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Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease

Cenci, M. Angela LU orcid ; Skovgård, Katrine LU and Odin, Per LU orcid (2022) In Neuropharmacology 210.
Abstract

Dopamine replacement therapy with L-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of... (More)

Dopamine replacement therapy with L-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving L-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
5-HT1A/B agonist, Adenosine A2a receptors, Basal ganglia, Drug-induced dyskinesias, Glutamate receptors, Metabotropic glutamate receptors
in
Neuropharmacology
volume
210
article number
109027
publisher
Elsevier
external identifiers
  • scopus:85126521212
  • pmid:35292330
ISSN
0028-3908
DOI
10.1016/j.neuropharm.2022.109027
language
English
LU publication?
yes
id
0d1108f0-f77d-4808-80d1-cc5eb6a00e40
date added to LUP
2022-05-03 16:39:19
date last changed
2024-06-14 14:59:24
@article{0d1108f0-f77d-4808-80d1-cc5eb6a00e40,
  abstract     = {{<p>Dopamine replacement therapy with L-DOPA is the most efficacious symptomatic treatment for Parkinson's disease, but its utility is limited by a development of motor fluctuations and abnormal involuntary movements (dyskinesia) in the majority of patients. These complications are attributed to the combined effects of dopaminergic degeneration and non-physiological reinstatement of dopamine transmission by the standard oral medications. There is substantial evidence that this altered state of dopamine transmission causes pathophysiological changes to a variety of non-dopaminergic neurotransmitter systems in the brain. This evidence has prompted an interest in developing drugs that target non-dopaminergic receptors for the purpose of improving L-DOPA-induced dyskinesia and/or motor fluctuations. We here review all the most important categories of non-dopaminergic targets that have been investigated so far, but with a particular focus on modulators of glutamatergic and serotonergic transmission, which continue to inspire significant efforts towards clinical translation. In particular, we discuss both the experimental rationale and the clinical experience thus far gained from studying 5-HT1A and 5-HT1B receptor agonists, NMDA and AMPA receptor antagonists, mGluR5 negative allosteric modulators, mGluR4 positive allosteric modulators, and adenosine A2a receptor antagonists. We also review compounds with complex pharmacological properties that are already used clinically or about to enter an advanced phase of clinical development (amantadine, safinamide, zonisamide, pridopidine, mesdopetam). We conclude with an outlook on possible directions to address unmet needs and improve the chance of successful translation in this therapeutic area.</p>}},
  author       = {{Cenci, M. Angela and Skovgård, Katrine and Odin, Per}},
  issn         = {{0028-3908}},
  keywords     = {{5-HT1A/B agonist; Adenosine A2a receptors; Basal ganglia; Drug-induced dyskinesias; Glutamate receptors; Metabotropic glutamate receptors}},
  language     = {{eng}},
  month        = {{06}},
  publisher    = {{Elsevier}},
  series       = {{Neuropharmacology}},
  title        = {{Non-dopaminergic approaches to the treatment of motor complications in Parkinson's disease}},
  url          = {{http://dx.doi.org/10.1016/j.neuropharm.2022.109027}},
  doi          = {{10.1016/j.neuropharm.2022.109027}},
  volume       = {{210}},
  year         = {{2022}},
}