Intranasal anti-caspase-1 therapy preserves myelin and glucose metabolism in a model of progressive multiple sclerosis.

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.

• Authors: Leina B Saito, Jason P Fernandes, Mackenzie J Smith, Matthew A L Doan, William G Branton, Laura M Schmitt, Melinda Wuest, Maria C Monaco, Eugene O Major, Frank Wuest, Christopher Power
• Journal: Glia (Glia) Vol. 69 Issue 1 Pg. 216-229 (01 2021) ISSN: 1098-1136 [Electronic] United States
• PMID: 32882086 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Fluorodeoxyglucose F18
• Cuprizone
• Caspase 1
• Glucose

Topics

• Animals
• Caspase 1
• Cuprizone (toxicity)
• Disease Models, Animal
• Fluorodeoxyglucose F18
• Glucose
• Humans
• Inflammation
• Mice
• Mice, Inbred C57BL
• Multiple Sclerosis, Chronic Progressive
• Myelin Sheath