Nimesulide Aggravates Kainic Acid‐Induced Seizures in the Rat

Abstract

Treatment of rats with kainic acid (10 mg/kg, intraperitoneally) triggers limbic seizures. Cyclooxygenase‐2 mRNA is expressed in the hippocampus and cortex after 8 hr and marked cell loss occurs after 72 hr in the CA1‐CA3 areas of the hippocampus. We examined the effect of the cyclooxygenase‐2 inhibitor, nimesulide (N‐(4‐nitro‐2‐phenoxyphenyl)‐methanesulfonamide), on kainate‐induced seizures and delayed neurotoxicity. Nimesulide (10 mg/kg, intraperitoneally) was well tolerated given alone or 6–8 hr after kainate. However, pretreatment with nimesulide augmented seizures and increased the mortality rate from ∼10% to 69%. We examined the effect of nimesulide on delayed cell loss after 72 hr in the surviving animals with histological staining. Cell loss did not seem to be reduced in animals treated with nimesulide 6–8 hr after kainate, but in the surviving animals pretreated with nimesulide less cell loss occurred. We conclude that nimesulide should be used with caution as an antiinflammatory drug in patients with convulsive disorders.

Inhibition of endocannabinoid metabolism attenuates enhanced hippocampal neuronal activity induced by kainic acid

“…Following basal recording, rats were administered KA (10 mg kg 21 ; Sigma-Aldrich, Gillingham, UK) dissolved in saline to induce increased excitatory activity (Kunz and Oliw, 2001;Westbrook and Lothman, 1983). Separate groups of rats were injected with the FAAH inhibitor URB597 (Alexis Biochemicals, Lausen, Switzerland) at doses of 0.3 mg kg 21 (n 5 5 rats) or 1 mg kg 21 [n 5 5 rats; dissolved in 5% EtOH/5% Cremophor EL (Fluka Biochemika, Buchs, Switzerland)/90% saline, (v/v %)], or with vehicle (n 5 5 rats), coadministered with KA.…”

Effect of Phenylbutazone on Pentylenetetrazole-Induced Seizure in Mice

“…It has been reported that the pretreatment of COX-2 inhibitors including celecoxib aggravated kainic acidinduced seizure activity in rodents and aggravated kainic acid-induced neuronal death in the hippocampus (Baik et al, 1999). 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).…”

“…PGE2 activated on the electroencephalogram, while prostaglandin E1inhibit pentylenetetrazole-induced convulsions in rats (Kim et al, 2008). The drugs that inhibit COX-2 activity, such as indomethacin and selective COX-2 inhibitors, could reduce hippocampal cell death and seizure frequencies in several animal models of epilepsy (Jung et al, 2006;Kunz and Oliw, 2001a;Shafiq et al, 2003). Thus, drugs that reduce the production of PGs may have useful therapeutic effects in epilepsy.…”

Novel antiseizure drug mechanisms

“…Different drugs with anticyclooxygenase (COX) activity, such as indomethacin, aspirin and nimesulide, could either inhibit or exacerbate seizures. This is likely a result of the specific actions of COX inhibitors on the basal production of the various prostaglandins and also on the different profiles of prostaglandins produced by different seizure models [80,81]. Glucocorticoids have been demonstrated to be proconvulsant if given in large amounts in the kainate model [82].…”