Main author: Sif Ólafsdóttir
Institution or Company: Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland
Co-Authors, Institution or Company:
Helena Pivonkova, Wellcome—Medical Research Council Cambridge Stem Cell Institute & Department of Veterinary Medicine, University of Cambridge. Katrin Volbracht, Wellcome—Medical Research Council Cambridge Stem Cell Institute & Department of Veterinary Medicine, University of Cambridge. Omar de Faria Jr, Wellcome—Medical Research Council Cambridge Stem Cell Institute & Department of Veterinary Medicine, University of Cambridge. Ragnhildur Þóra Káradóttir, Wellcome—Medical Research Council Cambridge Stem Cell Institute & Department of Veterinary Medicine, University of Cambridge, Department of Physiology, BioMedical Center, Faculty of Medicine, University of Iceland.
Introduction: Multiple sclerosis (MS) is an autoimmune disease characterised by CNS inflammation and myelin damage. Iceland has one of the highest prevalence rates of MS in the world. Despite advancements in modifying the immunological aspects of MS, yet no myelin regenerative treatments exist. Myelin regeneration can occur spontaneously in demyelinating diseases, such as MS, and is essential for functional recovery. However, it often fails, due to oligodendrocyte precursor cells (OPCs) failing to differentiate into new myelinating oligodendrocytes, leading to sustained clinical disability.
We have recently found that OPCs in the white matter receive synaptic input from neuronal axons and respond to glutamate via AMPA receptors in vivo. Blocking this signalling prevents OPCs from differentiating and blocks remyelination. Indicating, that OPC glutamate signalling is essential for effective myelin regeneration.
We are now investigating if increasing the axon-OPC communication via AMPA receptor agonists can improve myelin repair, using an in vivo toxin induced lesion model in rats.
Methods: We will test structurally similar compounds that either do or do not augment OPCs’ glutamate-evoked currents. We will test the myelin regenerative potential of the AMPAkines by inducing demyelinating lesions and administering these AMPAkines orally twice a day. Following 21 days of oral drug administration, remyelination will be assessed.
Results: Our preliminary data show that remyelination can be increased by enhancing glutamate signalling in demyelinating lesions, using AMPAkines.
Conclusions: This work will clearly identify whether repurposing AMPAkines to promote myelin regeneration is a potential therapeutic strategy for MS.
