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 a-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 beta-catenin degradation is essential for preventing LID, because too much GSK-3 inhibition increases beta-catenin levels, which is related to cancers.