title: Neuroprotective effects of JGK-263 in transgenic SOD1-G93A mice of amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Glycogen synthase kinase-3β (GSK-3β) activity plays a central role in motor neuron degeneration. GSK-3β inhibitors have been shown to prolong motor neuron survival and suppress disease progression in amyotrophic lateral sclerosis (ALS). In this study, we evaluated the therapeutic effects of a new GSK-3b inhibitor, JGK-263, on ALS in G93A SOD1 transgenic mice.
  
  
  METHODS
  Previously, biochemical efficacy of JGK-263 was observed in normal and mutant (G93A) hSOD1-transfected motor neuronal cell lines (NSC34). Based on these previous results, we administered JGK-263 orally to 93 transgenic mice with the human G93A-mutated SOD1 gene. The mice were divided into three groups: a group administered 20mg/kg JGK-263, a group administered 50mg/kg JGK-263, and a control group not administered with JGK-263. Clinical status, rotarod test, and survival rates of transgenic mice with ALS were evaluated. Sixteen mice from each group were selected for further biochemical study that involved examination of motor neuron count, apoptosis, and cell survival signals.
  
  
  RESULTS
  JGK-263 administration remarkably improved motor function and prolonged the time until symptom onset, rotarod failure, and death in transgenic mice with ALS compared to control mice. In JGK-263 groups, choline acetyltransferase (ChAT) staining in the ventral horn of the lower lumbar spinal cord showed a large number of motor neurons, suggesting normal morphology. The neuroprotective effects of JGK-263 in ALS mice were also suggested by western blot analysis of spinal cord tissues in transgenic mice.
  
  
  CONCLUSIONS
  These results suggest that JGK-263, an oral GSK-3β inhibitor, is promising as a novel therapeutic agent for ALS. Still, further biochemical studies on the underlying mechanisms and safety of JGK-263 are necessary.
authors.affiliation: Department of Neurology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Suk-Won
authors.initials: SW
authors.lastname: Ahn
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gye Sun
authors.initials: GS
authors.lastname: Jeon
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jee-Heun
authors.initials: JH
authors.lastname: Shon
authors.affiliation: Department of Neurology, Seoul Medical Center, Seoul, Republic of Korea.
authors.forename: Jee-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Je-Young
authors.initials: JY
authors.lastname: Shin
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Department of Neurology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of New Drug Development, R&D Center, Jeil Pharmaceutical Co. Ltd., 117-1 Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Ye
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Neurology, Boramae Medical Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoon-Ho
authors.initials: YH
authors.lastname: Hong
authors.affiliation: Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: jjsaint@snu.ac.kr.
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Sung
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000704:Analysis of Variance; D000818:Animals; D053148:Caspase 3; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009046:Motor Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016037:Single-Blind Method; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D045304:Cytochromes c; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D002795:Choline O-Acetyltransferase; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3
keywords: ALS; Amyotrophic lateral sclerosis; GSK-3β inhibitor; Glycogen synthase kinase-3; JGK-263; Transgenic mouse