COX‐2 oxidative metabolite of endocannabinoid 2‐AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity

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Abstract
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 E2glyceryl ester (PGE2‐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 PGE2‐G are not mediated via a cannabinoid receptor 1, but mediated through ERK, p38 mitogen‐activated protein kinase, IP3, and NF‐κB signal transduction pathways. In addition, the PGE2‐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.