#VisualAbstract: Metformin for survivors of pediatric brain tumors

1. Metformin was found to be safe and tolerable in survivors of pediatric brain tumors.

2. Metformin was associated with retention of memory and processing speed abilities, as well as a reduction of white matter loss.

Evidence Rating Level: 1 (Excellent)

It is believed that endogenous neural precursor cells (NPCs) can promote tissue repair in the human brain due to its precursor cell populations. This is an important consideration due to limited self-repair capacities of the brain, such that agents inducing proliferation and differentiation of NPCs in vivo, validated in rodent models, could benefit humans. The hypoglycemic agent metformin has been found to increase neurogenesis in rodent models, particularly through activating the atypical protein kinase C (APKC)-CREB-binding protein (CBPT) pathway in NPCs. Metformin also improved cognitive faculties such as spatial memory. Its ability to decrease disease-related hippocampal neuron loss, metformin may also have the ability to recruit NPCs to repair brain tissue in humans. This pilot randomized, double-blind, placebo-controlled clinical trial with crossover focused on survivors of pediatric brain tumors treated with cranial radiation due to the hippocampus and white matter, high in NPCs, are most commonly damaged during cranial radiation. Specifically, safety and feasibility of metformin among this population was investigated. A total of 24 participants were randomly assigned to 12-week cycles of metformin (n = 11; M [SD] age = 7.26 [3.34] years) and placebo (n = 12; M [SD] age = 6.44 [3.63] years) in either an AB or BA sequence. A 10-week washout period occurred at crossover. Cranial radiation of participants occurred 2 to 15 years prior to the study. Blood draws, MRI, medication and procedural adherence, and cognition were measured throughout the study. A total of 12 participants were medulloblastoma survivors. This study found that, in spite of increased mild gastrointestinal events, metformin was both tolerable and safe. It also appeared that metformin reduced the negative impacts of radiation on processing speed, memory, and white matter loss consistent with the population. While this study’s sample was relatively small, it suggests that metformin may be beneficial to this population through the recruitment of NPCs to repair tissue damage and retain cognitive faculties.

Click to read the study in Nature

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