Quinpirole inhibits levodopa-induced dyskinesias at structural and behavioral levels: Efficacy negated by co-administration of isradipine.

Autor: Collier TJ; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA. Electronic address: collie69@msu.edu., Begg L; Department of Biomedical Sciences, Grand Valley State University, 1 Campus Dr., Allendale, MI 49401, USA., Stancati JA; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA., Mercado NM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA., Sellnow RC; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Cell and Molecular Biology Program, Michigan State University, East Lansing, MI 48824, USA., Sandoval IM; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA. Electronic address: Ivette.Sandoval@barrowneuro.org., Sortwell CE; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA., Steece-Collier K; Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave. N.W., Grand Rapids, MI 49503, USA; Hauenstein Neuroscience Center, Mercy Health Saint Mary's, 220 Cherry St. S.E., Grand Rapids, MI 49503, USA.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2023 Nov; Vol. 369, pp. 114522. Date of Electronic Publication: 2023 Aug 26.
DOI: 10.1016/j.expneurol.2023.114522
Abstrakt: Dopamine depletion associated with parkinsonism induces plastic changes in striatal medium spiny neurons (MSN) that are maladaptive and associated with the emergence of the negative side-effect of standard treatment: the abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Prevention of MSN dendritic spine loss is hypothesized to diminish liability for LID in Parkinson's disease. Blockade of striatal CaV1.3 calcium channels can prevent spine loss and significantly diminish LID in parkinsonian rats. While pharmacological antagonism with FDA approved CaV1 L-type channel antagonist dihydropyridine (DHP) drugs (e.g, isradipine) are potentially antidyskinetic, pharmacologic limitations of current drugs may result in suboptimal efficacy. To provide optimal CaV1.3 antagonism, we investigated the ability of a dual pharmacological approach to more potently antagonize these channels. Specifically, quinpirole, a D2/D3-type dopamine receptor (D2/3R) agonist, has been demonstrated to significantly reduce calcium current activity at CaV1.3 channels in MSNs of rats by a mechanism distinct from DHPs. We hypothesized that dual inhibition of striatal CaV1.3 channels using the DHP drug isradipine combined with the D2/D3 dopamine receptor agonist quinpirole prior to, and in conjunction with, levodopa would be more effective at preventing structural modifications of dendritic spines and providing more stable LID prevention. For these proof-of-principle studies, rats with unilateral nigrostriatal lesions received daily administration of vehicle, isradipine, quinpirole, or isradipine + quinpirole prior to, and concurrent with, levodopa. Development of LID and morphological analysis of dendritic spines were assessed. Contrary to our hypothesis, quinpirole monotherapy was the most effective at reducing dyskinesia severity and preventing abnormal mushroom spine formation on MSNs, a structural phenomenon previously associated with LID. Notably, the antidyskinetic efficacy of quinpirole monotherapy was lost in the presence of isradipine co-treatment. These findings suggest that D2/D3 dopamine receptor agonists when given in combination with levodopa and initiated in early-stage Parkinson's disease may provide long-term protection against LID. The negative interaction of isradipine with quinpirole suggests a potential cautionary note for co-administration of these drugs in a clinical setting.
Competing Interests: Declaration of Competing Interest The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have nothing to disclose.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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