Tags

Type your tag names separated by a space and hit enter

The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease.
Pharmacol Rev. 2013 Jan; 65(1):171-222.PR

Abstract

L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways.

Authors+Show Affiliations

Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

23319549

Citation

Huot, Philippe, et al. "The Pharmacology of L-DOPA-induced Dyskinesia in Parkinson's Disease." Pharmacological Reviews, vol. 65, no. 1, 2013, pp. 171-222.
Huot P, Johnston TH, Koprich JB, et al. The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. Pharmacol Rev. 2013;65(1):171-222.
Huot, P., Johnston, T. H., Koprich, J. B., Fox, S. H., & Brotchie, J. M. (2013). The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. Pharmacological Reviews, 65(1), 171-222. https://doi.org/10.1124/pr.111.005678
Huot P, et al. The Pharmacology of L-DOPA-induced Dyskinesia in Parkinson's Disease. Pharmacol Rev. 2013;65(1):171-222. PubMed PMID: 23319549.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease. AU - Huot,Philippe, AU - Johnston,Tom H, AU - Koprich,James B, AU - Fox,Susan H, AU - Brotchie,Jonathan M, Y1 - 2013/01/10/ PY - 2013/1/16/entrez PY - 2013/1/16/pubmed PY - 2013/5/29/medline SP - 171 EP - 222 JF - Pharmacological reviews JO - Pharmacol Rev VL - 65 IS - 1 N2 - L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways. SN - 1521-0081 UR - https://www.unboundmedicine.com/medline/citation/23319549/The_pharmacology_of_L_DOPA_induced_dyskinesia_in_Parkinson's_disease_ L2 - http://pharmrev.aspetjournals.org/cgi/pmidlookup?view=long&pmid=23319549 DB - PRIME DP - Unbound Medicine ER -