Blocking NLRP3 inflammasome eases MS severity in mouse model

Blocking the activity of a protein complex called the NLRP3 inflammasome lessened disease severity in a mouse model of multiple sclerosis (MS), a study reports.

Results point to NLRP3 as a promising target to ease inflammation in people with MS, but additional studies will be needed to determine the specific mechanisms through which the molecule exerts its effects.

The study, “Inhibiting the NLRP3 Inflammasome with MCC950 Alleviates Neurological Impairment in the Brain of EAE Mice,” was published in Molecular Neurobiology.

Recommended Reading

November 2, 2023 Columns by Benjamin Hofmeister

With multiple sclerosis, the right caregiver is everything

NLRP3 inflammasome may trigger inflammation in multiple sclerosis

The immune system is normally responsible for defending the body against infectious invaders. But in MS, immune cells launch an inflammatory attack that damages healthy parts of the brain and spinal cord.

The NLRP3 inflammasome is a complex of immune proteins inside cells that works as a sensor for viruses and other infectious agents. If the complex is activated, it triggers the cell to release inflammatory signaling molecules to sound the alarm and alert the immune system.

Accumulating evidence suggests that abnormal NLRP3 inflammasome activity plays a role in the inflammation that drives MS, which implies that blocking the activity of this protein complex may be a viable treatment strategy.

Scientists in China tested this idea with an NLRP3-blocking compound dubbed MCC950. The team used the compound in mice with experimental autoimmune encephalitis (EAE), a common mouse model of MS, and were especially interested in how this treatment would affect disease-related damage to nerve cells and myelin-making cells called oligodendrocytes.

“In the present study, MCC950 was used to investigate the effect of NLRP3 inflammasome on the pathological changes in the brain of EAE mice, especially neuron damage and oligodendrocytes loss,” the scientists wrote.

Lesser damage to neurons, myelin in mice given NLRP3-blocking compound

Results showed that treating the mice every other day with MCC950, starting on the day of EAE induction, resulted in a significantly lower clinical score than that of untreated EAE mice — indicating that blocking the NLRP3 inflammasome eased the severity of disease.

Treated mice also had markedly less neuron damage in their brain and showed fewer signs of synapse loss, referring to the connections between nerve cells.

Likewise, lesser damage to oligodendrocytes was evident with treatment, which remained at levels similar to healthy mice, and treated mice had a “remarkably” lower degree of demyelination, or myelin loss.

The treatment also reduced the inflammatory activity of microglia and astrocytes, which are brain cells believed to play a role in driving MS.

“We show that MCC950, a selective blocker for the NLRP3 inflammasome, not only ameliorates pathological changes in the spinal cord of EAE mice but also prevents neuronal damage, demyelination, and oligodendrocyte loss in the brain,” the scientists concluded.

These findings, the researchers said, broadly support the idea that blocking the NLRP3 inflammasome might be a beneficial approach in treating MS.

Zyversa Therapeutics, which was not involved with this study, is developing an experimental therapy designed to block the NLRP3 inflammasome called IC 100, which has also shown promise in MS models.

“It is encouraging that the research published in Molecular Neurobiology substantiates our published MS data with Inflammasome ASC Inhibitor IC 100, providing support for its use as a potential therapeutic option,” Stephen C. Glover, co-founder, chairman, president, and CEO of Zyversa, said in a company press release.