‘Rings of fire’: blocking the death of brain cells in MS

Scientists have discovered a fundamental mechanism by which brain cells are damaged in MS, linking inflammation and neurodegeneration. The research suggests that, in MS, brain cells can undergo a process called pyroptosis, or ‘fiery death’. A drug known as VX-765 was shown to block this cell death, suggesting this might be a way to protect brain cells in MS.

In MS, the protective myelin sheath of the nerve cells in the brain or spinal cord is damaged by the immune system, which prevents signals from being conducted efficiently along the nerve fibres and can even make these cells vulnerable to death. The death of cells in the brain and spinal cord – not only nerve cells, but also other brain cells, such as oligodendrocytes – is a major contributor to the disease process of MS. Since oligodendrocytes help repair damage to the myelin, the loss of these cells exacerbates the damage and prevents repair and restoration of function.

As such, scientists have long hypothesised that preventing cell death may alleviate some of the symptoms and progression of MS. Now, a new study reveals a mechanism by which inflammation might cause these cells to die and a drug that may be able to prevent the cells from dying, potentially mitigating some of the disease processes.

In the study, recently been published in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America, scientists identified a process in MS by which cells die called ‘pyroptosis’. ‘Pyroptosis’ roughly translates from Greek to fiery death and is a type of cell death resulting from specific inflammatory processes.

‘Rings of fire’

The scientists first examined brain tissue from people with MS and those without, examining the cell microscopically and examining the genes that the cells were using. The team discovered that the oligodendrocytes and microglia (brain immune cells) exhibited characteristics of pyroptosis and had structures on them which resembled ‘rings of fire’. These rings form little pores in the cells where inflammatory signals leak out, perpetuating and spreading inflammatory signals to neighbouring cells before dying themselves. This mechanism has been observed in Alzheimer’s disease, traumatic brain/spinal cord injury and epilepsy. But exactly how it works in the brain has never been fully examined. This is the first time that the full process of pyroptosis has been understood in the brain.

Importantly, the scientists were then able to block pyroptosis in cells grown in the laboratory using a drug known as VX-765, a drug currently in clinical trials for epilepsy, and subsequently prevent cell death. When they gave VX-765 to mice with an MS-like disease, the mice showed rapid improvements in their neurological symptoms, suggesting that blocking the cell death improved the disease outcomes.

This study has revealed, for the first time, one of the fundamental mechanisms by which MS inflammation may trigger cells to die. As the cells go through this process, they seem to also perpetuate the inflammatory signal. As VX-765 was able the block neurodegeneration and has been shown here to protect the spinal cord from inflammation in animals with an MS-like disease, this opens up the possibility that the drug could be used to treat MS.

With thanks to MS Research Australia – the lead provider of research summaries on our website.