Metformin and Neural Repair in Mouse Models of Cerebral Palsy

IN BRIEF © JESSICA LIVINGSTON-THOMAS AND CINDI MORSHEAD, 2018 

Introduction

Cerebral Palsy (CP) results in the loss of several types of cells in the brain, including neurons and oligodendrocytes:

• Neurons are the cells that transmit signals in the brain
• Oligodendrocytes are the cells that insulate the axons (the nerve fibres that transmit nerve impulses) to allow them to transmit their signals.

Both types of cells are necessary for brain function. One approach to repair the brain is to replace the cells lost after injury. We know from studies in animals that the brain responds to injury by increasing production of new neural cells. This process is called neurogenesis.

However, by itself, this increased production of neural cells is not enough to repair the brain. We want to explore treatments that promote neurogenesis. To try to do this, we aim to use drugs and other treatments to activate the stem cells that exist in the brain.

Neurogenesis

The brain contains neural stem cells that can help in ongoing neurogenesis throughout a person’s lifetime. Neural stem cells—like other stem cells in the body—have the ability to make copies of themselves, and also to make a number of different cell types that make up the brain. Once a new cell is born, it must travel through the brain tissue to the right place and then mature into a specific cell type. Without these processes, most new cells will die.

In the fully developed healthy brain, new cells that are born either participate in memory formation, or die, because they are not needed or used. In the injured brain, however, new cells are born and travel toward the site of the injury, most likely following chemical signals. However, these cells are not enough to affect functional recovery.

What is metformin?

Metformin is an oral medication that helps people with diabetes control their blood sugar. Several recent studies have also found that metformin can promote regeneration in the brain by increasing the number of neurons and oligodendrocytes. For this reason, research is now exploring whether metformin can be used to treat neurological conditions, such as CP, by replacing lost cells in the injured brain.

Metformin has also been shown to increase the growth of blood vessels (a process called angiogenesis). This could also prove useful in brain repair, because it may improve the flow of blood and a variety of chemicals important for brain growth. Importantly, metformin is already proven to be safe and is approved by the federal government, making it possible and realistic to try metformin in the treatment of CP.

The treatment potential of metformin

Metformin has been shown to affect neurogenesis in a number of ways, and we are studying these in the context of CP. For example, metformin can increase the number of neural stem cells in the brain. It can also affect the migration, survival, and maturation of newborn cells. Ultimately, metformin treatment leads to more new cells in the damaged brain following injury.

In our lab, we use animal models (mice with CP) to study the treatment potential of metformin. By doing this, we have shown that metformin treatment increases the number of the brain’s stem cells and improves migration of new cells into damaged areas of the brain (Dadwal et al. 2015). Metformin treatment also promotes these cells to mature and become the two important cell types of the brain – neurons and oligodendrocytes – that are lost in injured brains of people with CP.

Our early studies have shown that animals that receive metformin soon after the brain injury have significantly less motor impairment. This outcome is associated with an increase in newly born cells. We are now studying whether metformin can improve learning challenges that are prominent in some people with CP. Our preliminary findings in the mouse models of CP suggest that metformin treatment may have benefits on functions like memory and problem-solving skills.

Another question we are exploring is whether neural stem cells are necessary and/or sufficient for the recovery we observe following treatment. It is important to understand how metformin works in the brain to cause the positive outcomes. This is because metformin can affect other things in the brain, like blood vessel formation and the inflammatory response. To study this, we are using a specific kind of mouse that allows us to destroy neural stem cells before the injury and during the recovery phase. By examining whether functional recovery still occurs without neural stem cells, we will improve our understanding of the mechanisms of metformin-induced recovery. This, in turn, will allow us to design more effective treatments.

What don’t we yet know about the use of metformin?

We are excited about the results from our research investigating metformin so far, but there are many things that we still need to understand better. For example:

• How soon after brain injury does metformin treatment need to be started? Is there a time limit?
  So far, we have started metformin treatment beginning the day after injury. However, it not be possible to begin clinical treatment that quickly in human infants and young children. We know that there are several changes that take place in the brain during the days and weeks that follow brain injuries that can lead to CP. Therefore, it is important to know whether delaying metformin treatment for days, weeks, or even months can still affect functional recovery. We are currently exploring the concept of a “window of opportunity” for starting treatment.
• How long do we need to treat with metformin to see beneficial effects?

Metformin is safe drug for diabetes, and is used by millions of people worldwide. We want to know if benefits from metformin can be seen with longer- or shorter-term treatments. We want to examine potential negative effects, such as too much neurogenesis or blood vessel formation in the brain as a result of longer-term treatment. These are very important considerations that have implications as we plan to explore the clinical applications of our mouse work in humans.

• Do male and female mice respond differently to metformin treatment?
  We have observed some differences in the way that male and female mice respond to metformin treatment. Such variation could result from differences in the brain “environment” of males and females, differences in the neural stem cells themselves, or hormonal differences. In order to ensure treatment benefits in people with CP, we must understand why there are differences in how males and females respond to metformin

Conclusion

Metformin is an promising drug that may be effective in the treatment of people with CP following brain injury. Using research with mice, we have shown that metformin leads to an increase in the number of neurogenic stem cells. Metformin also supports the migration, survival, and maturation of cells that are lost in an injured brain. Most importantly, we have seen that animals that receive metformin treatment show functional improvements following CP. However, there are several critical questions that must be addressed in order to be able to apply these findings to people. Ongoing work in our lab is looking into all these questions, and more.

Acknowledgements

Special thanks to Carla Lowe and Natalie Murdock for critically reviewing this document.