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Positive allosteric modulation of AMPA receptors via PF4778574 leads to reduced demyelination and clinical disability in experimental models of multiple sclerosis
M. Sindi, M. Dietrich, D. Klees, J. Gruchot, C. Hecker, J. Silbereis, A. Issberner, HP. Hartung, T. Ruck, H. Stark, T. Kurz, P. Küry, SG. Meuth, P. Albrecht
Language English Country Switzerland
Document type Journal Article
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- MeSH
- Allosteric Regulation MeSH
- Receptors, AMPA * metabolism MeSH
- Demyelinating Diseases drug therapy metabolism MeSH
- Encephalomyelitis, Autoimmune, Experimental * drug therapy metabolism immunology MeSH
- Fingolimod Hydrochloride pharmacology therapeutic use MeSH
- Disease Models, Animal MeSH
- Mice, Inbred C57BL * MeSH
- Mice MeSH
- Multiple Sclerosis * drug therapy metabolism immunology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: Multiple Sclerosis (MS), a debilitating central nervous system (CNS) disorder, is characterized by inflammation, demyelination, and neuronal degeneration. Despite advancements in immunomodulatory treatments, neuroprotective or restorative strategies remain inadequate. Our research is focusing on the potential of the positive allosteric modulator of AMPA receptors (AMPA-PAM), PF4778574, in addressing MS symptoms. METHODS: We utilized the MOG35-55 induced experimental autoimmune encephalomyelitis (EAE) model in C57BL6J mice to examine PF4778574's therapeutic and prophylactic efficacy. Our comprehensive approach included clinical scoring, optical coherence tomography (OCT), optomotor response (OMR) and histological assessments. Additionally, we explored the effects of PF4778574 in comparison and in combination with the immunomodulatory agent fingolimod, and investigated the impact on Cuprizone induced toxic demyelination. RESULTS: Prophylactic administration of PF4778574 showed notable improvement in clinical EAE indices and reduction in neuronal loss. While it did not diminish microglial activity, it reduced demyelinated areas in optic nerves and in the corpus callosum. Both PF4778574 and fingolimod significantly enhanced clinical EAE scores and decreased demyelination. However, their combination did not yield additional benefits. In the cuprizone model, PF4778574 increased oligodendrocyte precursor and mature myelin-forming cells, suggesting a pro-remyelinating effect. DISCUSSION: PF4778574 demonstrates promise in mitigating EAE effects, especially in terms of clinical disability and demyelination. These results suggest AMPA-PAMs as potential targets of interest for MS treatment beyond immunomodulatory approaches.
Brain and Mind Center University of Sydney Sydney NSW Australia
Department of Medical Research Multiple Sclerosis Unit Biogen Cambridge MA United States
Department of Neurology Maria Hilf Clinics Mönchengladbach Germany
Department of Neurology Palacky University Olomouc Olomouc Czechia
References provided by Crossref.org
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