Triiodothyronine ameliorates S-ketamine-induced hypomyelination via the PPARα pathway in neonatal rat

Growing evidence suggests that prolonged or repeated exposure to general anesthesia is associated with white matter alteration in children, which may underlie subsequent cognitive and behavioral abnormalities. Numerous infants undergo anesthesia for surgery each year, so it is imperative to identify the risk factors and find preventative treatment to prevent the effects of early anesthesia exposure. Thyroid hormones play a pivotal role in the process of myelination of white matter. Clinical studies have shown that thyroid hormone levels are decreased after infant surgery, whether thyroid hormone supplementation can prevent long-term toxicity of anesthesia remains to be elucidated. Here we used S-ketamine, an anesthetic drug commonly used in pediatric anesthesia, to investigate changes in thyroid hormones after anesthesia and their effects on myelin development. Our findings showed a significant decrease in thyroid hormones following S-ketamine anesthesia. The administration of triiodothyronine (T3) supplements ameliorated the S-ketamine-induced impairments in motor coordination and myelination. S-ketamine-induced hypothyroidism predominantly affects the differentiation of OPCs to mature oligodendrocytes. Further analysis revealed significant alterations in lipid metabolism, and we observed that S-ketamine inhibited PPARα in OPCs. Treatment with T3 effectively rescued S-ketamine-induced suppression of PPARα. The protective effects of T3 were significantly compromised by the PPARα inhibitor GW6471. The pharmacological activator of PPARα, fenofibrate, rescued the motor coordination deficits and the inhibition of OPC maturation induced by S-ketamine. In conclusion, our study demonstrates that S-ketamine anesthesia induces the decline of thyroid hormone and hypomyelination in neonatal rats. Administration of T3 ameliorates S-ketamine-induced hypomyelination through the PPARα signaling pathway.