Neuroprotective effects of INT-777 against Aβ1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice

作     者：WU Xian LYU Yang-ge DU Yi-feng CHEN Fang Miranda N REED HU Mei Vishnu SUPPIRAMANIAM TANG Su-su HONG Hao 

作者机构：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 Alabama USA 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2018年第32卷第9期

页      面：688-689页

核心收录：

学科分类：1002[医学-临床医学] 100205[医学-精神病与精神卫生学] 10[医学] 

基　　金：National Natural Science Foundation of China(81573413 81773714 81273497 81603113) Natural Science Foundation of Jiangsu Province(BK20150705) Fundamental Research Funds for the Central Universities (2632017PT01) 

主　　题：Alzheimer disease INT-777 TGR5 Aβ1-42 neurotoxicity 

摘      要：OBJECTIVE To investigate the neuroprotective effects of TGR5 agonist INT-777 in the Aβ_(1-42)-treated mouse model of acute *** Cognitive impairment was induced by single intracerebroventricular injection of aggregated Aβ_(1-42)(410 pmol per mouse;5 μL)into the mouse brain in normal ICR ***3 d,INT-777(0.75,1.5 or 3.0 μg per mouse) was infused into the same *** 3 d later,the cognition function was evaluated by Morris water maze(MWM),novel objective recognition(NOR),and Y maze ***,the levels of TGR5,TNF-α,IL-1β,IL-6,NF-κB p65,Iba1,caspase 3,Bcl-2,Bax,PSD95,and synaptophysin in the hippocampus and frontal cortex were detected using Western *** activation in the hippocampal CA1,CA3 and DG regions and frontal cortex were detected by *** staining was used to detect the apoptotic *** number of spines in the hippocampal CA1,CA3 and DG regions and frontal cortex was detected by GolgiCox *** INT-777(1.5 or 3.0 μg per mouse) significantly ameliorated memory impairment in the Aβ_(1-42)-treated mice,evidenced by increased the time spent in the target quadrant(P0.05),and the number of target crossings(P0.05) in the MWM test,increased the discrimination index in the NOR test(P0.05),and increased the number of correct choices(P0.05,P0.01) and decreased the latency(P0.05) to enter the shock-free compartment in the Y-maze ***,this treatment reversed Aβ_(1-42)-induced TGR5 down-regulation(P0.05,P0.01),suppressed the increase of nuclear NF-κB p65(P0.05,P0.01) and mitigated neuroinflammation,evidenced by lower proinflammatory cytokines such as TNF-α(P0.05),IL-1β(P0.05),IL-6(P0.05,P0.01),and less Iba1-positive cells in the hippocampal CA1,CA3 and DG regions and frontal cortex(P0.05,P0.01) as well as the protein level of ***-777(1.5 or3.0 μg per mouse) also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells(P0.05,P0.01),de