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 anti-epileptic drug levetiracetam (LEV) could interfere with the inositol 1,4,5-trisphosphate (IP(3))-dependent release of intracellular Ca(2+) 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 [Ca(2+)](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 [Ca(2+)](i) increase, elicited either by 1 microM BK or by 100 microM ATP (IC(50), 0.39 +/- 0.01 microM for BK and 0.20 +/- 0.01 microM 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 [Ca(2+)](i) response to BK, LEV inhibitory effect was mainly exerted on the IP(3)-dependent stores. In fact, the drug was still effective after the pharmacological blockade of ryanodine receptors. Furthermore, LEV did not affect Ca(2+) stored in the intracellular deposits since it did not reduce the amplitude of [Ca(2+)](i) response either to thapsigargin or to ionomycin. In conclusion, LEV inhibits Ca(2+) release from the IP(3)-sensitive stores without reducing Ca(2+) storage into these deposits. Because of the relevant implications of IP(3)-dependent Ca(2+) release in neuron excitability and epileptogenesis, this novel effect of LEV could provide a useful insight into the mechanisms underlying its antiepileptic properties.
Cataldi
Mauro
M
Division of Pharmacology, Department of Neuroscience, Federico II University of Naples, Italy.
Lariccia
Vincenzo
V
Secondo
Agnese
A
di Renzo
Gianfranco
G
Annunziato
Lucio
L
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077287:Levetiracetam; D016716:PC12 Cells; D010889:Piracetam / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051381:Rats
D000927:Anticonvulsants; D000077287:Levetiracetam; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D001920:Bradykinin; D002118:Calcium; D010889:Piracetam