Metformin pretreatment rescues olfactory memory associated with subependymal zone neurogenesis in a juvenile model of cranial irradiation

Cranial irradiation (IR) is an effective adjuvant therapy in the treatment of childhood brain tumors but results in long-lasting cognitive deficits associated with impaired neurogenesis, as evidenced in rodent models. Metformin has been shown to expand the endogenous neural stem cell (NSC) pool and promote neurogenesis under physiological conditions and in response to neonatal brain injury, suggesting a potential role in neurorepair. Here, we assess whether metformin pretreatment, a clinically feasible treatment for children receiving cranial IR, promotes neurorepair in a mouse cranial IR model. Using immunofluorescence and the in vitro neurosphere assay, we show that NSCs are depleted by cranial IR but spontaneously recover, although deficits to proliferative neuroblasts persist. Metformin pretreatment enhances the recovery of neurogenesis, attenuates the microglial response, and promotes recovery of long-term olfactory memory. These findings indicate that metformin is a promising candidate for further preclinical and clinical investigations of neurorepair in childhood brain injuries.