Radiation can save lives for a child with a brain tumor. However, therapy can also damage the brain, leading to deficits in cognitive function, including learning and memory problems.
Thanks to funding from Medicine by Design, a University of Toronto scientist and her team are now closer to figuring out a way to protect the brain from damage to children in need of cranial radiation by using a drug that commonly used to treat diabetes.
“We found that by giving metformin, an approved, safe drug used to treat diabetes, as a pre-treatment in animal models, we can actually stop the damage,” he says Cindi Morshead, Professor and Chair of Anatomy in the Department of Surgery at the Temerty Faculty of Medicine.
The study, published in the journal Cell Reports Medicine, builds on previous work with metformin. Last summer, Morshead and researchers at the Hospital for Sick Children (SickKids) showed that metformin, given after skull irradiation, promotes neurogenesis, or the process of creating new neurons in the brain.
Morshead says that hopefully, given the safety of metformin, the research will move quickly to clinical trials.
“Anything we can do to keep children away from these long-term impairments would be very positive,” she says. “For children with brain tumors who need skull irradiation, it would be life-changing for them and their children to be able to do something that ensures their brain is less damaged in the first place, rather than trying to fix it after the fact families. “
In particular, the previous metformin study that looked at the administration of the metformin after skull irradiation and after damage occurred found that the benefits of metformin were only seen in adolescent women. According to Morshead, the more recent study did not show a gender-specific effect, suggesting that pretreating children with metformin could bring additional benefit.
Radiation cognitive deficits can be caused by the killing of newborn neurons that underlie learning and memory. According to Morshead, the study shows that metformin offers neuroprotection to animals given the drug prior to skull irradiation.
“Radiation is an insult to the brain, and our study showed that we can protect the microenvironment because the metformin reduces inflammation in the brain. After the drug treatment, newborn neurons were not lost and were able to make new connections over and over again in the part of the brain that is important for olfactory memory. “
Morshead, whose lab is at the Donnelly Center for Cellular and Biomolecular Research, says the researchers taught the animals for this project where to find a food reward based on a specific smell. One type of scent belonged to a dish that had a hidden tidbit and another type of smell belonged to a dish that had no hidden tidbit. Only mice treated with metformin prior to irradiation could remember which odor was associated with the treatment.
“It was really a remarkable effect. Those who weren’t given the metformin prior to radiation couldn’t remember the association, ”says Morshead. “Those given the metformin remembered the association weeks after the radiation. We therefore concluded that the mice that were not treated with metformin had long-term memory impairment and that metformin was protected against this impairment. “
The study is part of a large team project funded by Medicine by Design, led by Freda Miller, an Associate Scientist in the Neuroscience and Mental Health Program at SickKids and Professor in the Molecular Genetics Department. Miller’s research team, which includes eight labs at U of T and SickKids, takes a far-reaching approach to promoting self-repair in the brain and muscle. Miller and her colleagues at SickKids found that metformin could potentially be used for self-repair in the brain. Morshead’s metformin research builds on this original finding.
“I am delighted with this paper because it describes potential protective therapy for children who need skull radiation,” says Miller, who is also a professor at the University of British Columbia. “Just as importantly, the metformin story is a classic example of why we need to support basic research and why working in collaborative teams is essential.
“The original finding that metformin recruited endogenous brain stem cells came from fundamental studies of how stem cells build the brain through development and was then carried over to other models by highly interdisciplinary scientists like Dr. Morshead.”
Morshead recognizes donors such as Medicine by Design as strong supporters of this and other promising metformin work.
“My laboratory – as well as the laboratories of Freda Miller and Don Mabbott at SickKids and others – are grateful to have the opportunity to do this research, ”she says. “The opportunity to show these positive results with a drug that we know is safe, approved and available is really the best scenario. We hope that one day this will be a low risk solution for children who would otherwise live with cognitive deficits after surviving a brain tumor. “
In addition to her work with Miller on this large team project, Morshead is leading another Medicine by Design project that focuses on improving neuroplasticity in the brain and regenerating cells that are lost or damaged by stroke.