Acculmulating evidence indicates that a marked generation of oxygen free radicals derived from the metabolism of arachidonic acid causes neurodegeneration. Recently, we have demonstrated that the novel antioxidant actions mediated by phenidone, a dual inhibitor of cyclooxygenase/lipoxygenase pathways, may play a crucial role in preventing neuroexcitotoxicity in vitro [Neurosci. Lett. 272 (1999) 91], and that phenidone significantly attenuates kainic acid (KA)-induced seizures via inhibiting the synthesis of Fos-related antigen protein [Brain Res. 782 (1998) 337]. In order to extend our understanding of the pharmacological intervention of phenidone, we evaluated the antioxidant activity of this compound in vivo in the present study. In order to better understand the significance of a blockade of both the cyclooxygenase and lipoxygenase pathways, we studied the effects of aspirin (ASP; a non-selective inhibitor of cyclooxygenase), NS-398 (a selective inhibitor of cyclooxygenase-2), esculetin (an inhibitor of lipoxygenase) and phenidone on lipid peroxidation, protein oxidation, and glutathione (GSH) status in the rat hippocampus after KA administration. ASP (7.5 or 15 mg/kg), NS-398 (10 or 20 mg/kg), esculetin (5 or 10 mg/kg) or phenidone (25, 50 or 100 mg/kg) was administered orally five times every 12 h before the injection of KA (10 mg/kg, i.p.). The KA-induced toxic behavioral signs, oxidative stress (lipid peroxidation and protein oxidation), impairment of GSH status, and the loss of hippocampal neurons were dose-dependently attenuated by the phenidone, NS-398+esculetin, and ASP+esculetin. However, ASP, NS-398 and esculetin alone failed to protect against the neurotoxicities induced by KA. Therefore, the results suggest that protection by blockade of both cyclooxygenase and lipoxygenase pathways against KA-induced neuroexcitotoxicity is via antioxidant actions. However, a novel anticonvulsant/neuroprotective effect mediated by phenidone remains to be further characterized.