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

Abstract 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.
PMID
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Role of glycogen synthase kinase-3 in l-DOPA-induced neurotoxicity.

Authors

Mayor MeshTerms
Keywords

4-dihydroxyphenylalanine (L-DOPA)

Parkinson’s disease

glycogen synthase kinase-3 (GSK-3)

l-3

neurotoxicity

Journal Title expert opinion on drug metabolism & toxicology
Publication Year Start

 



PMID- 29233065
OWN - NLM
STAT- MEDLINE
DCOM- 20180101
LR  - 20180101
IS  - 1744-7607 (Electronic)
IS  - 1742-5255 (Linking)
VI  - 14
IP  - 1
DP  - 2018 Jan
TI  - Understanding the role of glycogen synthase kinase-3 in L-DOPA-induced dyskinesia
      in Parkinson's disease.
PG  - 83-90
LID - 10.1080/17425255.2018.1417387 [doi]
AB  - 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
      alpha-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.
FAU - Choi, Hojin
AU  - Choi H
AD  - a Department of Neurology , Hanyang University College of Medicine , Seoul ,
      South Korea.
FAU - Koh, Seong-Ho
AU  - Koh SH
AD  - a Department of Neurology , Hanyang University College of Medicine , Seoul ,
      South Korea.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20171215
PL  - England
TA  - Expert Opin Drug Metab Toxicol
JT  - Expert opinion on drug metabolism & toxicology
JID - 101228422
RN  - 0 (Antiparkinson Agents)
RN  - 0 (beta Catenin)
RN  - 46627O600J (Levodopa)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - Animals
MH  - Antiparkinson Agents/administration & dosage/*adverse effects
MH  - Dopamine/metabolism
MH  - Dyskinesia, Drug-Induced/enzymology/*etiology/prevention & control
MH  - Glycogen Synthase Kinase 3/antagonists & inhibitors/*metabolism
MH  - Humans
MH  - Levodopa/administration & dosage/*adverse effects
MH  - Neurotoxicity Syndromes/enzymology/etiology
MH  - Oxidative Stress/drug effects
MH  - Parkinson Disease/drug therapy
MH  - beta Catenin/metabolism
OTO - NOTNLM
OT  - 4-dihydroxyphenylalanine (L-DOPA)
OT  - Parkinson's disease
OT  - glycogen synthase kinase-3 (GSK-3)
OT  - l-3
OT  - neurotoxicity
EDAT- 2017/12/14 06:00
MHDA- 2018/01/02 06:00
CRDT- 2017/12/14 06:00
PHST- 2017/12/14 06:00 [pubmed]
PHST- 2018/01/02 06:00 [medline]
PHST- 2017/12/14 06:00 [entrez]
AID - 10.1080/17425255.2018.1417387 [doi]
PST - ppublish
SO  - Expert Opin Drug Metab Toxicol. 2018 Jan;14(1):83-90. doi:
      10.1080/17425255.2018.1417387. Epub 2017 Dec 15.