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Published on: November 20, 2015
Triiodothyronine ameliorates S-ketamine-induced hypomyelination via the PPARα pathway in neonatal rat
Mengqin Shan1, Chaoyang Tong2, Xin Fu1
1Department of Anesthesiology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, China.
Insights
Anesthesia can harm children's brain development by lowering thyroid hormones and impairing myelination. Thyroid hormone (T3) supplementation may prevent these effects by activating PPARα, protecting white matter development.
Area of Science:
- Neuroscience
- Developmental Biology
- Endocrinology
Background:
- General anesthesia in children is linked to white matter alterations and potential cognitive deficits.
- Thyroid hormones are crucial for white matter myelination, and levels can decrease after infant surgery.
Purpose of the Study:
- To investigate the impact of S-ketamine anesthesia on thyroid hormones and myelin development in neonatal rats.
- To determine if thyroid hormone supplementation can prevent anesthesia-induced neurotoxicity.
Main Methods:
- Neonatal rats were exposed to S-ketamine anesthesia.
- Thyroid hormone levels, motor coordination, and myelination were assessed.
- The role of PPARα signaling in S-ketamine-induced effects was examined using inhibitors and activators.
Main Results:
- S-ketamine anesthesia significantly decreased thyroid hormone levels and impaired motor coordination and myelination.
- Triiodothyronine (T3) supplementation reversed these deficits and protected oligodendrocyte precursor cell (OPC) differentiation.
- S-ketamine inhibited PPARα, which was rescued by T3; PPARα activation with fenofibrate also showed protective effects.
Conclusions:
- S-ketamine anesthesia causes hypothyroidism and hypomyelination in neonatal rats.
- T3 administration ameliorates these effects by modulating the PPARα signaling pathway, suggesting a potential therapeutic strategy.
Abstract:
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.
