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.

KEYWORDS:

• Parkinson’s disease
• glycogen synthase kinase-3 (GSK-3)
• l-3
• 4-dihydroxyphenylalanine (L-DOPA)
• neurotoxicity

Article highlights

• L-DOPA-induced dyskinesia (LID) is a common adverse effect with long-term L-DOPA treatment in Parkinson’s disease (PD).

• Many cellular mechanisms are involved in L-DOPA neurotoxicity in PD.

• Glycogen synthase kinase-3 has roles in diverse cellular functions in the nervous system and is dysregulated in several neurological diseases.

• GSK-3 is also associated with the pathophysiology of LID.

• Inhibition of GSK-3 may prevent or reduce LID in PD patients.

This box summarizes key points contained in the article.

Declaration of interest

No potential conflict of interest was reported by the author.

Additional information

Funding

This work was supported by the Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Science, ICT and Future Planning (2015R1A2A2A04004865), by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C2160), by the Korea Drug Development Fund (KDDF) funded by the Ministry of Science and ICT, Ministry of Trade, Industry & Energy, and Ministry of Health & Welfare (KDDF-201609-02, Republic of Korea), and by and the Medical Research Center (2017R1A5A2015395). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.