2. Academic Validation
  3. The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents

The selective GSK3 inhibitor, SAR502250, displays neuroprotective activity and attenuates behavioral impairments in models of neuropsychiatric symptoms of Alzheimer's disease in rodents

  • Sci Rep. 2019 Dec 2;9(1):18045. doi: 10.1038/s41598-019-54557-5.
Guy Griebel 1,  Jeanne Stemmelin 2,  Mati Lopez-Grancha 3,  Denis Boulay 4,  Gerald Boquet 5,  Franck Slowinski 6,  Philippe Pichat 7,  Sandra Beeské 8,  Shinji Tanaka 9,  Akiko Mori 9,  Masatake Fujimura 9,  Junichi Eguchi 9
Affiliations

Affiliations

  • 1 Sanofi, Strategy & Business Development, Chilly-Mazarin, France. guy.griebel@sanofi.com.
  • 2 Sanofi R&D, Global Project Management, Chilly-Mazarin, France.
  • 3 Sanofi R&D, Rare and Neurologic Disease Research, Chilly-Mazarin, France.
  • 4 Sanofi R&D, Translational In Vivo Models, Chilly-Mazarin, France.
  • 5 Sanofi R&D, Integrated Planning and Operations, Project Planning Management, Chilly-Mazarin, France.
  • 6 Sanofi R&D, Integrated Drug Discovery, Chilly-Mazarin, France.
  • 7 Sanofi R&D, Integrated Planning and Operations Management, Chilly-Mazarin, France.
  • 8 Sanofi R&D, Cardiovascular Diseases & Metabolism, Chilly-Mazarin, France.
  • 9 Research Division, Mitsubishi Tanabe Pharma Corporation, Kamoshida-cho, Aoba-ku, Yokohama, Japan.
PMID: 31792284 DOI: 10.1038/s41598-019-54557-5
Abstract

Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this Enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aβ25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aβ25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.

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