Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.
Sci Adv
; 9(49): eadj6187, 2023 Dec 08.
Article
in En
| MEDLINE
| ID: mdl-38064562
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Multiple Sclerosis
Limits:
Animals
Language:
En
Journal:
Sci Adv
Year:
2023
Document type:
Article
Affiliation country:
Country of publication: