Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor increases pentylenetetrazol seizure threshold in mice: possible involvement of adenosinergic mechanism

Abstract

Multiple lines of investigations have explored the role of cyclooxygenases (COX) in epilepsy and related neuropsychiatric disorders. Cyclooxygenase particularly, COX-2 expression was found to increase in brain during seizure paradigms. The present study was carried out to investigate the effect of rofecoxib, a selective COX-2 inhibitor against pentylenetetrazol (PTZ i.v.) seizure threshold in mice. The study was further extended to elucidate the possible involvement of adenosinergic mechanism in mediating its anticonvulsant action. Minimal dose of PTZ (i.v., mg/kg) needed to induce different phases (myoclonic jerks, generalized clonus and tonic extension) of PTZ convulsions were noted as an index of seizure threshold. Acute administration of rofecoxib (4mg/kg, i.p.) before PTZ infusion produced an elevation of seizure threshold for all the phases of convulsions. A lower dose of rofecoxib (2mg/kg, i.p.) showed an increase in PTZ seizure threshold for the onset of myoclonic jerks and tonic extension phases but not for generalized clonus. A still lower dose of rofecoxib (1mg/kg, i.p.) failed to increase the threshold in any of the convulsive phases induced by PTZ i.v. infusion. Pretreatment with sub-effective dose of rofecoxib (1mg/kg, i.p.) enhanced the action of sub-protective doses of either adenosine (25mg/kg, i.p.) or 2-chloroadenosine (1 or 2mg/kg, i.p.) in increasing the seizure threshold. On the contrary, treatment with caffeine (100 or 200mg/kg, i.p.) or theophylline (50 or 100mg/kg, i.p.), both non-selective A(1)/A(2) adenosine receptor antagonists reversed the anticonvulsant effect of rofecoxib (4mg/kg, i.p.). Further, dipyridamole (5mg/kg, i.p.), an adenosine uptake inhibitor displayed an anticonvulsant effect with rofecoxib (1mg/kg, i.p.). The study for the first time demonstrated the possible involvement of adenosinergic system in the anticonvulsant effects of rofecoxib against PTZ i.v. seizure threshold paradigm in mice.