Metformin Improves Functional Outcomes, Activates Neural Precursor Cells, and Modulates Microglia in a Sex-Dependent Manner After Spinal Cord Injury

Spinal cord injury (SCI) results in devastating patient outcomes with few treatment options. A promising approach to improve outcomes following SCI involves the activation of endogenous precursor populations including neural stem and progenitor cells (NSPCs) which are located in the periventricular zone (PVZ), and oligodendrocyte precursor cells (OPCs) found throughout the parenchyma. In the adult spinal cord, resident NSPCs are primarily mitotically quiescent and aneurogenic, while OPCs contribute to ongoing oligodendrogenesis into adulthood. Each of these populations is responsive to SCI, increasing their proliferation and migration to the site of injury; however, their activation is not sufficient to support functional recovery. Previous work has shown that administration of the FDA-approved drug metformin is effective at promoting endogenous brain repair following injury, and this is correlated with enhanced NSPC activation. Here, we ask whether metformin can promote functional recovery and neural repair following SCI in both males and females. Our results reveal that acute, but not delayed metformin administration improves functional outcomes following SCI in both sexes. The functional improvement is concomitant with OPC activation and oligodendrogenesis. Our data also reveal sex-dependent effects of metformin following SCI with increased activation of NSPCs in females and reduced microglia activation in males. Taken together, these findings support metformin as a viable therapeutic strategy following SCI and highlight its pleiotropic effects in the spinal cord.