咖啡胺衍生物K36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

Alleviative effect of caffeamide derivative K36 on cognition impairment in high-fat diet plus streptozotocin induced Type 2 diabetic rats

吳佩芩(Wu Pei-Chin)

指導教授 ： 沈賜川

國立臺灣師範大學/教育學院/人類發展與家庭學系/碩士(2018年)

https://doi.org/10.6345/THE.NTNU.DHDFS.011.2018.A06

摘要

近年來，隨著老齡化人口不斷增多，老化相關疾病也逐漸被重視。阿茲海默症為臨床上常見之神經退化疾病，流行病學研究發現，第二型糖尿病(Type 2 diabetes mellitus; T2DM)為阿茲海默症之風險因子之一，而胰島素阻抗為其主要表徵。本實驗探討咖啡胺衍生物K36對T2DM大鼠降血糖及改善認知功能之效果。Wistar大鼠以高脂飲食(脂肪含量佔總熱量60%)與STZ誘導為T2DM之動物模式後，每日管餵K36 (15 mg/kgBW) 13周，觀察K36對於胰島素訊息路徑與阿茲海默症生成途徑，所造成長期增益效應途徑、突觸表現改變之影響。結果顯示，K36可顯著降低T2DM大鼠血糖、胰島素阻抗，及改善血脂異常之效果(p <0.05)。莫式水迷宮結果顯示，K36顯著改善T2DM大鼠學習與記憶的能力(p <0.05)。西方墨點法結果顯示，於胰島素訊息路徑方面，K36能夠顯著增加大腦皮質之胰島素分解酵素(Insulin degrading enzyme; IDE)、胰島素受體(insulin receptor; IR)、胰島素受體基質1 (insulin receptor substrate-1; IRS-1)及葡萄糖轉運蛋白4 (glucose transporter 4; GLUT4)的蛋白表現 (p <0.05)；在突觸功能表現方面，K36能夠增加大腦皮質與海馬迴的突觸蛋白Drebrin、PSD-95 (p <0.05)；阿茲海默症風險因子β類澱粉樣蛋白(β-Amyloid; Aβ)的生成途徑方面，結果顯示K36可顯著降低大腦皮質與海馬迴BACE (β-site APP cleaving enzyme, BACE)與類澱粉樣前驅蛋白 (Amyloid-β precursor protein; APP)的表現(p <0.05)；在腦部神經之長期增益效應部分，K36能夠顯著增加大腦皮質與海馬迴N-甲基-D-天門冬胺酸(N-methyl-D-aspartate; NMDA)受體之次單位NMDAR1與NMDAR2B，以及海馬迴攜鈣素(Calmodulin; CaM)的表現，而K36也能增加皮質攜鈣素(CaM)及CaMKIIβ的表現量(p<0.05)。綜合以上結果顯示，K36能夠改善腦部胰島素訊息路徑、降低Aβ之生成、改善突觸後功能及長期增益效應，進而改善T2DM大鼠認知功能。

關鍵字

認知功能障礙 ； 阿茲海默症 ； 第二型糖尿病 ； 咖啡胺衍生物K36

並列摘要

Currently, as the increasing in aging population, the aging-related diseases are noticed in the world. Alzheimer’s disease is one of the most common neurodegenerative diseases. Type 2 diabetes mellitus (T2DM) is a risk factor of Alzheimer’s disease characterized as insulin resistance. This study aims to investigate the effect of caffeamide K36 on hypoglycemia and improving cognitive impairment in T2DM rats. Wistar rats were fed with high fat diet (HFD; 60% of kcal) and STZ injection to induce T2DM, and then administrated with K36 (15 mg/kg BW) for 13 weeks. Results show that K36 reduces insulin resistance and improves dyslipidemia significantly in T2DM rats (p<0.05). The result from Morris Water Maze shows that K36 improves the ability of learning and memory in T2DM rats (p<0.05). Western blotting analysis reveals that K36 significantly increases the insulin signaling-related proteins expression, including insulin receptor (IR), insulin receptor substrate-1(IRS-1) and glucose transporter 4 (GLUT4) in cortex (p<0.05). In addition, K36 increases the synaptic function-related proteins expression, including postsynaptic density protein-95 (PSD-95) and drebrin in both cortex and hippocampus. Moreover, K36 decreases the expression of BACE (β-site APP cleaving enzyme) and amyloid-β precursor protein (APP) significantly (p<0.05). K36 increases LTP (long-term potential)-related proteins expression, including NMDA (N-methyl-D-aspartate) subunit NMDAR1 and NMDAR2B in cortex and hippocampus significantly. K36 enhances the expression of Calmodulin (CaM) in hippocampus. K36 also increases CaM and CalMKIIβ expression in cortex. Above observations demonstrate that K36 may alleviate cerebral insulin resistance, reduce the accumulation of Aβ, ameliorate postsynaptic function and LTP ability, and enhance the cognitive and memory ability in T2DM rats.

並列關鍵字

cognitive impairment ； Alzheimer’s disease ； T2DM ； caffeamide K36

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