Anticonvulsant activity of omeprazole in rats

Omeprazole has long been used as an effective agent to treat peptic ulcer. Recent studies have shown that in addition to inhibiting the H(+)-K(+)ATPase, it also inhibits carbonic anhydrase (CA) types I, II and IV. This led us to investigate its anticonvulsant effect in a rat model of electroconvulsion. Since other carbonic anhydrase inhibitors like acetazolamide induce tolerance upon repeated use, we tested the tolerance potential of omeprazole upon repeated administration of up to 1 week. The animals were divided into four groups receiving normal saline, omeprazole 0.5, 1 or 2 mg/kg intraperitoneally. CC(50), i.e. the threshold current inducing tonic hind limb extension in 50% of the rats was established using a technoconvulsometer which delivers currents of varying intensity via ear clip electrodes. The CC(50) was established 30 min after injection of omeprazole. In another group of rats, omeprazole 2 mg/kg was given for 6 days and the CC(50) determined on days 0, 1, 3 and 6. Also the concentration of omeprazole in the brain was determined using high performance liquid chromatography. The CC(50) in vehicle-treated rats was 98 mA, which increased to 126, 135 and 162 mA with 0.5, 1 and 2 mg/kg of omeprazole, respectively. On repeat-dose studies the CC(50) on day 0 was 96 mA, on day 1 166 mA, on day 3 129 mA and on day 6 102 mA. The average brain concentration of omeprazole was 53.2+/-6.9 ng/g of brain tissue. In conclusion, this study has shown omeprazole to be an effective anticonvulsant, but rapidly develops tolerance to its anticonvulsant action. This study can stimulate interest in the development of agents with dual function -- inhibition of CA as well as the accompanying Na(+)-K(+) ATPase -- and such agents may prove to be effective anticonvulsants without exhibiting tolerance.