T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor.
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 GABA(A) 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 GABA(A) 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.
Handforth
Adrian
A
Neurology Service (W127), Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Los Angeles, CA 90073, USA. charles.handforth@va.gov
Homanics
Gregg E
GE
Covey
Douglas F
DF
Krishnan
Kathiresan
K
Lee
Jae Yeol
JY
Sakimura
Kenji
K
Martin
Fredricka C
FC
Quesada
Arnulfo
A
D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D020329:Essential Tremor / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004962:Estranes / Q000627:therapeutic use; D005013:Ethosuximide / Q000627:therapeutic use; D006246:Harmaline; D007555:Isoxazoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009281:Naphthalenes / Q000627:therapeutic use; D009570:Nitriles / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000378:metabolism; D000078305:Zonisamide
C115894:17-hydroxyestrane-3-carbonitrile; D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D003521:Cyclopropanes; D004962:Estranes; D007555:Isoxazoles; D009281:Naphthalenes; D009570:Nitriles; D011963:Receptors, GABA-A; C484287:NNC 55-0396; D000078305:Zonisamide; D005013:Ethosuximide; D006246:Harmaline