謝秀梅Hsiu-Mei Hsieh陳彥旭Yen-Hsu Chen2019-09-052011-8-232019-09-052011http://etds.lib.ntnu.edu.tw/cgi-bin/gs32/gsweb.cgi?o=dstdcdr&s=id=%22GN0698430453%22.&%22.id.&http://rportal.lib.ntnu.edu.tw:80/handle/20.500.12235/104361高血糖症（Hyperglycemia）為糖尿病（diabetes mellitus）之主要病徵，並且被認為與認知障礙及失智症之風險增加相關。然而高血糖症在發炎反應中造成之效應並未被清楚解明。我們在雄性C57BL/6J小鼠中利用鏈黴硝化反構體streptozotocin摧毀胰臟的β胰島細胞，進而引起持續的高血糖症，誘發高血糖症的十天後，再利用立體定位手術在小鼠的海馬迴注射脂多醣體（LPS），接著去評估小鼠的認知功能以及分析其中分子機制。我們發現單獨對小鼠作高血糖或急性脂多醣體的注射處理均會引起空間認知以及嫌惡學習及記憶之缺失。另外，給予海馬迴急性注射脂多醣體會增加高血糖小鼠嫌惡學習及獲得空間學習的認知能力嚴重受損，主要原因可能是血清張力素及正腎上腺素神經元之間失衡所造成。Exendin-4是類胰高血糖胜肽-１受體（glucagon-like peptide-1 receptor）的促效劑。已經有許多的證據顯示Exendin-4會通過血腦障壁，並且在阿茲海默氏症（Alzheimer’s disease）以及帕金森氏症（Parkinson’s disease）的患者中藉由減弱其中的細胞毒性來改善症狀。在我們的研究中，我們發現了Exendin-4可以挽救由高血糖以及注射脂多醣體所造成的空間認知以及嫌惡學習及記憶之缺失，並且可以改善海馬迴中的發炎反應以及細胞凋亡，除此之外Exendin-4也減少了海馬迴中乙型類澱粉蛋白的量。綜合上述結果，我們建議Exendin-4可以作為一個預防神經退化性疾病的潛力藥物。Hyperglycemia is a main characteristic of diabetes mellitus (DM) pathology and has been linked to increased risk of cognitive impairment and dementia. However, the priming effects of the hyperglycemia in inflammation are still unclear. Chronic hyperglycemia was induced in male C57BL/6J mice to mimic DM by intraperitoneal injection of streptozotocin (STZ), which specifically destroys pancreatic β-islet cells. Ten days after STZ treatment, intrahippocampal infusion of vehicle or lipopolysaccharides (LPS) was given to these hyperglycemic/normoglycemic mice. We then examined the cognitive function and molecular alteration of these mice. Severe impairment of the aversive memory and spatial learning acquisition was induced by LPS in hyperglycemic mice via unbalance of the serotonergic and noradrenergic system. Furthermore, the spatial learning and memory was correlated inflammatory response (COX1, COX2, CD45), Aβ1-42, NF-κB, and cognitive related neurotransmitters’ deficit. Exendin-4 (EX-4) is a glucagon-like peptide-1 receptor (GLP-1R) agonist, Evidences suggest that EX-4 could cross the blood brain barrier and attenuate the cellular toxicity in the Alzheimer’s disease or Parkinson’s disease. In this study, we showed that EX-4 treatment improved spatial and aversive learning and memory in intrahippocampal LPS injection or/and hyperglycemic mice. In summary, EX-4 might be considered as potential adjuvant entity for preventing neurodegerative diseases.Exendin-4高血糖症發炎反應脂多醣體鏈黴硝化反構體空間學習與記憶嫌惡學習與記憶Exendin-4HyperglycemiaInflammationLPSStreptozotocinSpatial and aversive learning and memory