Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions in mice

Abstract

Numerous studies have implicated prostaglandins as potential modulators in seizure activity. The objective of the present study was to elucidate the effect of rofecoxib (selective COX-2 inhibitor) alone or in combination with newer antiepileptic drug tiagabine (gamma-amino acid reuptake inhibitor) against pentylenetetrazol (PTZ) (80 mg/kg, i.p.)-induced chemoconvulsions in mice. Rofecoxib or tiagabine was administered 45 min prior to the PTZ challenge. In combination study, rofecoxib was administered 10 min before tiagabine and after 35 min the animals were challenged with convulsive dose of PTZ. Mean onset time of jerks, clonus and extensor phases following PTZ challenge was noted. Pretreatment with rofecoxib (1-5.0 mg/kg, i.p.) or tiagabine (1-10 mg/kg, i.p.) dose dependently protected the animals against PTZ-induced convulsions. The mean onset time of jerks, clonus and extensor phase were increased. A subeffective dose of rofecoxib (0.5 mg/kg, i.p.) potentiated the effect of subprotective dose of tiagabine (0.5 mg/kg, i.p.). The results of the present study suggested that the protective effect of rofecoxib, a COX-2 inhibitor against PTZ-induced convulsions may be possibly through the GABAergic modulation. Rofecoxib may have a place as adjuvant therapy with standard antiepileptic drugs such as tiagabine in the treatment of epilepsy.

Effect of Phenylbutazone on Pentylenetetrazole-Induced Seizure in Mice

“…Similarly the effect of tiagabine, a GABA reuptake inhibitor and a newer antiepileptic was also potentiated by rofecoxib (Dhir and Kulkarni, 2006). Such similar studies have been reported by Tandon et al (2003) against electro-and chemoconvulsions, respectively (Tandon et al, 2003).…”

“…In this study PTZ-induced seizure threshold in control mice was 34.75±1.54 mg kg −1 and pretreatment with Phenylbutazone significantly increased the PTZinduced seizure threshold in a dose dependently manner in mice. Previous studies have been demonstrated the protective effect of COX-inhibitors in various models of epilepsy in animals (Dhir and Kulkarni, 2006;Dhir, 2005;, but effects of intraperitoneally injection of different doses of NSAIDs have not shown. The Effect of COX inhibitors on neuronal death also is disputed.…”

“…The broad COX inhibitor such as ibuprofen caused deficits in spatial learning in a water maze (Shaw et al, 2003), whereas several reports showed the post-treatment of COX-2 inhibitors restored the memory deficit and learning behaviors and prevented seizure-induced neuronal death (Gobbo and O'Mara, 2004;Kunz and Oliw, 2001a;2001b). The effects of COX-2 inhibitors on the PTZ-induced seizures are also controversial; Dhir and coauthors reported the anticonvulsant effect of COX-2 inhibitors (Dhir and Kulkarni 2006;Dhir et al, 2006a), while Akasura and coauthors showed that COX-2 inhibitors have neither anticonvulsant nor proconvulsant effects on PTZ-induced seizures (Akarsu et al, 2006). Treatment with indomethacin, a COX-inhibitor offered full recovery in the E1 mouse, a genetically prone mouse (Okada et al, 2001).…”

“…Glutamate is anc excitatory neurotransmitter that can leads to decrease in GABA input, results in convulsions. Therefore, it may be conceived that COX inhibitors is acting through glutamate and GABAergic modulation (Dhir and Kulkarni, 2006). Other mechanisms by which PGE2 could indirectly contribute to synaptic plasticity include modulation of adrenergic, noradrenegic and glutamatergic neurotransmission and regulation of membrane excitability (Minghetti and Pocchiari, 2007).…”

“…Furthermore, the induction of astrocytic COX-2 was observed in epilepsy patients with hippocampal sclerosis and the concentrations of PGs increased in the cerebrospinal fluid of these patients (Desjardins et al, 2003). In one model of lithium chloride and tacrine induced status epilepticus seizures, there was an increased expression of COX-2 enzyme protein particularly, in dorsal hippocampus, further resulting in elevated brain PGE2 levels (Dhir and Kulkarni, 2006). In another study, COX-2 induction was found to be responsible for epileptic neuronal injury and that selective COX-2 inhibitors are neuroprotective (Kawaguchi et al, 2005).…”