Developmental neurotoxicity in the context of multiple sevoflurane exposures: Potential role of histone deacetylase 6

Abstract

Animal studies have demonstrated that multiple exposures to sevoflurane during the postnatal period lead to impaired synaptogenesis and cognitive deficits in adulthood. However, the underlying mechanisms remain unclear. Histone deacetylase 6 (HDAC6), a unique isoform of class II histone deacetylases (HDACs), mediates diverse cellular processes such as cell survival, inflammation, intracellular trafficking and protein degradation. Varieties of literature suggest the importance of HDAC6 in memory formation and abnormal neurodegenerative diseases. The aim of this study was to investigate potential roles of HDAC6 in sevoflurane-induced developmental neurotoxicity. Postnatal day 7 (P7) rat pups were randomly assigned to control group and sevoflurane group (n = 6 for each group). They were exposed to 60% oxygen and 40% nitrogen with or without 3% sevoflurane for 2 h daily for three consecutive days (P7, P8 and P9). Immediately after the last exposure, both hippocampi were harvested for detection of HDAC6 expression and activity. Next, P7 rat pups were divided into control group, sevoflurane group, sevoflurane + Tubastatin A, and Tubastatin A groups (n = 6 for each group in molecular experiments; n = 16 for each group in behavioral testing). A dose of 25 mg/kg body weight of Tubastatin A (a selective HDAC6 inhibitor) were administrated intraperitoneally 30 min prior to each sevoflurane exposure. After treatments, expression levels of synaptophysin and postsynaptic density 95 protein (PSD95) were quantified using Western blot, and synaptic ultrastructure was evaluated by transmission electron microscopy. Additional pups were raised until P49 to measure cognitive performance using the Morris water maze test. Our results demonstrated that multiple sevoflurane exposures enhanced HDAC6 expression and activity in hippocampi of the developing brain. Tubastatin A ameliorated sevoflurane-induced decreases in synaptophysin and PSD95 expression during development, as well as synaptic ultrastructural damage and cognitive deficits in adulthood. In conclusion, HDAC6 is involved in the developmental neurotoxicity caused by multiple sevoflurane exposures and its inhibition may prevent related damage.