Omega-3 Polyunsaturated Fatty Acids Prevent Sevoflurane-induced Cognitive and Fine Motor Dysfunctions in Neonatal Mice by Enhancing Phosphorylated Tau Glymphatic System Clearance Pathway

Multiple neonatal sevoflurane exposures can cause cognitive and fine motor deficits. Although the underlying mechanisms are unclear, a recent study has discovered that repeated neonatal sevoflurane exposures impair the glymphatic system circulation function and lead to long-term cognitive dysfunction. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) have been demonstrated to enhance the glymphatic system circulation function in mice with traumatic brain injury. Nevertheless, the impacts of ω-3 PUFAs on sevoflurane-induced glymphatic system impairment remain insufficiently explored. Thus, we evaluated whether ω-3 PUFAs pretreatment can prevent sevoflurane-induced cognitive and fine motor deficits through modulating the glymphatic system function in this study. Female mice were fed an ω-3 PUFAs-enriched diet, commencing from the second day of their gestation through to 14 days postpartum. Their offspring were exposed to 3% sevoflurane for 2 h daily on postnatal days 6-8 (P6-P8). Simultaneously, the glymphatic system circulation function was evaluated through tracer intracisternal injection at P14 and P35. Western Blot, ELISA, immunohistochemistry, and fluorescent immunochemistry analyses were performed to assess the clearance of phosphorylated tau and AQP4 depolarization at P14. Behavioral tests were conducted from P30 to P35. TEM, Western Blot, mitochondrial functional assays, and TUNEL staining were performed to determine mitochondrial function, neuroinflammation, and cellular Apoptosis at P35. Our study found that sevoflurane disrupted the glymphatic system in neonatal mice, and that reduced glymphatic transport was directly related to the buildup of phosphorylated Tau Protein in the developing brain. More importantly, ω-3 PUFAs can prevent cognitive and fine motor deficits induced by multiple exposures to sevoflurane in neonates through rescuing the decreased AQP4 polarization via PDGF-B/PDGFRβ signaling, enhancing phosphorylated tau glymphatic system clearance pathway, and attenuating mitochondrial dysfunction and neurotoxicity.

Glymphatic system; Neurotoxicity; Phosphorylated tau; Sevoflurane; ω-3 PUFAs.