Dexmedetomidine alleviates sevoflurane-induced neurotoxicity during late pregnancy by modulating apoptotic pathways and BDNF receptor expression.

Abstract

To investigate the associations between the neurotoxicity of sevoflurane and the neuroprotection provided by dexmedetomidine, we measured apoptotic gene and protein expression, brain-derived neurotrophic factor (BDNF) levels, and receptor expression, and neuronal apoptosis. Pregnant rats were treated with dexmedetomidine, 2.5% sevoflurane for 6 h, or a combination of 2.5% sevoflurane for 6 h with dexmedetomidine on gestational day 18 (G18). The apoptotic genes and proteins expression, BDNF and receptor expression, and neuronal apoptosis were assessed in offspring hippocampi on postnatal day 1 (P1) and P41. Dendritic spine density, synaptophysin protein fluorescence staining, and cognitive function were evaluated on P41. Maternal sevoflurane exposure increased Bax mRNA and protein expression, decreased Bcl-2 mRNA and protein expression, enhanced neuronal apoptosis, decreased the ratio of mature BDNF (mBDNF) to proBDNF, reduced mBDNF and tropomyosin receptor kinase B (TrkB) protein expression, and increased p75 neurotrophin receptor (p75NTR) protein expression in the hippocampi of neonatal rats. In juvenile rats, maternal sevoflurane exposure reduced mBDNF and TrkB protein expression, dendritic spine density, the proportion of time spent in the target quadrant, and the number of crossings over the platform while increasing escape latency in the Morris water maze. All abnormalities induced by maternal sevoflurane exposure, except for mBDNF levels on P41, were alleviated by dexmedetomidine. Dexmedetomidine mitigates sevoflurane-induced neuronal development abnormalities and cognitive impairments during late pregnancy by improving hippocampal Bcl-2 and Bax mRNA and protein expression, as well as proBDNF-p75NTR and mBDNF-TrkB protein expression in offspring.