Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against Homocysteine-Induced Impairments in Rat Caudate Nucleus Through CB1 Receptor

Abstract

Homocysteine (Hcy) is a high risk factor for Alzheimer's disease (AD). Caudate nucleus (CN), the major component of basal ganglia in the brain, is also involved in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the true natural ligand for cannabinoid type-1 (CB1) receptors and the most abundant endogenous cannabinoid, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in the hippocampus and CN. However, it is still not well understood whether that 2-AG is also able to protect CN neurons from Hcy harmful insults. In the present work, we explored that 2-AG significantly protects CN neurons in culture against Hcy-induced response. 2-AG is capable of inhibiting elevation of Hcy-induced cyclooxygenase-2 expression associated with nuclear factor-kappaB/p38MAPK/ERK1/2 signaling pathway through CB1 receptors-dependent way in primary cultured CN neurons. Our study reveals the therapeutic potential for 2-AG for the treatment of neurodegenerative diseases, such as AD.

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

“…URB602 inhibits the phosphorylation of NF-κB and degradation of IκB-α in response to Hcy in the primary CN neurons via the CB1 receptor A preceding study showed that the NF-κB signaling pathway was involved in the lipopolysaccharide (LPS)-induced or Hcy-induced neuroinflammation in the hippocampus and CN [14,25,40,41]. To determine whether this signaling pathway is involved in the URB602 suppression of COX-2 induced by Hcy in the CN neurons, we detected the phosphorylation level of NF-κB in the CN neurons.…”

“…In the hippocampus and CN, mitogen-activated protein kinase (MAPK) ERK1/2 is also known to be involved in the antiinflammatory properties of eCBs [12,14,25,40,41]. Therefore, we tested the level of phospho-ERK1/2 (p-ERK1/2) by Western blot.…”

“…The methods for obtaining primary cultured CN neurons have been described in detail elsewhere [14,25]. Briefly, primary CN cultures were obtained from neonatal Sprague-Dawley rats (within 24 h) which were provided by the Experimental Animal Research Center of Hubei Province.…”

“…The p38MAPK signal pathway is one of the important branches of the MAPK pathway [12,14,25,40,41]. To explore whether the p38MAPK signal pathway is involved in the effects of URB602 in the CN neurons, we treated the CN neurons with Hcy in the absence and presence of URB602 or SR1.…”

“…In the last decade, the endocannabinoid system (eCBs), comprised of cannabinoid receptors (CB1 and CB2), endocannabinoids and their interrelated biosynthesis or degradation enzymes, has been recognized to be important in controlling many physiological and pathological processes and has become an area of interest for novel drug development [11,12,14,25]. 2-Arachidonoyl glycerol (2-AG), the main endocannabinoid, is synthesized on demand and rapidly inactivated by enzymatic hydrolysis, therefore limiting their potential protective effects [5].…”