The antiepileptic drug levetiracetam decreases the inositol 1,4,5-trisphosphate-dependent [Ca2+]i increase induced by ATP and bradykinin in PC12 cells

The present study explores the hypothesis that the new antiepileptic drug levetiracetam (LEV) could interfere with the inositol 1,4,5-trisphosphate (IP3)-dependent release of intracellular Ca2+ initiated by G(q)-coupled receptor activation, a process that plays a role in triggering and maintaining seizures. We assessed the effect of LEV on the amplitude of [Ca2+](i) response to bradykinin (BK) and ATP in single Fura-2/acetoxymethyl ester-loaded PC12 rat pheochromocytoma cells, which express very high levels of LEV binding sites. LEV dose-dependently reduced the [Ca2+](i) increase, elicited either by 1 mu M BK or by 100 mu M ATP (IC50, 0.39 +/- 0.01 mu M for BK and 0.20 +/- 0.01 mu M for ATP; Hill coefficients, 1.33 +/- 0.04 for BK and 1.38 +/- 0.06 for ATP). Interestingly, although the discharge of ryanodine stores by a process of calcium-induced calcium release also took place as part of the [Ca2+](i) response to BK, LEV inhibitory effect was mainly exerted on the IP3-dependent stores. In fact, the drug was still effective after the pharmacological blockade of ryanodine receptors. Furthermore, LEV did not affect Ca2+ stored in the intracellular deposits since it did not reduce the amplitude of [Ca2+](i) response either to thapsigargin or to ionomycin. In conclusion, LEV inhibits Ca2+ release from the IP3-sensitive stores without reducing Ca2+ storage into these deposits. Because of the relevant implications of IP3-dependent Ca2+ release in neuron excitability and epileptogenesis, this novel effect of LEV could provide a useful insight into the mechanisms underlying its antiepileptic properties.