ANTIEPILEPTIC EFFECTS OF ALLOPURINOL ON EL MICE ARE ASSOCIATED WITH CHANGES IN SOD ISOENZYME ACTIVITIES

We have investigated the potential antiepileptic action of superoxide dismutase (SOD) activities in the brain of the epileptic mutant EL mou se. EL mice which experienced frequent seizures (EL[s]) had abnormally low levels of SOD isoenzyme activity in the hippocampal area. Once ep ileptogenicity was established in these animals, activity of cyanide-s ensitive Cu,Zn-SOD was maintained at significantly lower levels than i n control mice. However, cyanide-insensitive Mn-SOD activity was not d ifferent from non-epileptic controls. In EL mice which had not experie nced seizure provoking stimulations and exhibited no seizures (EL[ns]) there was moderately lower levels of SOD isoenzyme activities compare d to controls. In spite of the low level of Cu,Zn-SOD activity in EL[s ] mice, the Cu,Zn-SOD protein content was high in the hippocampus of t hese animals, suggesting that inactive Cu,Zn-SOD might be induced duri ng development. After allopurinol (ALP) was given orally to EL[s] mice , Cu,Zn-SOD activities increased dramatically in the hippocampus and s eizure activity was decreased. Even after 48 h, when antiepileptic act ion of ALP was lost, the SOD activity was maintained at the high level associated with initial ALP administration. EL[s] mice also showed DN A fragmentation in the hippocampal CA1 region and the parietal cortex, detected with in situ terminal transferase-mediated dUTP nick labelin g with the aid of alkaliphosphatase or peroxidase. The degree of DNA f ragmentation was less severe in EL[ns] mice. We propose that abnormali ties in region specific Cu,Zn-SOD isoenzyme activity might produce fre e radicals, leading to DNA fragmentations and cell loss. This might co ntribute to hippocampal epileptogenesis in EL mice. (C) 1998 Elsevier Science B.V. All rights reserved.