PubAg

Main content area

Monoacylglycerol lipase inhibitor protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through COX-2 signaling

Author:
Dong, Manman, Lu, Yongli, Zou, Ziliang, Yang, Hongwei
Source:
Life sciences 2015 v.138 pp. 64-71
ISSN:
0024-3205
Subject:
Alzheimer disease, acylglycerol lipase, cannabinoids, caspase-3, enzyme inhibitors, glycerol, homocysteine, immunoblotting, neurodegenerative diseases, neurons, neuroprotective effect, neurotoxicity, phosphorylation, prostaglandin synthase, rats, risk factors, serine, signal transduction, therapeutics, transcription factor NF-kappa B
Abstract:
URB602 is a selective inhibitor of monoacylglycerol lipase (MAGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl glycerol (2-AG). It has been described that URB602 significantly enhances depolarization-induced increases in 2-AG. A high level of homocysteine (Hcy) is a modifiable risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the protective effects of URB602 on Hcy-induced impairments underlying its cellular and molecular mechanism in primary cultured caudate nucleus (CN) neurons.The expressions of cyclooxygenase-2 (COX-2), ERK1/2, NF-κB and IκB-α as well as cleaved caspase-3 and p-Bcl-2 in Hcy-, URB602 or SR1 (a selective inhibitor of CB1 receptor)-treated primary cultured neurons in CN were measured by immunoblotting technique and neurotoxicity assays were performed by using Hoechst staining.The MAGL inhibitor URB602 exerted a neuroprotective effect on Hcy-induced impairment through suppression of cyclooxygenase-2 (COX-2) elevation and ERK1/2 and NF-κB phosphorylation as well as suppressions of IκB-α degradation in a CB1 receptor-dependent way. Moreover, anti-neuronal impairments of URB602 were mediated by modulating down-regulation of cleaved caspase-3 expression and up-regulation of p-Bcl-2 expression in a CB1 receptor-dependent manner in primary cultured CN neurons.These data suggest that the MAGL inhibitor is a promising therapeutic target for some neurodegenerative disorders, such as AD, via the COX-2 signaling pathway.
Agid:
6031819