The Antiepileptic Drug Levetiracetam Decreases the Inositol 1,4,5-Trisphosphate-Dependent [Ca2+]i Increase Induced by ATP and Bradykinin in PC12 Cells

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Abstract
The present study explores the hypothesis that the new anti-epileptic drug levetiracetam (LEV) could interfere with the inositol 1,4,5-trisphosphate (IP3)-dependent release of intracellular Ca2+ initiated by Gq-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 μM BK or by 100 μM ATP (IC50, 0.39 ± 0.01 μM for BK and 0.20 ± 0.01 μM 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.