Neuroprotective effects of INT-777 against Aß1-42-induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction in mice.
Brain Behav Immun
; 73: 533-545, 2018 10.
Article
en En
| MEDLINE
| ID: mdl-29935310
ABSTRACT
Increasing evidence demonstrates that the neurotoxicity of amyloid-beta (Aß) 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 Aß1-42-treated mouse model of acute neurotoxicity. Single intracerebroventricular (i.c.v.) injection of aggregated Aß1-42 (410â¯pmol/mouse; 5⯵l) into the mouse brain induced cognitive impairment, neuroinflammation, apoptosis, and synaptic dysfunction. In contrast, INT-777 (1.5 or 3.0⯵g/mouse, i.c.v.) significantly improved Aß1-42-induced cognitive impairment, as reflected by better performance in memory tests. Importantly, INT-777 treatment reversed Aß1-42-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 Aß1-42-treated mice. Our results indicate that INT-777 has potent neuroprotective effects against Aß1-42-induced neurotoxicity. Taken together, these findings suggest that the activation of TGR5 could be a novel and promising strategy for the treatment of AD.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ácidos Cólicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Brain Behav Immun
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
CEREBRO
/
PSICOFISIOLOGIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
China