کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8960761 | 1646430 | 2018 | 50 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Neuroprotective effects of INT-777 against Aβ1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
ایمنی شناسی و میکروب شناسی
ایمونولوژی
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چکیده انگلیسی
Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aβ) deposition plays a causative role in Alzheimer's disease (AD). Herein, we evaluated the neuroprotective effects of 6α-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777), a specific G-protein coupled bile acid receptor 1 (TGR5) agonist, in the Aβ1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aβ1-42 (410â¯pmol/mouse; 5â¯Î¼l) into the mouse brain induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction. In contrast, INT-777 (1.5 or 3.0â¯Î¼g/mouse, i.c.v.) significantly improved Aβ1-42-induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aβ1-42-induced TGR5 down-regulation, suppressed the increase of nuclear NF-κB p65, and mitigated neuroinflammation, as evidenced by lower proinflammatory cytokines and less Iba1-positive cells in the hippocampus and frontal cortex. INT-777 treatment also pronouncedly suppressed apoptosis through the reduction of TUNEL-positive cells, decreased caspase-3 activation, increased the ratio of Bcl-2/Bax, and ameliorated synaptic dysfunction by promoting dendritic spine generation with the upregulation of postsynaptic and presynaptic proteins (PSD95 and synaptophysin) in Aβ1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aβ1-42-induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Brain, Behavior, and Immunity - Volume 73, October 2018, Pages 533-545
Journal: Brain, Behavior, and Immunity - Volume 73, October 2018, Pages 533-545
نویسندگان
Xian Wu, Yang-Ge Lv, Yi-Feng Du, Fang Chen, Miranda N. Reed, Mei Hu, Vishnu Suppiramaniam, Su-Su Tang, Hao Hong,