Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing 210009, China.
Department of Drug Discovery and Development, School of Pharmacy, Auburn University, Auburn, AL, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2019 Jan 10;88:360-374. doi: 10.1016/j.pnpbp.2018.08.016. Epub 2018 Aug 23.
Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease (AD) and memory impairment. Herein, we evaluated the neuroprotective effects of 6-ethyl-23(S)-methyl-cholic acid (INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the LPS-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of LPS remarkably induced mouse behavioral impairments in Morris water maze, novel object recognition, and Y-maze avoidance tests, which were ameliorated by INT-777 (1.5 or 3.0 μg/mouse, i.c.v.) treatment. Importantly, INT-777 treatment reversed LPS-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, evidenced by lower proinflammatory cytokines, less activation of microglia, and increased the ratio of p-CREB/CREB or mBDNF/proBDNF in the hippocampus and frontal cortex. In addition, INT-777 treatment also suppressed neuronal apoptosis, as indicated by the reduction of TUNEL-positive cells, decreased activation of caspase-3, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction as evidenced by the upregulation of PSD95 and synaptophysin in the hippocampus and frontal cortex. Taken together, this study showed the potential neuroprotective effects of INT-777 against LPS-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.
神经炎症在阿尔茨海默病（AD）和记忆障碍的病理生理学中起着重要作用。在此，我们评估了 6-乙基-23(S)-甲基胆酸（INT-777），一种特定的 G 蛋白偶联胆汁酸受体 1（TGR5）激动剂，对 LPS 处理的急性神经毒性小鼠模型的神经保护作用。单次侧脑室（i.c.v.）注射 LPS 可显著诱导 Morris 水迷宫、新物体识别和 Y 迷宫回避测试中的小鼠行为障碍，这些障碍可被 INT-777（1.5 或 3.0 μg/只，i.c.v.）治疗改善。重要的是，INT-777 治疗逆转了 LPS 诱导的 TGR5 下调，抑制了核 NF-κB p65 的增加，并减轻了神经炎症，表现为促炎细胞因子减少，小胶质细胞激活减少，以及海马体和前额叶皮质中 p-CREB/CREB 或 mBDNF/proBDNF 的比值增加。此外，INT-777 治疗还抑制了神经元凋亡，这表现为 TUNEL 阳性细胞减少，caspase-3 激活减少，Bcl-2/Bax 比值增加，以及海马体和前额叶皮质中 PSD95 和突触小体素的上调改善了突触功能障碍。综上所述，本研究表明 INT-777 具有对抗 LPS 诱导的认知障碍、神经炎症、凋亡和突触功能障碍的潜在神经保护作用。
