Wang Xuan-Kang, Sun Ting, Li Yu-Jiao, Wang Yu-Hong, Li Yan-Jiao, Yang Liu-Di, Feng Dan, Zhao Ming-Gao, Wu Yu-Mei
Department of Pharmacology, School of Pharmacy, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, P.R. China.
Student Brigade, The Fourth Military Medical University, Xi'an, Shaanxi Province 710032, P.R. China.
Oncotarget. 2017 Nov 18;8(64):107409-107422. doi: 10.18632/oncotarget.22467. eCollection 2017 Dec 8.
Type 2 diabetes (T2DM) has been associated with learning and memory impairment; however, drugs for diabetes could not prevent the development of cognitive decline in T2DM patients. In the present study, compounds derived from thiazolidinediones (TZD), a PPAR-γ agonist, were synthesized by conjuncting the alkyl-substituted benzimidazole group to TZD group (ATZDs). Based on the evaluation, the neuroprotection of ATZD2 was further investigated using a streptozotocin-induced T2DM rat model. Pharmacokinetic study showed that ATZD2 could pass the blood-brain barrier (BBB) while the rosiglitazone (RSG, the precursor compound of ATZD2) not. Administration of ATZD2 significantly promoted the survival rate and attenuated fasting blood glucose (FBG) levels as compared to RSG treatment in T2DM rats. Furthermore, ATZD2 treatment ameliorated the impairment of learning and memory by Morris water maze test. The beneficial effects of ATZD2 were associated with the down-regulation of hypoxia induced factor-1α, aldose reductase, and Bax expression which are related to T2DM pathology. ATZD2 treatment also attenuated the expression of inflammatory cytokines and restored the balance of redox in the diabetic hippocampus. These effects were more potent as compared with that of RSG at the same dose. The data indicate that ATZD2 may be a potent agent for the treatment of cognitive dysfunction in T2DM.
2型糖尿病（T2DM）与学习和记忆障碍有关；然而，糖尿病药物无法预防T2DM患者认知功能下降的发展。在本研究中，通过将烷基取代的苯并咪唑基团与噻唑烷二酮（TZD）基团（ATZDs）结合，合成了源自PPAR-γ激动剂噻唑烷二酮的化合物。基于评估，使用链脲佐菌素诱导的T2DM大鼠模型进一步研究了ATZD2的神经保护作用。药代动力学研究表明，ATZD2可以通过血脑屏障（BBB），而罗格列酮（RSG，ATZD2的前体化合物）则不能。与RSG治疗相比，给予ATZD2可显著提高T2DM大鼠的存活率并降低空腹血糖（FBG）水平。此外，通过莫里斯水迷宫试验，ATZD2治疗改善了学习和记忆障碍。ATZD2的有益作用与缺氧诱导因子-1α、醛糖还原酶和Bax表达的下调有关，这些与T2DM病理相关。ATZD2治疗还减弱了炎症细胞因子的表达，并恢复了糖尿病海马体中的氧化还原平衡。与相同剂量的RSG相比，这些作用更有效。数据表明，ATZD2可能是治疗T2DM认知功能障碍的有效药物。
