Wang Lihui, Cao Jinjin, Xu Qianqian, Lu Xiaomei, Yang Xin, Song Qiong, Chen Shuai, Du Kechen, Huang Renbin, Zou Chunlin
Key Laboratory of Longevity and Aging-Related Diseases of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, China.
Department of Pharmacology, Guangxi Medical University, Nanning, China.
Front Pharmacol. 2021 Dec 16;12:708141. doi: 10.3389/fphar.2021.708141. eCollection 2021.
Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.
糖尿病（DM）是认知障碍的独立危险因素。尽管糖尿病性认知障碍的病因复杂且具有多因素性，但海马神经元凋亡被认为是糖尿病所致认知障碍的主要原因。2-十二烷基-6-甲氧基环己-2,5-二烯-1,4-二酮（DMDD）是从某植物根部提纯而来。先前的研究表明，DMDD在延缓某些糖尿病并发症方面安全有效。然而，DMDD改善2型糖尿病小鼠糖尿病性认知障碍的疗效尚未见报道。在本研究中，通过Y迷宫和新物体识别实验对db/db小鼠进行行为评估。使用小鼠lncRNA微阵列分析检测db/db小鼠海马中的基因表达谱。通过蛋白质免疫印迹法测定db/db小鼠和高糖处理的HT22细胞中神经退行性变相关蛋白和凋亡相关蛋白的变化。我们观察到，DMDD治疗显著改善了db/db小鼠的空间工作记忆和物体识别记忆障碍。进一步研究表明，DMDD治疗后，db/db小鼠海马中神经退行性变相关蛋白tau减少。DMDD治疗后，db/db小鼠海马中有11种lncRNA和4种mRNA（包括促凋亡基因Hif3a）表达存在显著差异。与db/m对照小鼠相比，糖尿病db/db小鼠海马中Hif3a、裂解的PARP和caspase 3蛋白的表达显著增加，而DMDD治疗后则降低。在高糖处理的HT22细胞中也观察到了DMDD的类似有益作用。这些数据表明，DMDD可通过降低促凋亡蛋白Hif3a的表达来抑制神经元凋亡，从而减轻认知障碍。总之，我们的研究表明，DMDD极有可能成为治疗糖尿病性认知障碍的新型预防和治疗化合物。
