Metformin Activates Resident Neural Stem and Progenitor Cells, Reduces Inflammation and Improves Functional Recovery Following Spinal Cord Injury

Abstract

The mammalian spinal cord contains a population of neural stem and progenitor cells (NSPCs) located within the periventricular region lining the central canal. These cells are primarily quiescent under homeostatic conditions and are activated following injury, however, this response is not sufficient to support functional recovery in mammals. We propose that enhancing resident NSPC activation is a promising approach to promote neurorepair and improve functional outcomes following spinal cord injury (SCI). The FDA-approved drug metformin has demonstrated efficacy in promoting functional recovery following brain injury through pleiotropic effects including NSPC activation, increased neurogenesis and oligodendrogenesis and modulation of the injury microenvironment including the inflammatory response. We hypothesize that metformin administration will promote functional recovery following SCI concomitant with activation of NSPCs and reduced inflammation. In a first series of in vitro experiments, we found that metformin significantly increases the size of the NSPC pool in females, but not males; increases neurogenesis in males and enhances oligodendrogenesis in both sexes. We next examined the effect of metformin treatment following SCI. Metformin was delivered to mice for 14 days starting immediately following SCI or starting at 7 days after SCI. Mice were tested on a skilled walking test and using gait analysis at 1 and 2 weeks following the start of metformin treatment. Mice that received metformin starting at the time of injury recovered motor function by 2 weeks post-treatment however, delayed administration was not effective at improving functional outcomes. Interestingly, the functional outcomes observed in both treatment paradigms were correlated with metformin's effect on inflammation, as measured by the numbers of Iba1+ microglia/macrophages. In mice that received metformin immediately post-SCI, Iba1+ cells were significantly reduced compared to vehicle-treated SCI mice. Delayed metformin treatment did not lead to reduced inflammation relative to vehicle-treated SCI mice. Together, these results support metformin as a viable therapeutic strategy to expand and enhance NSPCs, decrease inflammation and enhance functional outcomes when administered in the acute phase following SCI.