Pregnancy swimming prevents early brain mitochondrial dysfunction and causes sex-related long-term neuroprotection following neonatal hypoxia-ischemia in rats

Neonatal hypoxia-ischemia (HI) is a major cause of cognitive impairments in infants. Antenatal strategies improving the intrauterine environment can have high impact decreasing pregnancy-derived intercurrences. Physical exercise alters the mother-fetus unity and has been shown to prevent the energetic challenge imposed by HI. This study aimed to reveal neuroprotective mechanisms afforded by pregnancy swimming on early metabolic failure and late cognitive damage, considering animals' sex as a variable. Pregnant Wistar rats were submitted to daily swimming exercise (20′ in a tank filled with 32 °C water) during pregnancy. Neonatal HI was performed in male and female pups at postnatal day 7. Electron chain transport, mitochondrial mass and function and ROS formation were assessed in the right brain hemisphere 24 h after HI. From PND45, reference and working spatial memory were tested in the Morris water maze. MicroPET-FDG images were acquired 24 h after injury (PND8) and at PND60, following behavioral analysis. HI induced early energetic failure, decreased enzymatic activity in electron transport chain, increased production of ROS in cortex and hippocampus as well as caused brain glucose metabolism dysfunction and late cognitive impairments. Maternal swimming was able to prevent mitochondrial dysfunction and to improve spatial memory. The intergenerational effects of swimming were sex-specific, since male rats were benefited most. In conclusion, maternal swimming was able to affect the mitochondrial response to HI in the offspring's brains, preserving its function and preventing cognitive damage in a sex-dependent manner, adding relevant information on maternal exercise neuroprotection and highlighting the importance of mitochondria as a therapeutic target for HI neuropathology. Pregnancy swimming has a great impact in the offspring's brain development. Maternal exercise induces a sex-dependent preconditioning response in the brain tissue following neonatal hypoxia-ischemia, mainly through early mitochondrial function preservation, preventing energetic failure and ROS production, improving brain glucose utilization and decreasing HI-induced cognitive impairments at adult age. [Display omitted] •Brain energetic failure is a primary cause of damage following neonatal hypoxia ischemia (HI).•Pregnancy swimming has shown beneficial effects preventing HI brain damage.•Mitochondrial function is preserved following HI in the offspring of exercised dams.•Spatial memor