論文 - 詳細
| RRC ID | 11791 |
|---|---|
| 著者 | Handforth A, Homanics GE, Covey DF, Krishnan K, Lee JY, Sakimura K, Martin FC, Quesada A. |
| タイトル | T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. |
| ジャーナル | Neuropharmacology |
| 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 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. |
| 巻・号 | 59(6) |
| ページ | 380-7 |
| 公開日 | 2010-11-1 |
| DOI | 10.1016/j.neuropharm.2010.05.012 |
| PII | S0028-3908(10)00137-1 |
| PMID | 20547167 |
| PMC | PMC3787716 |
| MeSH | Analysis of Variance Animals Benzimidazoles / therapeutic use Calcium Channel Blockers / therapeutic use* Calcium Channels, T-Type / metabolism* Cyclopropanes / therapeutic use Disease Models, Animal Essential Tremor / chemically induced Essential Tremor / drug therapy* Essential Tremor / metabolism Estranes / therapeutic use Ethosuximide / therapeutic use Harmaline Isoxazoles / therapeutic use Male Mice Mice, Inbred ICR Mice, Knockout Naphthalenes / therapeutic use Nitriles / therapeutic use Receptors, GABA-A / metabolism Zonisamide |
| IF | 4.431 |
| 引用数 | 38 |
| WOS 分野 | PHARMACOLOGY & PHARMACY NEUROSCIENCES |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC01465 |