Discovery of ‘Fiery’ Cell Death Mechanism May Be MS ‘Game-Changer’

Researchers have unveiled a new cell death mechanism called pyroptosis — also known as “fiery death” — as a main factor driving neurodegeneration and loss of myelin in people with multiple sclerosis (MS).

An inhibitor of pyroptosis, currently undergoing testing in human clinical trials for epilepsy, decreased central nervous system inflammation and reduced several of the neurobehavioral deficits in a mouse model of MS.

“This could be a game changer, because we discovered a fundamental mechanism by which brain cells are damaged in MS that couples inflammation with neurodegeneration,” Chris Power, neurologist, co-director of the University of Alberta MS Centre in Canada, and study lead author, said in a press release.

The study “Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis” was published in the journal Proceedings of the National Academy of Sciences.

Pyroptosis is a type of programmed cell death that is driven by pro-inflammation signals, but its role in MS was previously unknown.

Now, researchers at the University of Alberta found that pyroptosis is a primary mechanism driving the loss of myelin in the central nervous system in MS.

They revealed that this cell death process was significantly activated in post-mortem brain samples from MS patients, relative to non-MS controls.

Researchers performed further experiments using human microglia cells, the primary immune cells of the central nervous system, and myelin-producing cells called oligodendrocytes. Both cell types underwent pyroptosis after receiving MS-relevant stimuli, and the same was observed in animal models of MS, namely the experimental autoimmune encephalomyelitis (EAE) model.

Pyroptosis is mediated by the inflammatory activity of a protein called caspase-1, for which a pharmacological inhibitor is available and currently undergoing testing in clinical trials for epilepsy. The inhibitor is called VX-765.

Researchers tested the inhibitor VX-765 in the EAE model. Mice were treated with VX-765 (50 mg/kg injected into the abdomen) daily, or with an innocuous substance (control mice).

Results showed the treatment not only reduced inflammation in the central nervous system of the animals, but also prevented injury to nerve cells’ axons and reduced the severity of neurobehavioral deficits in the animals after only three days of treatment.

“We think this drug would break the cycle of neurotoxic inflammation and thus prevent future loss of brain cells in MS,” said Brienne McKenzie, PhD, the study’s first author.

“The drug is already known to be safe in humans,” said Power.

These findings open the possibly for new ways to monitor MS progression and for developing new therapies.

“Existing MS treatments work to reduce inflammation, but there is nothing that targets the brain cells themselves,” said Avindra Nath, MD, clinical director of the National Institute of Neurological Disorder and Stroke at the National Institutes of Health (NIH) in Bethesda. “This paper identifies a clinically relevant novel pathway that opens the doors to new therapeutic targets that prevent cell damage.”

“The study’s findings make a key contribution to the MS field in identifying a novel mechanism that contributes to progression in MS,” added Karen Lee, PhD, vice president of research at the MS Society of Canada. “The MS Society of Canada is encouraged by the results of this study and what it means for people living with MS — hope for another avenue through which treatment options can be explored to stop MS in its tracks.”