Understanding the role of glycogen synthase kinase-3 in L-DOPA-induced dyskinesia in Parkinson's disease.

Abstract

INTRODUCTION:

Levodopa (L-DOPA) is the most commonly used drug for Parkinson's disease (PD), but its long-term use is associated with various complications, including L-DOPA-induced dyskinesia (LID). Many studies have suggested that L-DOPA neurotoxicity and LID are associated with glycogen synthase kinase-3 (GSK-3) activation. Areas covered: LID is caused by striatal dopamine (DA) denervation in PD and pulsatile L-DOPA treatment. These factors lead to dysregulated DA transmission, abnormal intracellular signaling and transcription factors in striatal neurons, and altered gene expression and plasticity at corticostriatal synapses. The mechanisms of L-DOPA toxicity involve oxidative stress, L-DOPA oxidation to quinone, mitochondrial dysfunction, and α-synuclein. GSK-3 has been suggested to play key roles in all the mechanisms associated of L-DOPA toxicity and LID in PD. Expert opinion: GSK-3 plays critical roles in L-DOPA-induced neurotoxicity, and the development of specific methods to inhibit GSK-3 function may help prevent L-DOPA neurotoxicity and LID in PD. However, balanced GSK-3 inhibition and less β-catenin degradation is essential for preventing LID, because too much GSK-3 inhibition increases β-catenin levels, which is related to cancers.

• Authors: Hojin Choi, Seong-Ho Koh
• Journal: Expert opinion on drug metabolism & toxicology (Expert Opin Drug Metab Toxicol) Vol. 14 Issue 1 Pg. 83-90 (Jan 2018) ISSN: 1744-7607 [Electronic] England
• PMID: 29233065 (Publication Type: Journal Article, Review)

Chemical References

• Antiparkinson Agents
• beta Catenin
• Levodopa
• Glycogen Synthase Kinase 3
• Dopamine

Topics

• Animals
• Antiparkinson Agents (administration & dosage, adverse effects)
• Dopamine (metabolism)
• Dyskinesia, Drug-Induced (enzymology, etiology, prevention & control)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Humans
• Levodopa (administration & dosage, adverse effects)
• Neurotoxicity Syndromes (enzymology, etiology)
• Oxidative Stress (drug effects)
• Parkinson Disease (drug therapy)
• beta Catenin (metabolism)