title: Monoacylglycerol lipase inhibitor protects primary cultured neurons against homocysteine-induced impairments in rat caudate nucleus through COX-2 signaling.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Physiology and Pathophysiology, College of Medical Sciences, China Three Gorges University, 443002 Yichang, Hubei, PR China.
authors.forename: Manman
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Physiology and Pathophysiology, College of Medical Sciences, China Three Gorges University, 443002 Yichang, Hubei, PR China.
authors.forename: Yongli
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Physiology and Pathophysiology, College of Medical Sciences, China Three Gorges University, 443002 Yichang, Hubei, PR China.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Physiology and Pathophysiology, College of Medical Sciences, China Three Gorges University, 443002 Yichang, Hubei, PR China. Electronic address: yhw0224@yahoo.com.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yang
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects*; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006710:Homocysteine / Q000633:toxicity*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D043884:Receptor, Cannabinoid, CB1; C501835:URB602; D006710:Homocysteine; D051546:Cyclooxygenase 2; D008994:Monoacylglycerol Lipases
keywords: Alzheimer's disease; Caudate nucleus; Cyclooxygenase-2; Endocannabinoid; Monoacylglycerol lipase; Neuroinflammation