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Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice

Moreira, Carlos G; Morawska, Marta M; Baumann, Aron; Masneuf, Sophie; Linnebank, Michael; Sommerauer, Michael; Landolt, Hans-Peter; Noain, Daniela; Baumann, Christian R (2020). Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice. Neuropharmacology, 181:108353.

Abstract

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Pharmacology
Life Sciences > Cellular and Molecular Neuroscience
Language:English
Date:7 October 2020
Deposited On:19 Nov 2020 07:07
Last Modified:08 Mar 2025 04:36
Publisher:Elsevier
ISSN:0028-3908
OA Status:Green
Publisher DOI:https://doi.org/10.1016/j.neuropharm.2020.108353
PubMed ID:33038358
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