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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 maintaini...
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Published in: | The Journal of pharmacology and experimental therapeutics 2005-05, Vol.313 (2), p.720-730 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 μM BK or by 100 μM ATP (IC 50 , 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
[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. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.104.079327 |