title: Effect of JGK-263 as a new glycogen synthase kinase-3β inhibitor on extrinsic apoptosis pathway in motor neuronal cells.
abstract: Glycogen synthase kinase-3β (GSK-3β) has been identified as one of the important pathogenic mechanisms in motor neuronal death. GSK-3β inhibitor has been investigated as a modulator of apoptosis and has been shown to confer significant protective effects on cell death in neurodegenerative diseases. However, GSK-3β is known to have paradoxical effects on apoptosis subtypes, i.e., pro-apoptotic in mitochondrial-associated intrinsic apoptosis, but anti-apoptotic in death receptor-related extrinsic apoptosis. In this study, we evaluated the effect of a new GSK-3β inhibitor (JGK-263) on motor neuron cell survival and apoptosis, by using low to high doses of JGK-263 after 48 h of serum withdrawal, and monitoring changes in extrinsic apoptosis pathway components, including Fas, FasL, cleaved caspase-8, p38α, and the Fas-Daxx interaction. Cell survival peaked after treatment of serum-deprived cells with 50 μM JGK-263. The present study showed that treatment with JGK-263 reduced serum-deprivation-induced motor neuronal apoptosis by inactivating not only the intrinsic, but also the extrinsic apoptosis pathway. These results suggest that JGK-263 has a neuroprotective effect through effective modulation of the extrinsic apoptosis pathway in motor neuron degeneration.
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul, South Korea.
authors.forename: Gye Sun
authors.initials: GS
authors.lastname: Jeon
authors.forename: Jee-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Ahn
authors.forename: Kyung-Seok
authors.initials: KS
authors.lastname: Park
authors.forename: Yoon-Ho
authors.initials: YH
authors.lastname: Hong
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Ye
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Park
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Kim
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: Amyotrophic lateral sclerosis; Extrinsic apoptosis; Glycogen synthase kinase-3; JGK-263; Motor neuron