Inhibitory effect of INT-777 on lipopolysaccharide-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice

被引：58

作者：

Wu, Xian ^{[1
]}

Lv, Yang-Ge ^{[1
]}

Du, Yi-Feng ^{[2
]}

Hu, Mei ^{[1
]}

Reed, Miranda N. ^{[2
]}

Long, Yan ^{[1
]}

Suppiramaniam, Vishnu ^{[2
]}

Hong, Hao ^{[1
]}

Tang, Su-Su ^{[1
]}

机构：

[1] China Pharmaceut Univ, Dept Pharmacol, Key Lab Neuropsychiat Dis, Nanjing 210009, Jiangsu, Peoples R China

[2] Auburn Univ, Sch Pharm, Dept Drug Discovery & Dev, Auburn, AL 36849 USA

来源：

PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY | 2019年 / 88卷

关键词：

Alzheimer's disease; INT-777; TGR5; Lipopolysaccharide; Cognitive impairment; BILE-ACID RECEPTOR; NF-KAPPA-B; INDUCED MEMORY IMPAIRMENT; LONG-TERM POTENTIATION; AMYLOID-BETA; NEURONAL APOPTOSIS; ALZHEIMERS-DISEASE; GPBAR1; TGR5; IN-VIVO; DEFICIT;

D O I：

10.1016/j.pnpbp.2018.08.016

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 mu g/mouse, i.c.v.) treatment. Importantly, INT-777 treatment reversed LPS-induced TGR5 down-regulation, suppressed the increase of nuclear NF-kappa B 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.

引用

页码：360 / 374

页数：15