Progesterone alleviates esketamine-induced hypomyelination via PI3K/Akt signaling pathway in the developing rat brain

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Anesthetic neurotoxicity is a growing concern, with esketamine use increasing in pediatric surgery.
• Oligodendrocyte precursor cells (OPCs) are crucial for brain myelination during development.
• The impact of esketamine on OPC development and myelination requires further investigation.

Purpose of the Study:

• To determine if esketamine exposure disrupts OPC development and causes hypomyelination in rats.
• To explore the role of PI3K/Akt phosphorylation in esketamine-induced effects on OPCs and myelination.
• To evaluate the potential of progesterone to counteract esketamine's neurodevelopmental toxicity.

Main Methods:

• Sprague Dawley rats of various ages (P1, P3, P7, P12) were exposed to esketamine (40mg/kg).
• Progesterone treatment (16 mg/kg/day for 3 days) was administered post-esketamine exposure.
• Corpus callosum tissues were analyzed using western blot and immunofluorescence at P8 and P14.

Main Results:

• Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) and mature oligodendrocyte (CC1+) numbers.
• Esketamine at P7 increased mature oligodendrocyte apoptosis and decreased OPC proliferation and differentiation.
• These effects correlated with dephosphorylation of the PI3K/Akt pathway.

Conclusions:

• Esketamine exposure causes stage-dependent abnormalities in OPCs/OLs, leading to hypomyelination.
• Esketamine interrupts OPC development via the PI3K/Akt signaling pathway.
• Progesterone promotes OPC differentiation and ameliorates esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation.