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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

In English

Författare

  • Stefan Schuster
  • Evelyne Doudnikoff
  • Daniella Rylander
  • Amandine Berthet
  • Incarnation Aubert
  • Carina Ittrich
  • Bertrand Bloch
  • M. Angela Cenci
  • D. James Surmeier
  • Bastian Hengerer
  • Erwan Bezard
Visa allt

Summary, in English

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.

Publiceringsår

2009

Språk

Engelska

Sidor

518-526

Publikation/Tidskrift/Serie

Biological Psychiatry

Volym

65

Issue

6

Dokumenttyp

Artikel i tidskrift

Förlag

Elsevier

Ämne

  • Neurosciences

Nyckelord

  • medium spiny neurons
  • isradipine
  • Parkinson's
  • disease
  • Electron microscopy

Status

Published

Forskningsgrupp

  • Basal Ganglia Pathophysiology

ISBN/ISSN/Övrigt

  • ISSN: 0006-3223