Journal
NEUROSCIENCE LETTERS
Volume 454, Issue 1, Pages 91-96Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.neulet.2009.02.065
Keywords
Epilepsy; GABA; Glutamate; Inositol-1,4,5-triphosphate receptor; Zonisamide
Categories
Funding
- Japanese Ministry of Education, Science and Culture [18390316, 18659330]
- Mitsubishi Pharma Research Foundation
- Japan Epilepsy Research Foundation
- Grants-in-Aid for Scientific Research [18659330, 18390316] Funding Source: KAKEN
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To clarify the antiepileptic mechanisms of zonisamide (ZNS), we determined the interaction between ZNS and inositol-1,4.5-triphosphate receptor (IP3R) on exocytosis of GABA and glutamate in rat frontal cortex using microdialysis. ZNS increased basal GABA release, but not glutamate, concentration-dependently, and reduced concentration-dependently K+-evoked GABA and glutamate releases. Inhibition and activation of IP3R reduced and enhanced basal and K+-evoked GABA releases, respectively. The K+-evoked glutamate release was reduced and enhanced by IP3R antagonist and agonist, respectively, whereas basal glutamate release was increased by IP3R agonist but not affected by IP3R antagonist. Under extracellular Ca2+ depletion, IP3R agonist increased basal GABA and glutamate releases. The latter effects of IP3R agonist were weakly enhanced by ZNS, but such stimulatory action of ZNS was abolished by extracellular Ca2+ depletion. In contrast, ZNS-inhibited the stimulatory effect of IP3R agonist on K+-evoked release. The stimulatory effect of IP3R agonist on basal release was regulated by N-type voltage-sensitive Ca2+ channel (VSCC) rather than P- and L-type VSCCs, whereas the stimulatory effect of IP3R agonist on K+-evoked release was regulated by P- and L-type VSCCs rather than N-type VSCC. These results suggest that ZNS-activated N-type VSCC enhances IP3R-associated neurotransmitter release during resting stage, whereas ZNS-induced suppression of P- and L-type VSCCs possibly attenuates IP3R-associated neurotransmitter release during neuronal hype rexcitability. Therefore, the combination of both of these two actions of ZNS on IP3R-associated neurotransmitter release mechanism seems to be involved, at least in part, in the mechanisms of antiepileptic and neuroprotective actions of ZNS. Crown Copyright (C) 2009 Published by Elsevier Ireland Ltd. All rights reserved.
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