RGD Reference Report - Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.

General

Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.
Authors:	Schuster, S Doudnikoff, E Rylander, D Berthet, A Aubert, I Ittrich, C Bloch, B Cenci, MA Surmeier, DJ Hengerer, B Bezard, E
Citation:	Schuster S, etal., Biol Psychiatry. 2009 Mar 15;65(6):518-26. Epub 2008 Oct 23.
RGD ID:	6906919
Pubmed:	PMID:18947822 (View Abstract at PubMed)
DOI:	DOI:10.1016/j.biopsych.2008.09.008 (Journal Full-text)
BACKGROUND: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. METHODS: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. RESULTS: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. CONCLUSIONS: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
Drug-Induced Dyskinesia		ISO	Cacna1d (Rattus norvegicus)	6906919; 6906919		RGD
Drug-Induced Dyskinesia		IMP		6906919		RGD

Objects Annotated

Genes (Rattus norvegicus)

Cacna1d (calcium voltage-gated channel subunit alpha1 D)

Genes (Mus musculus)

Cacna1d (calcium channel, voltage-dependent, L type, alpha 1D subunit)

Genes (Homo sapiens)

CACNA1D (calcium voltage-gated channel subunit alpha1 D)

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Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.