Department of Pharmacology, J. N. Medical College, KLE Academy of Higher Education and Research (KLE University), Nehru Nagar, Belagavi, Karnataka, India; Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research (KLE University), Nehru Nagar, Belagavi, Karnataka, India.
Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research (KLE University), Nehru Nagar, Belagavi, Karnataka, India.
Life Sci. 2018 Aug 15;207:364-371. doi: 10.1016/j.lfs.2018.06.021. Epub 2018 Jun 21.
Type-2 diabetes mellitus (DM) is associated with cognitive impairment. Increasing evidence establishes that neuro-inflammatory and oxidative stress condition plays a main role in the development of neurodegeneration. Epalrestat, an aldose reductase inhibitor is commonly prescribed for the treatment of diabetic peripheral neuropathy. Its beneficial effects for antioxidant, anti-inflammatory potential and being rhodanine structure containing compound suggests possible role for treatment of DM associated with cognitive dysfunction.
In the present study, we evaluated the effect of epalrestat (54, 27, 13.5 mg/kg, p.o.) and donepezil (1 mg/kg, p.o.) on Tau protein levels, oxidative stress and inflammatory markers in high fat diet (HFD) and Streptozotocin (STZ; 35 mg/kg, i.p.) induced cognitive impairment in diabetic rats.
The epalrestat - 54, 27 mg/kg p.o. and donepezil treatment significantly increased CAT (p < 0.001, p < 0.01, p < 0.001) and GSH (p < 0.001, p < 0.01, p < 0.001) activities respectively as compared to diabetic control rats. In addition, similar dose of epalrestat treatment indicated considerably lowered TAU protein levels (p < 0.001, p < 0.05) while no significant effect was noted with donepezil. These treatments significantly decreased gene expression of TNF-α (1.6, 1.6, 1.7 fold change) and IL-6 (2.5, 1.9, 1.7 fold change). Histopathological examination indicated that epalrestat could attenuate apoptosis of neurons, vacuolations and clumped processes, disorganization and thinning of all the layers.
Our findings suggest that diabetic rats treated with epalrestat could ameliorate the cognition deficits and might act as a beneficial agent for prevention and treatment of cognitive impairment in diabetes.
2 型糖尿病（DM）与认知障碍有关。越来越多的证据表明，神经炎症和氧化应激状态在神经退行性变的发展中起着主要作用。醛糖还原酶抑制剂依帕司他通常用于治疗糖尿病周围神经病变。其抗氧化、抗炎潜力以及作为含有雷琐酸结构的化合物的有益作用表明，它可能在治疗与认知功能障碍相关的糖尿病方面发挥作用。
在本研究中，我们评估了依帕司他（54、27、13.5mg/kg，po）和多奈哌齐（1mg/kg，po）对高脂肪饮食（HFD）和链脲佐菌素（STZ；35mg/kg，ip）诱导的糖尿病大鼠认知障碍的 Tau 蛋白水平、氧化应激和炎症标志物的影响。
依帕司他-54、27mg/kg po 和多奈哌齐治疗可显著增加 CAT（p<0.001，p<0.01，p<0.001）和 GSH（p<0.001，p<0.01，p<0.001）的活性，与糖尿病对照组大鼠相比。此外，依帕司他的类似剂量治疗表明 Tau 蛋白水平显著降低（p<0.001，p<0.05），而多奈哌齐则没有显著效果。这些治疗可显著降低 TNF-α（1.6、1.6、1.7 倍变化）和 IL-6（2.5、1.9、1.7 倍变化）的基因表达。组织病理学检查表明，依帕司他可减轻神经元凋亡、空泡化和聚集过程、所有层的结构紊乱和变薄。
我们的研究结果表明，依帕司他治疗的糖尿病大鼠可改善认知障碍，并可能成为预防和治疗糖尿病认知障碍的有益药物。
