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

Adrian Handforth, Gregg E. Homanics, Douglas F. Covey, Kathiresan Krishnan, Jae Yeol Lee, Kenji Sakimura, Fredricka C. Martin, Arnulfo Quesada

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Essential tremor is a common disorder that lacks molecular targets for therapeutic development. T-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 GABAA receptor α1 subunit-null model. Mice were given ethosuximide, zonisamide, the neuroactive steroid (3β,5α,17β)-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 GABAA α1-null model by at least 70% (range 70-93%). Because the T-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 T-type calcium antagonists suppress tremor in two animal tremor models suggests that T-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.

Original languageEnglish
Pages (from-to)380-387
Number of pages8
JournalNeuropharmacology
Volume59
Issue number6
DOIs
StatePublished - Nov 2010

Keywords

  • Calcium channel
  • Cerebellum
  • Essential tremor
  • Ethosuximide
  • Harmaline
  • Inferior olive
  • Zonisamide

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