Endocannabinoid 2-Arachidonylglycerol Protects Primary Cultured Neurons Against LPS-Induced Impairments in Rat Caudate Nucleus

Abstract

Inflammation plays a pivotal role in the pathogenesis of many diseases in the central nervous system. Caudate nucleus (CN), the largest nucleus in the brain, is also implicated in many neurological disorders. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and the true natural ligand for CB1 receptors, has been shown to exhibit neuroprotective effects through its anti-inflammatory action from proinflammatory stimuli in hippocampus. However, it is still not clear whether 2-AG is also able to protect CN neurons from proinflammation stimuli. In the present study, we discovered that 2-AG significantly protects CN neurons in culture against lipopolysaccharide (LPS)-induced inflammatory response. 2-AG is capable of suppressing elevation of LPS-induced cyclooxygenase-2 expression associated with ERK/p38MAPK/NF-κB signaling pathway in CB1 receptor-dependant manner in primary cultured CN neurons. Moreover, 2-AG inhibits LPS-induced increase in voltage-gated sodium channel currents and hyperpolarizing shift of activation curves through CB1 receptor-dependant pathway. Our study suggests the therapeutic potential of 2-AG for the treatment of some inflammation-induced neurological disorders and pain.

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

“…URB602 suppresses excessive COX-2 expression in response to Hcy in the cultured CN neurons through the CB1 receptor, not the CB2 receptor URB602, a selective inhibitor of MAGL activity, is known to elevate the levels of endogenous 2-AG and enhance 2-AG-mediated signaling in neurons, without affecting the level of arachidonoyl ethanolamide (anandamide, AEA), another endocannabinoid ligand [37]. As a key player in inflammation, COX-2 is markedly elevated by a variety of stimulation of inflammation [12,25,41]. Hcy serves as an inducer of proinflammatory response to induce neural injury.…”

“…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.…”

“…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].…”