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Hypoxia-ischemia (HI) injury is a leading cause of neonatal death and long-term disability, and existing treatment options for HI offer only modest benefit. Early intervention with the drug metformin has been shown to promote functional improvement in numerous rodent models of injury and has pleiotropic cellular effects in the brain. We have previously shown that 1 week of metformin treatment initiated 24 ​h after HI in neonatal mice resulted in improved motor and cognitive performance, activation of endogenous neural precursor cells (NPCs), and increased oligodendrogenesis. While promising, a limitation to this work is that immediate pharmacological intervention is not always possible in the clinic. Herein, we investigated whether delaying metformin treatment to begin in the subacute phase post-HI would still effectively promote recovery. Male and female C57/BL6 mice received HI injury postnatally, and metformin treatment began 7 days post-HI for up to 4 weeks. Motor and cognitive performance was assessed across time using behavioural tests (cylinder, foot fault, puzzle box). We found that metformin improved motor and cognitive behaviour, decreased inflammation, and increased oligodendrocytes in the motor cortex. Our present findings demonstrate that a clinically relevant subacute metformin treatment paradigm affords the potential to treat neonatal HI, and that improved outcomes occur through modulation of the inflammatory response and oligodendrogenesis.

Stroke is the leading cause of adult disability with few treatment options for stroke survivors. Astrocyte reprogramming to neurons enables the targeted in vivo generation of new cells at the site of injury and represents a novel approach for brain repair. A number of studies have demonstrated successful conversion of astrocytes to neurons in various models of brain injury and disease; however, the impact of this strategy on tissue and functional outcome following stroke is not well established. Using AAV delivery of the transcription factor NeuroD1, we reprogrammed astrocytes 7 days after endothelin-1 induced cortical stroke, and studied the long-term cellular and functional outcomes. We found that by 63 days post-stroke, 20% of neurons in the perilesional cortex were reprogrammed. Furthermore, reprogrammed neurons had matured into regionally appropriate neuronal subtypes. Importantly, this treatment was associated with improved functional outcome using the foot fault test and gait analysis. Together, our findings indicate that in vivo reprogramming is a promising regenerative approach for stroke repair.

No abstract

Hypoxia‐ischemia (HI) is one of the leading causes of neonatal death and long‐term disability. Currently, the only standard treatment for HI is therapeutic hypothermia, which affords only modest benefit. The drug metformin has been shown to have pleiotropic effects in the brain, including activation of endogenous neural precursor pools. Importantly, administration of metformin leads to improved functional improvements following neonatal HI. Our previous work has demonstrated that metformin treatment beginning 24 hours after HI injury on post‐natal day (P8), and lasting for 1 week leads to attenuation of motor deficits at P22 and activation of endogenous neural precursor cells (NPCs) in the subventricular zone (SVZ). NPCs expanded in number, migrated into the parenchyma and differentiated into neurons and glia. Improved cognitive outcomes in young adults was also observed with extended metformin treatment in HI injured mice. Given these promising outcomes, and to improve the clinical application of the therapeutic intervention, we asked if delayed metformin treatment would be equally effective at improving functional outcomes. Male and female C57/BL6 mice were subjected to HI (or a sham procedure) at P8. Metformin (or vehicle) treatment began on P15 and lasted 4 weeks. Motor and cognitive functions were assessed across time using various behavioural assays (cylinder, foot fault, and puzzle box). Tissue was collected at P28 and 63 and analyzed for changes in inflammation, proliferation and differentiation. We found that delaying metformin treatment was effective at promoting motor and cognitive recovery. Treatment led to a decrease in inflammation after injury, as seen by a reduction in microglia, and an increase in oligodendrocytes in the motor cortex. Hence, our findings demonstrate that a clinically relevant delayed metformin treatment paradigm has therapeutic potential following neonatal HI. Support or Funding Information CIHR, Medicine by Design