T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor |
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Authors: | Adrian Handforth Gregg E. Homanics Kathiresan Krishnan Kenji Sakimura Arnulfo Quesada |
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Affiliation: | a Neurology Service (W127), Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA b Departments of Anesthesiology and Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA c Department of Developmental Biology, Washington University School of Medicine, St Louis, MO, USA d Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul, Republic of Korea e Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan f Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA g Department of Neurobiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA |
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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. |
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Keywords: | Essential tremor Harmaline Ethosuximide Zonisamide Calcium channel Cerebellum Inferior olive |
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