α-硫辛酸緩解高脂飲食及STZ誘發第二型糖尿病大鼠認知功能損傷之探討

Abstract

近年來臨床和流行病學研究發現，第二型糖尿病(T2DM)與阿茲海默症(AD)的發展有很高的相關性，有研究指出胰島素可參與AD相關蛋白如β-澱粉樣蛋白(Aβ)之調節。α-硫辛酸(ALA)已被證實可以改善糖尿病大鼠的胰島素阻抗。本研究探討ALA改善高脂飲食(HFD)及鏈脲佐菌素(STZ)誘導的糖尿病大鼠認知障礙、腦胰島素抵抗及突觸可塑性異常的效果。Wistar雄性大鼠給予HFD (60%脂肪卡路里) 4週後，以腹腔注射(ip) STZ (30mg/kg體重)誘發糖尿病。糖尿病大鼠每日管餵ALA 13週後，進行被動迴避試驗及Morris水迷宮試驗以評估大鼠認知功能。大鼠犧牲後採集血液及腦組織分析，並以Western blotting檢測海馬迴和皮質的胰島素訊息路徑、長期增益效應(LTP)及突觸可塑性相關蛋白的表現。被動迴避試驗與Morris水迷宮試驗結果顯示，給予ALA處理能顯著改善HFD/STZ誘導的糖尿病大鼠的認知功能障礙(p<0.05)。Western blotting分析結果顯示，給予ALA處理能顯著改善糖尿病大鼠海馬迴與皮質的突觸可塑性相關蛋白以及胰島素訊號傳導相關蛋白之表現(p<0.05)。在本研究結果發現，ALA可經由緩解糖尿病大鼠腦部胰島素阻抗來改善大腦神經突觸的可塑性及認知功能。目前ALA已是市面上的保健食品，希望可透過此研究讓ALA在未來也能作為阿茲海默症疾病的輔助用藥。

Recently, clinical and epidemiological studies suggest that T2DM is strongly interrelated with Alzheimer's disease (AD), and proposed that insulin involved in the modulation of AD-related proteins such as β-Amyloid (Aβ). Studies also reported that α-lipoic acid (ALA) improved insulin resistance in diabetic rats. This study examines the ameliorative effect of ALA on cognition impairment, cerebral insulin resistance and synaptic plasticity abnormality in high-fat diet (HFD) plus streptozotocin (STZ) induced diabetic rats. Male Wistar rats fed HFD (60% fat of calorie) for 4 weeks were intraperitoneally (ip) injected STZ (30mg/kg b.w.) to induce diabetes. The diabetic rats were orally administered with ALA once a day for 13 weeks. Passive avoidance test and Morris water maze test was performed to assess cognitive ability of rats. The blood and brain specimens were collected for biochemical analysis after the rats were sacrificed. Western blotting was used to determine the protein expressions of hippocampal and cortex insulin signaling pathway, long-term potentiation and synaptic plasticity-related proteins expression. The result from the passive avoidance test and Morris Water Maze test shows that the administration of ALA significantly improved the cognitive impairment in HFD/STZ-induced diabetic rats (p<0.05). Western blotting analysis indicates the expression of cerebral, including hippocampal and cortex, synaptic plasticity-related protein, and cerebral insulin signaling-related protein significantly increased in ALA-treated diabetic rats (p<0.05). The findings in this study suggest that ALA may ameliorate cognition impairment via improving cerebral synaptic plasticity and alleviating cerebral insulin resistance in diabetic rats.