Levetiracetam Inhibits Glutamate Transmission Through Presynaptic P/Q-type Calcium Channels on the Granule Cells of the Dentate Gyrus

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2009 Nov 6

PMID 19888964

Citations 32

Authors

Chun-Yao Lee

Chih-Chuan Chen

Horng-Huei Liou

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: Levetiracetam is an effective anti-epileptic drug in the treatment of partial and generalized seizure. The purpose of the present study was to investigate whether levetiracetam regulates AMPA and NMDA receptor-mediated excitatory synaptic transmission and to determine its site of action in the dentate gyrus (DG), the area of the hippocampus that regulates seizure activities.

Experimental Approach: Whole-cell patch-clamp method was used to record the AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSC(AMPA) and EPSC(NMDA)) in the presence of specific antagonists, from the granule cells in the DG in brain slice preparations from young Wistar rats (60-120 g).

Key Results: Levetiracetam (100 microM) inhibited both evoked EPSC(AMPA) and EPSC(NMDA) to an equal extent (80%), altered the paired-pulse ratio (from 1.39 to 1.25), decreased the frequency of asynchronous EPSC and prolonged the inter-event interval of miniature EPSC(AMPA) (from 2.7 to 4.6 s) without changing the amplitude, suggesting a presynaptic action of levetiracetam. The inhibitory effect of levetiracetam on evoked EPSC(AMPA) was blocked by omega-agatoxin TK (100 nM), a selective P/Q-type voltage-dependent calcium channel blocker, but not by nimodipine (10 microM) or omega-conotoxin (400 nM).

Conclusions And Implications: These results suggest that levetiracetam modulated the presynaptic P/Q-type voltage-dependent calcium channel to reduce glutamate release and inhibited the amplitude of EPSC in DG. This effect is most likely to contribute to the anti-epileptic action of levetiracetam in patients.

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References

Zucker R . Short-term synaptic plasticity. Annu Rev Neurosci. 1989; 12:13-31. DOI: 10.1146/annurev.ne.12.030189.000305. View

Redman S . Quantal analysis of synaptic potentials in neurons of the central nervous system. Physiol Rev. 1990; 70(1):165-98. DOI: 10.1152/physrev.1990.70.1.165. View

Muralidharan A, Bhagwagar Z . Potential of levetiracetam in mood disorders: a preliminary review. CNS Drugs. 2006; 20(12):969-79. DOI: 10.2165/00023210-200620120-00002. View

Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, Margineanu D . Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Seizure. 2001; 10(4):279-86. DOI: 10.1053/seiz.2000.0504. View

Ozawa S, Kamiya H, Tsuzuki K . Glutamate receptors in the mammalian central nervous system. Prog Neurobiol. 1998; 54(5):581-618. DOI: 10.1016/s0301-0082(97)00085-3. View

Gorji A, Madeja M, Straub H, Kohling R, Tuxhorn I, Ebner A . Effect of levetiracetam on epileptiform discharges in human neocortical slices. Epilepsia. 2002; 43(12):1480-7. DOI: 10.1046/j.1528-1157.2002.23702.x. View

Pisani A, Bonsi P, Martella G, De Persis C, Costa C, Pisani F . Intracellular calcium increase in epileptiform activity: modulation by levetiracetam and lamotrigine. Epilepsia. 2004; 45(7):719-28. DOI: 10.1111/j.0013-9580.2004.02204.x. View

Alexander S, Mathie A, Peters J . Guide to Receptors and Channels (GRAC), 3rd edition. Br J Pharmacol. 2008; 153 Suppl 2:S1-209. PMC: 2275471. DOI: 10.1038/sj.bjp.0707746. View

Perkel D, Nicoll R . Evidence for all-or-none regulation of neurotransmitter release: implications for long-term potentiation. J Physiol. 1993; 471:481-500. PMC: 1143972. DOI: 10.1113/jphysiol.1993.sp019911. View

10.

Mori Y, Mikala G, Varadi G, Kobayashi T, Koch S, Wakamori M . Molecular pharmacology of voltage-dependent calcium channels. Jpn J Pharmacol. 1996; 72(2):83-109. DOI: 10.1254/jjp.72.83. View

11.

Nadler J . The recurrent mossy fiber pathway of the epileptic brain. Neurochem Res. 2003; 28(11):1649-58. DOI: 10.1023/a:1026004904199. View

12.

Yang X, Weisenfeld A, Rothman S . Prolonged exposure to levetiracetam reveals a presynaptic effect on neurotransmission. Epilepsia. 2007; 48(10):1861-9. DOI: 10.1111/j.1528-1167.2006.01132.x. View

13.

Niespodziany I, Klitgaard H, Margineanu D . Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci Lett. 2001; 306(1-2):5-8. DOI: 10.1016/s0304-3940(01)01884-5. View

14.

Craig A, Boudin H . Molecular heterogeneity of central synapses: afferent and target regulation. Nat Neurosci. 2001; 4(6):569-78. DOI: 10.1038/88388. View

15.

Qian J, Noebels J . Presynaptic Ca2+ channels and neurotransmitter release at the terminal of a mouse cortical neuron. J Neurosci. 2001; 21(11):3721-8. PMC: 6762720. View

16.

Cunningham M, Woodhall G, Thompson S, Dooley D, Jones R . Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci. 2004; 20(6):1566-76. DOI: 10.1111/j.1460-9568.2004.03625.x. View

17.

Lee C, Lee C, Tsai T, Liou H . PKA-mediated phosphorylation is a novel mechanism for levetiracetam, an antiepileptic drug, activating ROMK1 channels. Biochem Pharmacol. 2008; 76(2):225-35. DOI: 10.1016/j.bcp.2008.04.012. View

18.

Reid C, Bekkers J, Clements J . Presynaptic Ca2+ channels: a functional patchwork. Trends Neurosci. 2003; 26(12):683-7. DOI: 10.1016/j.tins.2003.10.003. View

19.

Muller M, Felmy F, Schneggenburger R . A limited contribution of Ca2+ current facilitation to paired-pulse facilitation of transmitter release at the rat calyx of Held. J Physiol. 2008; 586(22):5503-20. PMC: 2655367. DOI: 10.1113/jphysiol.2008.155838. View

20.

Rigo J, Hans G, Nguyen L, Rocher V, Belachew S, Malgrange B . The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol. 2002; 136(5):659-72. PMC: 1573396. DOI: 10.1038/sj.bjp.0704766. View