Investigating Effects of Metformin and Enriched Rehabilitation on Perinatal Hypoxia-Ischemia

Abstract

Hypoxia-ischemia (HI) insults can have profound effects on the immature brain, impairing development and leaving survivors with lifelong physical and cognitive deficits. Improvements in neonatal care have resulted in more newborns surviving HI, but effective treatments for the long-term consequences of this disorder have yet to be established. Using the Rice-Vannucci model of hypoxia-ischemia at postnatal day (PND) 7, we investigated the effects of metformin and enriched rehabilitation on short and long-term motor and cognitive outcome in both male and female Sprague-Dawley rats. A battery of behavioural tests was used to assess early development and motor function from PND 8-21, while long-term motor and cognitive function was assessed from PND 49 onwards. Metformin, administered from PND 8-49, improved several aspects of early development that were compromised following HI (weight gain, neurological reflexes). However, it worsened motor impairments in the adhesive strip removal task and Montoya staircase. Enriched rehabilitation, beginning at PND 21, improved motor function in the adhesive strip removal task, open field and Montoya staircase. Additionally, it enhanced cognition in the Barnes maze and Morris water maze. Our results indicated that, despite early beneficial effects on development, metformin was not effective at improving long-term outcome. Enriched rehabilitation led to significant improvements in several aspects of motor and cognitive function, even when administered 2 weeks post-injury. This data suggests that enriched rehabilitation, but not metformin, may be a valuable intervention for treating behavioural impairments resulting from episodes of perinatal hypoxia-ischemia.