Administering MSC‐Derived Exosomes After Hypoxia‐Induced Seizures in Neonatal Rats Improved Cognitive Function and Delayed the Onset of Epilepsy in Adulthood, Likely by Reducing Inflammation and Oxidative Stress

ABSTRACT Hypoxia‐induced neonatal seizures (HINSs) are a major cause of long‐term cognitive deficits and heightened epilepsy risk in adulthood. Early inflammatory responses following HINS contribute to these pathological outcomes. This study examined the sustained neuroprotective benefits of exosomes derived from mesenchymal stem cells (MSC‐exosomes) in a rat model of HINS, leveraging their anti‐inflammatory and neuroregenerative properties. Forty‐nine male and female Wistar rats were divided into four groups: (1) control + saline, (2) control + exosome, (3) hypoxia + saline, and (4) hypoxia + exosome. Neonatal rats (postnatal day 10) were subjected to hypoxia (5% O 2 for 15 min). Sixty minutes after the onset of hypoxia induction, pups received either MSC‐exosomes (30 µg/100 µL) or saline for 12 consecutive days (lactation period). Behavioral tests, hippocampal tissue analysis (for RT‐PCR and oxidative stress markers), and pentylenetetrazole (PTZ) kindling were performed at P60–P61. The study revealed that treatment with exosomes improved memory performance and reduced anxiety‐like behaviors in the hypoxia‐exposed group, as evidenced by the novel object recognition and elevated plus maze tests. These benefits were linked to decreased oxidative stress (lower malondialdehyde/MDA levels), reduced pro‐inflammatory markers (interleukin‐6 [IL‐6] and tumor necrosis factor‐α [TNF‐α]), and increased anti‐inflammatory signaling (higher IL‐10) in the hippocampus. Although exosome therapy delayed the onset of epileptogenesis, it did not lessen the intensity of seizures. The results indicate that administering MSC‐derived exosomes after HINS can reduce susceptibility to PTZ‐induced kindling, alleviate neuroinflammation, regulate oxidative stress, and protect against long‐term cognitive impairments. Together, these findings highlight the potential of exosome‐based interventions in mitigating the delayed neurological effects of HINS during adolescence.