Research ReportInvolvement of endogenous prostaglandin F2α on kainic acid-induced seizure activity through FP receptor: The mechanism of proconvulsant effects of COX-2 inhibitors
Introduction
Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat febrile conditions, pain states, and in the prevention of many diseases. However the role of prostaglandins (PGs) and NSAIDs in seizures has been disputed. COX-2 inhibitors such as NS-398, indomethacin and celecoxib and other NSAID aggravate seizure activity in animal models (Steinhauer and Hertting, 1981, Baik et al., 1999). In humans, prolonged generalized seizures result in injury and death of neurons. Neuronal damage occurs in the hippocampus, and memory impairment is a major neurological sequel. Systemic administration of kainic acid (KA) in rodents induces epileptic seizures and neuropathological changes in the limbic system, including the hippocampus and the amygdala (Lothman and Collins, 1981). The behavioral and histopathological features of kainic acid-induced seizures closely resemble temporal lobe epilepsy in humans.
The effect of COX-2 inhibitors on neuronal death is disputed. We previously reported that the pre-treatment with COX-2 inhibitors, including celecoxib, aggravated KA-induced seizures in rodents and increased neuronal death in the hippocampus (Baik et al., 1999). The broad COX inhibitor, ibuprofen, caused deficits in spatial learning in a water maze (Shaw et al., 2003), whereas several reports showed that the post-treatment with COX-2 inhibitors corrected learning and memory deficits and prevented seizure-induced neuronal death (Kunz and Oliw, 2001a, Gobbo and O'Mara, 2004). However, the notion that COX-2 inhibition is advantageous in neuropathologic conditions has recently been challenged (Salzberg-Brenhouse et al., 2003, Ajmone-Cat et al., 2006). Thus, it is necessary to clarify the roles of COX isozymes and PGs in neurological function.
Many studies suggest that COX-2 and PGs play an important role in epilepsy. COX-2 expression is induced in the hippocampus after KA-induced seizures, electrically induced kindling, and in the El mice (Baik et al., 1999, Okada et al., 2001). The effects of COX inhibitors, which are suggested to prevent the production of PGs during seizure activity, are inconsistent across seizure models, types of COX inhibitors, and time of administration (Wallenstein and Mauss, 1984). Thus, the role of COX isozymes and PGs in seizures is not clear. The role of increased PGs during seizures is a sustained issue in this field. High concentrations of PGE2, PGD2 and PGF2α are released during seizures and these PGs might influence seizure activity. Studies of seizure activity in animal models indicate that PGD2 and PGE1 have seizure-inhibiting properties (Forstermann et al., 1984, Bhattacharya and Parmar, 1987). In contrast, intracerebroventricular administration of PGF2α promotes chemically and electrically induced seizures (Climax and Sewell, 1981), while intra-amygdaloid administration of PGs had no effect on electrically kindled seizures (Croucher et al., 1991).
In the present study, we observed KA-seizure activity aggravated by COX inhibitors to examine the role of endogenous PGs during KA-induced seizures. We sought to determine 1) whether pre- or post-treatment with COX-2 inhibitors has similar effects on KA-induced seizures and neuronal death, 2) whether intracisternally administered PGE2, PGD2 and PGF2α modulate KA-induced seizures aggravated by COX-2 inhibitors, and 3) whether orally administered celecoxib, a NSAID used to treat chronic pain, has a similar effect on kainic acid-induced seizure activity as other COX-2 inhibitors.
Section snippets
Effect of COX inhibitor pre- and post-treatment on KA-induced seizure activity
Kainic acid (KA, 20 mg/kg; i.p.) induced seizure activity after 5 min and seizures were observed up to 2 h after application. Seizure rating scores peaked approximately 60 min after KA injection. Pre-treatment with COX inhibitors was associated with increases in KA-induced seizure activity (Fig. 1A). All of the COX inhibitors aggravated seizure activity 10 min after KA injection and peaked about 40–60 min later. Nimesulide (10 mg/kg), a COX-2 selective inhibitor aggravated seizure activity more
Discussion
In the present study, COX inhibitors administered before or after KA injection aggravated KA-induced seizure activity and hippocampal neuronal death. The intracisternal administration of PGF2α, but not PGE2 or PGD2, decreased aggravated seizure activity, and also reduced neuronal death. PGF2α (0.02 ng/kg in 10 μl, i.c.v) alone had little effect on KA-induced seizure activity in the absence of COX inhibitors. However, a FP receptor antagonist (10 and 50 ng/35 g mouse; i.c.v.) significantly
Experimental procedures.
All experimental procedures were approved by the Animal Care and Use Committee of the Ajou University. Adult male ICR mice weighing approximately 35 g were obtained from Koatech (Gyunggi, Korea). Animals were housed 3–4 per cage with free access to food and water.
Acknowledgment
This study was supported by the Chronic Inflammatory Disease Research Center (R13-2003-019-01005-0).
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