Understanding why a heart disease drug trialled in ALS may be beneficial

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neurone disease (MND). In ALS, motor neurones develop damage over time and stop functioning properly, causing muscle weakness and eventually paralysis.

With few approved treatment options for people with ALS, repurposing drugs approved as treatments for other conditions could lead to quicker development of new ALS treatments. Trimetazidine, a drug currently used to improve blood flow to the heart to treat angina attacks, can improve the function of mitochondria, the “power stations” of the cell that produce most of the energy used by cells, as well as reducing inflammation and having antioxidant effects. Because all three of these effects suggest it would be beneficial in people with ALS, trimetazidine was recently tested in ALS mouse models, where it improved mitochondrial function in muscle, slowed ALS progression and improved survival. This study aimed to identify whether trimetazidine could also improve the function of mitochondria in neurones, which may be crucial to protecting them from damage.

Why is the study important?

The heart disease drug trimetazidine has been shown previously to be beneficial in ALS mouse models, slowing ALS progression and improving survival. Gaining an in-depth understanding of why the drug is beneficial in ALS models could help us identify other drugs that we could test in ALS models that have similar effects. It could also show researchers which areas are the best targets for ALS treatment when developing new drugs.

What did the authors do and how did they do it?

The authors took neurones from brains and spinal cords of mice with genetic changes in SOD1, that can cause ALS, and used several methods to study the health of the mitochondria. They used a “mitochondrial stress test” to test how well the mitochondria functioned with or without treatment with trimetazidine. They also investigated the activity of the proteins used by mitochondria to generate energy after trimetazidine treatment. They used microscopes to look at mitochondrial shape and autophagy, the process by which our cells break down and recycle their components. Finally, they looked at mitochondrial health in blood cells from 14 people with ALS, and checked whether trimetazidine improved function in these cells.

First the authors showed that at rest, mitochondria from ALS mouse neurones used less oxygen and as a result produced less energy. When stressed with a toxin that forces mitochondria to work as hard as they can, mitochondria from ALS mice were still less active than those from non-ALS mice. Treating the cells with trimetazidine before the test restored these issues. Taking blood cells from people with ALS and treating them with trimetazidine also improved their performance in the mitochondrial stress test, allowing them to generate more energy when placed under stress.

The activity of proteins involved in many of these energy-generating reactions was lower in ALS mouse neurones, however trimetazidine was able to improve the activity of all of these proteins. Mitochondria in ALS mice were often smaller, which can reduce how active they are, however treatment with trimetazidine increased their size. Finally, when the authors looked at proteins involved in autophagy, they found neurones from ALS mice were not as effective at separating damaged parts of the cell that needed to be broken down and recycled (a process called autophagy). However, treatment with trimetazidine improved this.

What do the findings mean going forward for people with the disease?

The authors of this study have previously shown that treating ALS mice with trimetazidine improved survival and slowed ALS progression, with less neurone damage, less inflammation and improved mitochondrial function muscle. This study expands on a previous study from the same team of researchers, showing that trimetazidine also improves mitochondrial function in neurones. This may be responsible for some of the beneficial effects of the drug in ALS mice. Testing other drugs that are known to improve mitochondrial function in ALS models may help identify new drugs that can be repurposed for ALS, improving the speed of developing new treatments for ALS.

This study can be found at
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10970050/ 

Paper title
Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation

Lead author
Illari Salvatori and Cristaina Valle

Publication details including date of publication
International Journal of Molecular Science (2024), 25(6): 3251. Published online 2024 Mar 13. doi: 10.3390/ijms25063251