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 a novel 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 both EAE 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.
Original language | English |
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Journal | Science Advances |
Volume | 9 |
Issue number | 49 |
Early online date | 8 Dec 2023 |
DOIs | |
Publication status | E-pub ahead of print - 8 Dec 2023 |
Bibliographical note
Funding:This research was supported by the following grants: a Centre for Addiction and Mental Health Foundation Proof of Principle grant held by Dr. Fang Liu, a Canadian Institute of Health Research Proof of Principle Phase II grant held by Dr. Fang Liu and Dr. Iain R. Greig, and funding from the National Multiple Sclerosis Society (USA) Fast-Forward Commercialization Program held by Dr. Fang Liu and Dr. Iain R. Greig.
This manuscript has been made open access under a Creative Commons Attribution (CC BY) licence under the terms of the University of Aberdeen Research Publications Policy. https://creativecommons.org/licenses/by/4.0/