The study, published in the Proceedings of the National Academy of Sciences, is the first to provide insight into how pyroptosis, also called the “fiery death,” works at the molecular level in the brain. The researchers observed the process in an experimental animal model of MS and in brain tissue from patients with the disease, and found that an experimental drug may serve to prevent future loss of brain cells in MS.
According to the findings, the pore-forming protein gasdermin D (GSDMD) was recently identified as the principal executioner of the inflammasome-driven cell death. Although molecule caspase-1 can activate GSDMD, it was previously unknown whether this process contributes to neuroinflammation.
In the study, the researchers indicated molecular evidence of GSDMD-mediated pyroptosis as a primary mechanism of inflammatory demyelination in the central nervous system (CNS) during MS. The researchers found that pyroptosis occurred not only in myeloid cells, but also in myelin-forming oligodendrocytes, which they observed in the CNS tissue of individuals with MS, as well as in an animal model.
In both cell types, the experimental drug VX-765 inhibited caspase-1, which reduced the expression of inflammasome- and pyroptosis-associated proteins in the CNS, prevented axonal injury, and improved neurobehavioral performance. VX-765 is currently in clinical trials for epilepsy.
“This could be a game changer, because we discovered a fundamental mechanism by which brain cells are damaged in MS that couples inflammation with neurodegenerations,” lead study author Chris Power, MD, co-direct of the UAlberta MS Centre, said in a press release. “The drug is already known to be safe in humans.”
Overall, the findings identify a previously unrecognized mechanism of inflammatory demyelination that could lead to new therapeutic targets aimed at preventing damage to the brain cells themselves, which could mitigate the disease process in MS and other CNS inflammatory diseases.
“Existing MS treatments work to reduce inflammation, but there is nothing that targets the brain cells themselves,” Avindra Nath, clinical director of the National Institute of Neurological Disorder and Stroke at the National Institute of Health, said in the press release. “This paper identifies a clinically relevant novel pathway that opens the doors to new therapeutic targets that prevent cell damage.”
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McKenzie BA, Mamik MK, Saito LB, et al. Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. PNAS. 2018. https://doi.org/10.1073/pnas.1722041115