Cyclooxygenase-2 inhibitor inhibits the hippocampal synaptic reorganization by inhibiting MAPK/ERK activity and modulating GABAergic transmission in pilocarpine-induced status epilepticus rats

摘要

Recurring and spontaneous seizures in epilepsy result from cell signaling aberrations thought to include synaptic reorganization and various neurotransmitter abnormalities, especially gamma-amino butyric acid (GABA) and glutamate. Cyclooxygenase-2 (COX-2) activity produces oxidative stress and results in the production of prostaglandins that have many injurious effects. COX-2 transcription is induced by synaptic activity; therefore COX-2 may play a significant role in the pathogenesis of epilepsy. The present study aimed to elucidate the effect of COX-2 inhibitors on the pilocarpine-induced epileptic status rats and the possible mechanism of action. Celecoxib was administered 45 min prior to the pilocarpine administration. Celecoxib attenuated the likelihood of developing spontaneous recurrent seizures after pilocarpine-induced prolonged seizure. COX-2 protein expression was increased in hippocampus, which peaked 1 h and increased persistently 28 days after seizures. During the latent period, Celecoxib prevented microglia activation in the hilus and inhibited the abnormal neurogenesis and astrogliosis in the hippocampus. Celecoxib attenuated the activation of mitogen-activated protein kinase (MAPK). Phosphorylation of extracellular signal-regulated protein kinase (ERK) expression in the epilepsy-only group was 1.4 and 1.2 times higher than that of the epilepsy–celecoxib group at 1 and 4 days after status epilepticus (SE), respectively. MAPK/ERK is a signal pathway related to cell proliferation and differentiation. Protein expression from C-fos, an immediate early gene, was downregulated after celecoxib treatment. Also celecoxib upregulates the expression of GABAA receptors, mediating the majority of fast inhibitor synaptic transmissions in the brain. NS-398, another cox-2 inhibitor, enhanced the frequency and decay time of miniature inhibited postsynaptic currents (mIPSCs). In conclusion, the results of the present study strongly suggest the possible role of COX-2 in the pathophysiology of epilepsy and that the use of COX-2 inhibitors might be an adjuvant therapy in the treatment of epilepsy.