QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.079327v1 313/2/720    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cataldi, M. Articles by Annunziato, L. Search for Related Content PubMed PubMed Citation Articles by Cataldi, M. Articles by Annunziato, L.

CELLULAR AND MOLECULAR

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

Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy

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 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 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.

Address correspondence to: Dr. Lucio Annunziato, Division of Pharmacology, Department of Neuroscience, Federico II University of Naples, Via Pansini no. 5, 80131 Naples, Italy. E-mail: lannunzi{at}unina.it

This article has been cited by other articles:

				R. Surges, K. E. Volynski, and M. C. Walker Review: Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited Therapeutic Advances in Neurological Disorders, July 1, 2008; 1(1): 13 - 24. [Abstract] [PDF]

				T. A. Glauser, R. Ayala, R. D. Elterman, W. G. Mitchell, C. B. Van Orman, L. J. Gauer, Z. Lu, and on behalf of the N159 Study Group Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures Neurology, June 13, 2006; 66(11): 1654 - 1660. [Abstract] [Full Text] [PDF]