New study shows how to protect the brain to prevent depression and cognitive impairment caused by whole brain radiotherapy

Whole brain radiotherapy (WBRT) saves lives by treating cancer that has spread to the brain, but it also causes long-standing brain damage. Many patients who go through radiation treatment later develop memory problems, thinking difficulties, and depression because the WBRT creates chronic oxidative stress in the brain. There are currently no medicines that adequately prevent this, so patients endure these effects of WBRT that significantly lower their quality of life.

Now, a research team from University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center has discovered that an experimental neuroprotective drug, P7C3-A20, could protect the brain from these harmful side effects of WBRT.

The study, led by the Pieper Laboratory, published today in Redox Biology. 

“The results of our study were very encouraging,” said Andrew A. Pieper, senior author of the study, University Hospitals Morley-Mather Chair of Neuropsychiatry and the Rebecca E. Barchas Case Western Reserve University Professor of Translational Psychiatry. 

“In mice, WBRT caused chronic oxidative stress in the brain, most severely in the hippocampus, which is a region of the brain that is critical for learning, memory and mood,” said Edwin Vázquez-Rosa, assistant professor of Psychiatry in the Pieper Lab and lead author of the study. “In the mice, this damage led to memory loss and depression-like behaviors. These debilitating effects continued for a year, which is the equivalent of decades in people. Daily treatment with P7C3-A20, a neuroprotective compound that stabilizes brain nicotinamide adenine dinucleotide (NAD+) homeostasis, reduced that oxidative stress and prevented hippocampal damage, as well as cognitive impairment and depression-like activity in the mice.”

“The strength and breadth of protection were particularly exciting,” Pieper said. “P7C3-A20 suppressed neuroinflammation, protected both nerve cells and microglia, and prevented blood-brain barrier deterioration. Importantly, P7C3-A20 did not reduce the cancer-killing effects of radiation, and the mice tolerated P7C3-A20 treatment well over the entire year.”

Pieper is also the director of the Brain Health Medicines Center at the Harrington Discovery Institute at UH, serves as psychiatrist and investigator in the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC), and is co-founder of Glengary Brain Health, Inc, a company formed to further develop and commercialize this technology.

Next steps in this research involve testing P7C3-A20 with different radiation schedules and doses and defining the shortest effective time window after WBRT. 

“If these findings translate to humans, stabilizing brain energy balance (NAD+ homeostasis) by adding a drug like P7C3-A20 to WBRT could preserve cognition and mood without reducing the ability of radiation treatment to control cancer,” said Pieper.