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 InformationCIHR, Medicine by Design
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