Excitotoxicity involves over activation of brain excitatory glutamate receptors? and has been implicated in neurological, neurodegenerative and neuropsychiatric diseases.? Metabolism of AA through the PLA2 - COX pathway is increased after excitotoxic stimulation. However, the individual roles of the COX isoforms in this process are not well established. We assessed the role of the COX isoforms in the process of excitotoxicity by exposing either COX-1 KO or COX-2 KO mice to the prototypic excitotoxin KA. Seizure intensity and neuronal damage were significantly elevated in KA-exposed COX-2 KO, but not in COX-1 KO, mice. The increased susceptibility was not associated with an alteration in KA receptor binding activity or mediated through the CB1 endocannabinoid receptor. The frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was decreased in the CA1 pyramidal neurons of COX-2 KO mice, suggesting an alteration of GABAergic function. In wild-type mice, six weeks treatment with the COX-2 selective inhibitor celecoxib recapitulated the increased susceptibility to KA-induced excitotoxicity observed in COX-2 KO mice, further supporting the role of COX-2 in the excitotoxic process. The increased susceptibility to KA was also associated with decreased brain levels of PGE2, a biomarker of COX-2 activity. Our results suggest that COX-2 activity and its specific products may modulate neuronal excitability by affecting GABAergic neurotransmission. Further, inhibition of COX-2 but not COX-1, may increase the susceptibility to seizures.
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