細胞的增殖能力。結果將比較這些SAH病人的臨床情況。在動物模型中，我們將使用免疫組織化學染色，以驗證神經幹細胞在大鼠蛛網膜下腔出血模型所佔的角色，尤其是在SAH晚期。
Abstract: Aneurysmal subarachnoid hemorrhage (SAH) carries significant morbidity and mortality. We have done a serial studies on SAH since 2008. First, we proved that intrathecal lactate is a useful parameter in predicting long-term hydrocephalus in aneurysmal SAH patients. We further proposed that the level of intra-thecal CSF HO1 at day 7 post-SAH can be an effective outcome indicator in patients with SAH. We hypothesized that massive SAH caused compartmentalization of subarachnoid space and then start the next study of continuous drainage of CSF from lumbar drainage tube SAH. Our data showed that MDA(an oxidative marker) is predictive of outcome, and lumbar drain is the most significant factors correlate with level of MDA. To study the pathophysiology, we introduction of laser Doppler capillary anemometer provided the way to visualize the microcirculation vasculatures directly. We demonstrated microcirculation impairment after SAH of rat model. Further, we showed that DIND after SAH of patients was highly correlated with microcirculation changes on animal model. We have passed one year plan of National Science Council last year (plan number: NSC 102-2314-B-002-088). (1) We measure the levels of CSF sRAGE and RAGE ligands in SAH patients and correlate the data with clinical severity and outcome. (2) We set up a scoring system for microcirculation impairment and then we will use this score to predict DIND. In animal study, we investigate the role of neuronal RAGE and associated signaling following SAH. We also study the role of sRAGE in SAH model. We need one more year to complete the study. So, the first part of our plan is the continuous study of last year Second part of this plan is about neural stem cells (NSCs). Recently, we have demonstrated that intravenous transplantation of mesenchymal stem cells could enhance the functional recovery into stroke rats. Endogenous NSCs may become a potential therapeutic target for acute stroke treatment. In subarachnoid hemorrhage (SAH), neurogenesis may be significantly involved as a possible mechanism to alleviate functional deterioration and promote neurological recovery. To investigate the proliferation capacity of NSCs in neurological disorders provides a chance not only to delineate the pathogenesis of diseases, but also to find out potential treatment in the future. In second portion this project, we use the collected CSF from SAH patients of previous study. NSCs will be obtained from the forebrain of fetal Wistar rats. After adding human CSF into NSC culture medium, the proliferation capacity of stem cells will be measured. The results will be compared to the clinical condition of these SAH patients. In animal model, we will use IHC stain to verify the role of NSCs after SAH rat model, especially in the late stage of SAH.