MiR-497/PLD regulation contributes to cognitive dysfunction in neonatal rats after repeated sevoflurane exposure.

Background: Repeated sevoflurane exposure during early development can induce neurotoxic effects. MicroRNAs (miRNAs) are critical regulators of gene expression, playing essential roles in neural development and function, but their exact mechanisms remain unclear. This study investigates the role of the miR-497/Phospholipase D1(PLD1) axis, which is involved in neuronal differentiation and survival, in mediating the neurotoxic effects of repeated sevoflurane anesthesia.

Methods: Neonatal rats were treated with sevoflurane repeatedly. The expression levels of miR-497 in the rat hippocampi were assessed using qRT-PCR, and neuronal apoptosis was detected by TUNEL assay. PLD1 was predicted and confirmed as a target of miR-497. The regulatory relationship between PLD1 and miR-497 in primary neuronal cells was determined using luciferase reporter assays and Western blot. Immunohistochemistry was employed to examine PLD1 expression. A rescue experiment was performed to confirm the involvement of the miR-497/PLD1 pathway in sevoflurane-induced neurotoxicity. Cognitive performance was evaluated using Moris water maze.

Results: We identified the miR-497/PLD1 axis as the central mediator of sevoflurane-induced neurotoxicity. Repeated sevoflurane exposure triggered a striking upregulation of hippocampal miR-497, which directly targeted the 3'-UTR of PLD1 to suppress its expression. Functional validation demonstrated that miR-497 inhibition rescued neuronal injury and apoptosis, whereas silencing PLD1 abolished the neuroprotective effects of miR-497 suppression, establishing PLD1 as the indispensable downstream effector of miR-497.

Conclusions: Our study provides the first evidence that dysregulation of the miR-497/PLD1 axis drives sevoflurane-related newborn cognitive deficits. This mechanistic insight advances our understanding of anesthetic neurotoxicity, while targeting this newly identified axis may represent a novel therapeutic strategy to counteract anesthesia-associated neurodevelopmental risks.