2. Academic Validation
  3. Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis

  • Sci Adv. 2023 Dec 8;9(49):eadj6187. doi: 10.1126/sciadv.adj6187.
Dongxu Zhai 1,  Shuxin Yan 1,  James Samsom 1,  Le Wang 1,  Ping Su 1,  Anlong Jiang 1,  Haorui Zhang 2,  Zhengping Jia 2,  Izhar Wallach 3,  Abraham Heifets 3,  Chiara Zanato 4,  Chih-Chung Tseng 4,  Albert H C Wong 1 5 6 7,  Iain R Greig 4,  Fang Liu 1 5 7 8
Affiliations

Affiliations

  • 1 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St., Toronto M5T 1R8, Canada.
  • 2 Department of Neurosciences & Mental Health, The Hospital for Sick Children, 686 Bay St., Toronto M5G 0A4, Canada.
  • 3 Atomwise Inc., 221 Main Street, Suite 1350, San Francisco, CA 94105, USA.
  • 4 Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
  • 5 Institutes of Medical Science, University of Toronto, 1 King's College Cir., Toronto M5S 1A8, Canada.
  • 6 Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Cir., Toronto M5S 1A8, Canada.
  • 7 Department of Psychiatry, University of Toronto, 250 College St., Toronto M5T 1R8, Canada.
  • 8 Department of Physiology, University of Toronto, 1 King's College Cir., Toronto M5T 1R8, Canada.
PMID: 38064562 DOI: 10.1126/sciadv.adj6187
Abstract

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site. A machine learning approach was used to screen for small molecules targeting the AMPA Receptor GluA2 subunit. The lead candidate has potent effects in restoring neurological function and myelination while reducing the immune response in experimental autoimmune encephalitis and cuprizone MS mouse models without affecting basal neurotransmission or learning and memory. These findings facilitate development of a treatment for MS with a different mechanism of action than current immune modulatory drugs and avoids important off-target effects of glutamate receptor antagonists. This class of MS therapeutics could be useful as an alternative or complementary treatment to existing therapies.

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