Monoacylglycerol Lipase Inhibitor Protects Primary Cultured Neurons Against Homocysteine-induced Impairments in Rat Caudate Nucleus through COX-2 signaling.

AIMS:

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. 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.

MAIN METHODS:

The expressions of cyclooxygenase-2 (COX-2), ErkI/II, 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.

KEY FINDINGS:

MAGL inhibitor URB602 exerted 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 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 CB1 receptor-dependent manner in primary cultured CN neurons.

SIGNIFICANCE:

These data suggest that MAGL inhibitor is a promising therapeutic target for some neurodegenerative disorders, such as AD, via COX-2 signaling pathway.
Copyright © 2015. Published by Elsevier Inc.