Endocannabinoid 2-arachidonoylglycerol protects neurons by limiting COX-2 elevation.
Endocannabinoids are involved in synaptic signaling and neuronal protection; however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1 and CB2), is a substrate for cyclooxygenase-2 (COX-2) and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appeared to be mediated via the pertussis toxin-sensitive G protein-coupled CB1 receptor and MAPK/NF-kappaB signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches for protecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.
Zhang
Jian
J
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
Chen
Chu
C
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D004622:Embryo, Mammalian; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology*; D006624:Hippocampus / Q000201:enzymology; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000201:enzymology; D009474:Neurons / Q000201:enzymology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2