Multimodal imaging study of the 5-HT <sub>1A</sub> receptor biased agonist, NLX-112, in a model of L-DOPA-induced dyskinesia

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Graphical abstract

Highlights

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Hemiparkinsonian (HPK) rats show a specific L-DOPA-induced brain metabolic pattern.
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NLX-112 attenuated or reversed the cerebral effects of L-DOPA in dyskinetic HPK rats.
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The predominant action of NLX-112 is mediated by 5-HT1A autoreceptors in the raphe.
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This translational study supports development of NLX-112 as an anti-dyskinetic agent.

Abstract

Introduction

The leading treatment for motor signs of Parkinson's disease is L-DOPA, but, upon extended use, it can lead to levodopa-induced dyskinesia (LID). Serotonergic neurons are involved in LID etiology and previous pre-clinical studies have shown that NLX-112, a 5-HT _1A biased agonist, has robust antidyskinetic effects. Here, we investigated its effects in hemiparkinsonian (HPK) rats with a unilateral nigrostriatal 6-OHDA lesion.

Methods

We compared HPK rats with LID (i.e., sensitized to the dyskinetic effects of chronic L-DOPA) and without LID (HPK-non-LID), using [ ¹⁸F]FDG PET imaging and fMRI functional connectivity following systemic treatment with saline, L-DOPA, NLX-112 or L-DOPA + NLX-112.

Results

In HPK-non-LID rats, [ ¹⁸F]FDG PET experiments showed that L-DOPA led to hypermetabolism in motor areas (cerebellum, brainstem, and mesencephalic locomotor region) and to hypometabolism in cortical regions. L-DOPA effects were also observed in HPK-LID rats, with the additional emergence of hypermetabolism in raphe nuclei and hypometabolism in hippocampus and striatum. NLX-112 attenuated L-DOPA-induced raphe hypermetabolism and cingulate cortex hypometabolism in HPK-LID rats. Moreover, in fMRI experiments NLX-112 partially corrected the altered neural circuit connectivity profile in HPK-LID rats, through activity in regions rich in 5-HT _1A receptors.

Conclusion

This neuroimaging study sheds light for the first time on the brain activation patterns of HPK-LID rats. The 5-HT _1A receptor agonist, NLX-112, prevents occurrence of LID, likely by activating pre-synaptic autoreceptors in the raphe nuclei, resulting in a partial restoration of brain metabolic and connectivity profiles. In addition, NLX-112 also rescues L-DOPA-induced deficits in cortical activation, suggesting potential benefit against non-motor symptoms of Parkinson’s disease.

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Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.

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Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

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Author and article information

Contributors

Luc Zimmer

Journal

Journal ID (nlm-ta): Neuroimage Clin

Journal ID (iso-abbrev): Neuroimage Clin

Title: NeuroImage : Clinical

Publisher: Elsevier

ISSN (Electronic): 2213-1582

Publication date PMC-release: 15 August 2023

Publication date Collection: 2023

Publication date (Electronic): 15 August 2023

Volume: 39

Electronic Location Identifier: 103497

Affiliations

[a ]Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France

[b ]Hospices Civils de Lyon, Lyon, France

[c ]CERMEP-Imaging Platform, Bron, France

[d ]Neurolixis, Castres, France

Author notes

[* ]Corresponding author at: Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France. luc.zimmer@ 123456univ-lyon1.fr

Article

Publisher Item ID: S2213-1582(23)00188-2 Publisher ID: 103497

DOI: 10.1016/j.nicl.2023.103497

PMC ID: 10474496

PubMed ID: 37632990

SO-VID: ea927856-7a27-4548-a377-ed4173192ced

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

History

Date received : 1 October 2022

Date revision received : 20 July 2023

Date accepted : 14 August 2023