Ana Maria Rondelli (1), Kamil R Kranc (1), Sarah R Walmsley (2), Anna Williams (1) (1) Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom (2) Medical Research Council Centre for Inflammation Research, University of Edinburgh, Edinburgh, United KingdomThe myelin sheaths provide functional and trophic support for underlying axons. Inflammation-driven demyelination in the central nervous system is the pathological hallmark of Multiple Sclerosis (MS), leading to impaired conduction velocity and metabolic support, subsequent axonal death and progressive disability in MS patients. Regeneration of new myelin sheaths, (remyelination), occurs in MS but is rather limited especially during later disease. Therefore, much research is focussing on developing therapeutics to enhance the efficiency of remyelination and so reduce progressive disability.We hypothesise that activation of the hypoxic pathway is involved in remyelination. Imaging studies show us that tissue hypoxia is present in the brains of MS patients. Higher levels of the transcription factor HIF1α and its target genes, as cellular adaptations to tissue hypoxia, have also been detected in the MS brain. However, we do not know whether activation of this hypoxia pathway is detrimental or beneficial. For example, stroke research shows that a hypoxic insult can precondition the brain tissue, reducing brain damage associated with a subsequent second insult.We are using ex-vivo organotypic cerebellar slice cultures and in vivo toxin-induced animal model of demyelination exposed to 8% normobaric oxygen and then assessing remyelination efficiency. We have identified tools to measure activation of the hypoxic pathway in these systems and are testing 1) whether hypoxia is detrimental or beneficial to remyelination and 2) whether hypoxic preconditioning alters the subsequent response to demyelination.ReferencesAboul-Enein, F. et al. Preferential Loss of Myelin-Associated Glycoprotein Reflects Hypoxia-Like White Matter Damage in Stroke and Inflammatory Brain Diseases. J. Neuropathol. 62, 25–33 (2003).Marik, C., Felts, P. A., Bauer, J., Lassmann, H. & Smith, K. J. UKPMC Funders Group Lesion genesis in a subset of patients with multiple sclerosis : a role for innate immunity ? 130, 2800–2815 (2010).Graumann, U., Reynolds, R., Steck, A. J. & Schaeren-Wiemers, N. Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult. Brain Pathol. 13, 554–573 (2003).Miller, B. A. et al. Cerebral protection by hypoxic preconditioning in a murine model of focal ischemia-reperfusion. 12, 1663–1669 (2001).Funded by: Medical Research Council* entered into the PhD student poster competition This article was published on 2024-12-17