Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.
Biological Psychiatry. 2009-03-01; 65(6): 518-526
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1. Biol Psychiatry. 2009 Mar 15;65(6):518-26. doi: 10.1016/j.biopsych.2008.09.008.
Epub 2008 Oct 23.
Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary
movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.
Schuster S(1), Doudnikoff E, Rylander D, Berthet A, Aubert I, Ittrich C, Bloch B,
Cenci MA, Surmeier DJ, Hengerer B, Bezard E.
(1)Boehringer Ingelheim Pharma GmbH & Company KG, Biberach, Germany.
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.
PMID: 18947822 [Indexed for MEDLINE]