Effects of nestorone, a progesterone receptor agonist, on neonatal hypoxic-ischemic brain injury and reproductive functions in male and female rats.

Perinatal hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of neonatal death and neurological disorders. We recently demonstrated the neuroprotective effects of nestorone, a progesterone receptor agonist, in adult male rats subjected to focal cerebral ischemia; however, its effects on neonatal ischemic brain injury and on sexual differentiation and reproductive functions remain unclear. Therefore, the present study investigated the effects of nestorone on neonatal hypoxic-ischemic brain injury and reproductive functions in rats of both sexes. Seven-day-old male and female rat pups were subjected to occlusion of the right carotid artery and then exposed to 8 % oxygen (hypoxic-ischemia, HI). Brain lesion sizes and the numbers of activated astrocytes and microglia in male and female rats were significantly lower after administrating 10 μg/kg nestorone than vehicle 48 h after HI. Furthermore, the post-HI administration of nestorone for 7 days (10 μg/kg, once a day) significantly improved motor coordination and tactile responses 28 days after HI and cognitive performance 4 months after HI in male and female rats. The administration of nestorone did not affect the delivery rates or number of weaned pups in HI and sham-operated female rats or in intact female rats mated with HI or sham-operated males. These results suggest that nestorone exerts persistent neuroprotective effects against neonatal HI brain injury without serious adverse effects on reproductive functions in male and female rats. Therefore, nestorone is a promising potent and safe therapeutic agent in newborn infants with HIE of both sexes.