Artikel ; Online: Intranasal anti-caspase-1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis.
2020 Band 69, Heft 1, Seite(n) 216–229
Abstract: Inflammatory demyelination and axonal injury in the central nervous system (CNS) are cardinal features of progressive multiple sclerosis (MS), and linked to activated brain macrophage-like cells (BMCs) including resident microglia and trafficking ... ...
| Abstract | Inflammatory demyelination and axonal injury in the central nervous system (CNS) are cardinal features of progressive multiple sclerosis (MS), and linked to activated brain macrophage-like cells (BMCs) including resident microglia and trafficking macrophages. Caspase-1 is a pivotal mediator of inflammation and cell death in the CNS. We investigated the effects of caspase-1 activation and its regulation in models of MS. Brains from progressive MS and non-MS patients, as well as cultured human oligodendrocytes were examined by transcriptomic and morphological methods. Next generation transcriptional sequencing of progressive MS compared to non-MS patients' normal appearing white matter (NAWM) showed induction of caspase-1 as well as other inflammasome-associated genes with concurrent suppression of neuron-specific genes. Oligodendrocytes exposed to TNFα exhibited upregulation of caspase-1 with myelin gene suppression in a cell differentiation state-dependent manner. Brains from cuprizone-exposed mice treated by intranasal delivery of the caspase-1 inhibitor, VX-765 or its vehicle, were investigated in morphological and molecular studies, as well as by fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging. Cuprizone exposure resulted in BMC and caspase-1 activation accompanied by demyelination and axonal injury, which was abrogated by intranasal VX-765 treatment. FDG-PET imaging revealed suppressed glucose metabolism in the thalamus, hippocampus and cortex of cuprizone-exposed mice that was restored with VX-765 treatment. These studies highlight the caspase-1 dependent interactions between inflammation, demyelination, and glucose metabolism in progressive MS and associated models. Intranasal delivery of an anti-caspase-1 therapy represents a promising therapeutic approach for progressive MS and other neuro-inflammatory diseases. |
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| Mesh-Begriff(e) | Animals ; Caspase 1 ; Cuprizone/toxicity ; Disease Models, Animal ; Fluorodeoxyglucose F18 ; Glucose ; Humans ; Inflammation ; Mice ; Mice, Inbred C57BL ; Multiple Sclerosis, Chronic Progressive ; Myelin Sheath |
| Chemische Substanzen | Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Cuprizone (5N16U7E0AO) ; Caspase 1 (EC 3.4.22.36) ; Glucose (IY9XDZ35W2) |
| Sprache | Englisch |
| Erscheinungsdatum | 2020-09-03 |
| Erscheinungsland | United States |
| Dokumenttyp | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 639414-0 |
| ISSN | 1098-1136 ; 0894-1491 |
| ISSN (online) | 1098-1136 |
| ISSN | 0894-1491 |
| DOI | 10.1002/glia.23896 |
| Datenquelle | MEDical Literature Analysis and Retrieval System OnLINE |
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