COX-2 oxidative metabolite of endocannabinoid 2-AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity.
Neuroinflammation has been implicated in the pathogenesis of neurodegenerative diseases. Cyclooxygenase-2 (COX-2), an inducible enzyme converting arachidonic acid (AA) to prostaglandins, is the key player in neuroinflammation. It has been long thought that the COX-2-mediated neuronal injury/degeneration is attributed to the increased production of AA-derived prostaglandins. Recent studies show that endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is a natural substrate for COX-2, and it can be oxygenated by COX-2 to form prostaglandin glyceryl esters. In this study, we demonstrate that prostaglandin E(2) glyceryl ester (PGE(2)-G), a major COX-2 oxidative metabolite of 2-arachidonoylglycerol, enhanced hippocampal glutamatergic synaptic transmission indicated by the increased frequency of miniature excitatory post-synaptic currents, and induced neuronal injury/death revealed by the terminal transferase dUTP nick end labeling staining and caspase 3 activation. The actions of PGE(2)-G are not mediated via a cannabinoid receptor 1, but mediated through ERK, p38 mitogen-activated protein kinase, IP(3), and NF-kappaB signal transduction pathways. In addition, the PGE(2)-G-induced neurotoxicity is attenuated by blockade of the NMDA receptors. Our results suggest that the COX-2 oxidative metabolism of endocannabinoids is an important mechanism contributing to the inflammation-induced neurodegeneration.
Sang
Nan
N
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Zhang
Jian
J
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Chen
Chu
C
Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001095:Arachidonic Acids / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism*; D051379:Mice; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism* / Q000633:toxicity; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D009498:Neurotoxins; C518978:prostaglandin E2 glyceryl ester; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate; D051546:Cyclooxygenase 2; D053148:Caspase 3; D015232:Dinoprostone