The effect of CGP-40116 on pilocarpine evoked seizures in mice exposed to transient episode of brain ischemia

The objective of the study was to examine the role of N-methyl-D-aspartate (NMDA) receptors in the modulation of a brain tolerance after a transient c erebral ischemia. Adult mice were exposed for 30 min to bilateral clamping of common carotid arteries (BCCA) under anaesthesia. The competitive NMDA a ntagonist CGP-40116 was administered intraperitoneally (i.p.) in two experi mental paradigms, (a) acute treatment: twice, 4.0 mg/kg; 1.5 h before the c lamping of vessels and 6 h after re-circulation and (b) chronic treatment i n a dose of 1.0 mg/kg; started 24 h after re-circulation and continued once daily for 13 days with the last injection 24 h before the induction of con vulsions. Seizures were evoked with pilocarpine (400 mg/kg, i.p.) 14 days a fter BCCA. The preliminary study showed that BCCA induced protection agains t pilocarpine toxicity. The acute treatment with CGP-40116 partially dimini shed the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug led to a marked potentiation of the effect. The whole brain gamma -arninobutyric acid (GABA) analysis performed 14 days after BCCA showed a m oderate increase in vehicle-treated mice and a significant elevation after chronic treatment with CGP-40116. It can be concluded that NMDA antagonists may exert the opposite effects on the brain tolerance against pilocarpine toxicity after BCCA. The acute treatment with CGP-40116 diminished its indu ction while the chronic low-dose treatment enhanced a brain tolerance, poss ibly through the mechanism of chemical preconditioning. (C) 2000 Elsevier S cience B.V. All rights reserved.