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Caspase\u20101 is a pivotal mediator of inflammation and cell death in the CNS. We investigated the effects of caspase\u20101 activation and its regulation in models of MS. Brains from progressive MS and non\u2010MS patients, as well as cultured human oligodendrocytes were examined by transcriptomic and morphological methods. Next generation transcriptional sequencing of progressive MS compared to non\u2010MS patients' normal appearing white matter (NAWM) showed induction of caspase\u20101 as well as other inflammasome\u2010associated genes with concurrent suppression of neuron\u2010specific genes. Oligodendrocytes exposed to TNF\u03b1 exhibited upregulation of caspase\u20101 with myelin gene suppression in a cell differentiation state\u2010dependent manner. Brains from cuprizone\u2010exposed mice treated by intranasal delivery of the caspase\u20101 inhibitor, VX\u2010765 or its vehicle, were investigated in morphological and molecular studies, as well as by fluorodeoxyglucose\u2010positron emission tomography (FDG\u2010PET) imaging. Cuprizone exposure resulted in BMC and caspase\u20101 activation accompanied by demyelination and axonal injury, which was abrogated by intranasal VX\u2010765 treatment. FDG\u2010PET imaging revealed suppressed glucose metabolism in the thalamus, hippocampus and cortex of cuprizone\u2010exposed mice that was restored with VX\u2010765 treatment. These studies highlight the caspase\u20101 dependent interactions between inflammation, demyelination, and glucose metabolism in progressive MS and associated models. Intranasal delivery of an anti\u2010caspase\u20101 therapy represents a promising therapeutic approach for progressive MS and other neuro\u2010inflammatory diseases.<\/jats:p>","DOI":"10.1002\/glia.23896","type":"journal-article","created":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T17:38:14Z","timestamp":1599154694000},"page":"216-229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Intranasal anti\u2010caspase\u20101 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis"],"prefix":"10.1002","volume":"69","author":[{"given":"Leina B.","family":"Saito","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason P.","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology &amp; Immunology University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mackenzie J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A. 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