FTY720 administration following hypoxia-induced neonatal seizure reverse cognitive impairments and severity of seizures in male and female adult rats: The role of inflammation

Abstract

Hypoxia-induced neonatal seizure mainly leads to deleterious effects on brain function, especially cognitive impairments and increased susceptibility to epilepsy later in life. Early inflammation plays an important role in the pathology of these consequences. Therefore, we explored the long-term outcomes of Fingolimod treatment as an anti-inflammatory and neuroprotective agent in a rat model of HINS. Seizures were induced in rats (postnatal day 10) by 5% O2 exposure for 15 min. Sixty minutes after the onset of hypoxia, pups received FTY720 (0.3 mg.kg-1) or normal saline for 12 consecutive days (lactation period), and they were used at P60-P63 for behavioral tests, ELISA and Pentylenetetrazole kindling model. The results of open field, novel object recognition and elevated plus maze tasks showed that Fingolimod prevents hippocampal memory dysfunction and anxiety-like behavior in both male and female hypoxic groups, which was accompanied with decreased TNF-α level in hippocampus. In addition, FTY720 postponed epileptogenesis just in female hypoxic + FTY group and decreased severity of seizures in both genders. Our results suggest that, FTY720 treatment in immature rats, which were previously subjected to HINS, prevented the long-lasting deficits, like cognitive impairments, decreased the severity of seizures and related inflammation. In addition, FTY720 did not show significant interaction with gender in most of the experiments, except the average day to reach fully kindled state. Taken together, FTY720 has therapeutic potential for long lasting effects of HINS in both male and female animals at puberty.

Keywords: Anxiety; Fingolimod; HINS; Inflammation; Memory; Rat.