Dyskinesia and Parkinson’s disease: animal model, drug targets, and agents in preclinical testing

ABSTRACT

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease. PD patients exhibit a classic spectrum of motor symptoms, arising when dopamine neurons in the substantia nigra pars compacta are reduced by 60%. The dopamine precursor L-DOPA represents the most effective therapy for improving PD motor dysfunctions, thus far available. Unfortunately, long-term treatment with L-DOPA is associated with the development of severe side effects, resulting in abnormal involuntary movements termed levodopa-induced dyskinesia (LID). Amantadine is the only drug currently approved for the treatment of LID indicating that LID management is still an unmet need in PD and encouraging the search for novel anti-dyskinetic drugs or the assessment of combined therapies with different molecular targets.

Areas covered

This review provides an overview of the main preclinical models used to study LID and of the latest preclinical evidence on experimental and clinically available pharmacological approaches targeting non-dopaminergic systems.

Expert opinion

LIDs are supported by complex molecular and neurobiological mechanisms that are still being studied today. This complexity suggests the need of developing personalized pharmacological approach to obtain an effective amelioration of LID condition and improve the quality of life of PD patients.

KEYWORDS:

• L-DOPA-induced dyskinesia
• Parkinson’s disease
• animal models
• MPTP
• 6-OHDA
• preclinical studies
• therapeutic targets

Article highlights

• The inability of the available animal models to recapitulate the complexity of LID is one of the major limitations in transferring pre-clinical findings to the clinical phase.

• Potential risk (e.g. genetic) factors should be into account in assessing new therapeutic strategies.

• Targeting glutamatergic and serotoninergic system currently represents the most promising therapeutic approach for LID.

• Drug-repurposing strategies as well as multi-target therapies should be further explored for treating LID.

• Developing tailored pharmacological approaches could be helpful to obtain an effective amelioration of LID condition.

This box summarizes key points contained in the article.

Abbreviations

LID, AIMs, L-DOPA, SNpc, SNpr, MFB, PD, NHPs.

Declaration of interest

The authors declare no conflict of interest, financial or otherwise.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The study was funded through grants from the Italian Ministry of Health (Ricerca Corrente 2022-2024).