Cyclooxygenase-2 in Synaptic Signaling

Abstract

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme converting arachidonic acid to prostaglandins and a key player in neuroinflammation, has been implicated in the pathogenesis of neurodegenerative diseases such as multiple sclerosis, Parkinson's and Alzheimer's diseases, and in traumatic brain injury-and ischemia-induced neuronal damage, and epileptogenesis. Accumulated information suggests that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic modification. Inhibition or elevation of COX-2 has been shown to suppress or enhance excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE 2 , the predominant reaction product of COX-2, and the PGE 2 subtype 2 receptor (EP 2 )-protein kinase A pathway. Recent evidence shows that endogenous cannabinoids are substrates for COX-2 and can be oxygenated by COX-2 to form new classes of prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides). These COX-2 oxidative metabolites of endocannabinoids, as novel signaling mediators, modulate synaptic transmission and plasticity and cause neurodegeneration. The actions of these COX-2 metabolites are likely mediated by mitogen-activated protein kinase (MAPK) and inositol 1,4,5-trisphosphate (IP 3 ) signal transduction pathways. These discoveries suggest that the contributions of COX-2 to neurotransmission and brain malfunction result not only from its conversion of arachidonic acid to classic prostaglandins but also from its oxidative metabolism of endocannabinoids to novel prostaglandins. Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.

Association of Fatty Acid Desaturase Gene Polymorphisms with Blood Lipid Essential Fatty Acids and Perinatal Depression among Canadian Women: A Pilot Study

“…The major n-6 fatty acid in Western diets is LA, with this fatty acid representing about 90% of all the polyunsaturated fatty acids in North American diets. In the brain, however, ARA plays critical roles as a precursor of eicosanoids important in synaptic signaling, as a fatty acyl moiety in the anadamides 2-arachidonyl glycerol and arachidonyl ethanolamide, as well as other signaling molecules [13][14][15][49][50][51] . Although the possibility that increased LA or altered ARA metabolism may contribute to PPD has received little attention, altered ARA metabolism and anadamides are believed to be important in several neuropsychiatric diseases, including depression [49,50] .…”

Anti-inflammatory effect of chitosan oligosaccharides in RAW 264.7 cells

“…Furthermore, COX-2 is responsible for the production of large amounts of proinflammatory PGs at inflammatory sites. Therefore, as chronic phases of inflammation and infection correlate strongly with the increased production of PGE 2 , substances that inhibit PGE 2 production could be of therapeutic benefit [8][9][10]. Recently, it was reported that COS could inhibit nitric oxide (NO) formation in macrophage RAW 264.7 cells [11].…”

Evaluation of anticonvulsant effect of celecoxib, a selective cyclooxygenase-2 inhibitor in experimentally induced convulsions in albino rats

“…Yang and Chen suggested that COX-2 along with PGE2 regulate cell membrane excitability and long term synaptic plasticity in the hippocampus. 12 Oliveira et al reported that prostaglandin mediates induced inflammation in brain, which has epileptogenic properties. 13 Choi et al reported that glutamatergic neurons present in the hippocampus and cerebral cortex play a prominent role in onset of seizures, and also that COX-2 is mainly expressed within these regions.…”

“…15,16 PGE2 generated by induced brain COX-2 facilitates the recurrence of hippocampal seizure by stimulating neuronal excitability immediately after a seizure episode. 17 Chen et al also reported the regulatory role of PGE2 in membrane excitability and synaptic transmission in hippocampal neurons and suggested that the induced COX-2 accelerated the hyperexcitotoxicity immediately after seizure.…”