T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor

NEUROPHARMACOLOGY

卷:59

Article

Handforth, Adrian¹  Homanics, Gregg E.^2,3  Covey, Douglas F.⁴  Krishnan, Kathiresan⁴  Lee, Jae Yeol^5,6  Sakimura, Kenji⁷  Martin, Fredricka C.⁸  Quesada, Arnulfo^8,9 

[1] Vet Affairs Greater Los Angeles Healthcare Syst, Neurol Serv W127, Los Angeles, CA 90073 USA

[2] Univ Pittsburgh, Dept Anesthesiol & Pharmacol, Pittsburgh, PA USA

[3] Univ Pittsburgh, Dept Biol Chem, Pittsburgh, PA USA

[4] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA

[5] Kyung Hee Univ, Coll Sci, Res Inst Basic Sci, Seoul, South Korea

[6] Kyung Hee Univ, Coll Sci, Dept Chem, Seoul, South Korea

[7] Niigata Univ, Brain Res Inst, Dept Cellular Neurobiol, Niigata, Japan

[8] Vet Affairs Greater Los Angeles Healthcare Syst, Res Serv, Los Angeles, CA USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA

关键词: Essential tremor;    Harmaline;    Ethosuximide;    Zonisamide;    Calcium channel;    Cerebellum;    Inferior olive;   

DOI  :  10.1016/j.neuropharm.2010.05.012

来源: Elsevier

【 摘 要 】

Essential tremor is a common disorder that lacks molecular targets for therapeutic development. 1-type calcium channel activation has been postulated to underlie rhythmicity in the olivo-cerebellar system that is implicated in essential tremor. We therefore tested whether compounds that antagonize T-type calcium channel currents suppress tremor in two mouse models that possess an essential tremor-like pharmacological response profile. Tremor was measured using digitized spectral motion power analysis with harmaline-induced tremor and in the GABA(A) receptor alpha 1 subunit-null model. Mice were given ethosuximide, zonisamide, the neuroactive steroid (3 beta,5 alpha,17 beta)-17-hydroxyestrane-3-carbonitrile (ECN), the 3,4-dihydroquinazoline derivative KYS05064, the mibefradil derivative NNC 55-0396, or vehicle. In non-sedating doses, each compound reduced harmaline-induced tremor by at least 50% (range of maximal suppression: 53-81%), and in the GABA(A) alpha 1-null model by at least 70% (range 70-93%). Because the 1-type calcium channel Cav3.1 is the dominant subtype expressed in the inferior olive, we assessed the tremor response of Cav3.1-deficient mice to harmaline, and found that null and heterozygote mice exhibit as much tremor as wild-type mice. In addition, ECN and NNC 55-0396 suppressed harmaline tremor as well in Cav3.1-null mice as in wild-type mice. The finding that five 1-type calcium antagonists suppress tremor in two animal tremor models suggests that 1-type calcium channels may be an appropriate target for essential tremor therapy development. It is uncertain whether medications developed to block only the Cav3.1 subtype would exhibit efficacy. Published by Elsevier Ltd.

【 授权许可】

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