Influence of Vitamin D on Sevoflurane-Induced Neurotoxicity in Offspring Mice.

Abstract

BACKGROUND Numerous studies have demonstrated that sevoflurane might have neurotoxic effects on the developing brain. However, the underlying mechanisms and potential treatment are largely unknown. Vitamin D has immunomodulatory, anti-inflammatory, and neuroprotective effects. We aimed to investigate whether vitamin D could attenuate sevoflurane-induced neurotoxicity in the offspring of mice. METHOD Twenty 8-week-old pregnant Swiss albino mice were randomly divided into 4 groups with 5 mice each: Control, vitamin D (Vit-D), sevoflurane (Sevo), and sevoflurane-vitamin D (Sevo-Vit-D). Throughout the pregnancy, Vit-D and Sevo-Vit-D groups were intraperitoneally administered vitamin D, while Sevo and Control groups received 1 ml of saline. On the 14th day of pregnancy, Sevo and Sevo-Vit-D were exposed to 3% sevoflurane with 100% O2 for 2 hours. Control and Vit-D were exposed to 100% O2 for 2 hours. Newborn mice from the groups were included in the study. Tissue sections of the prefrontal cortex and hippocampus were examined by immunohistochemical methods and electron microscopy (EM) on postnatal day 7 and postnatal day 45 (PN7 and PN45). The immunohistochemical methods assessed the expression levels of inflammatory cytokines, apoptotic factors, neuroprotective proteins. Open field and elevated plus maze tests were performed to assess behavioral changes at PN45. RESULTS Vitamin D significantly attenuated the mean (95% confidence interval [CI]) sevoflurane-induced increase in the expression levels of inflammatory cytokines and apoptotic factors, such as interleukin-6 (IL-6; Sevo versus Sevo-Vit-D: 0.68 (0.66-0.7) versus 0.34 (0.32-0.35); P < .001), tumor necrosis factor alpha (TNF-α; Sevo vs Sevo-Vit-D: 0.89 (0.88-0.9) versus 0.53 (0.51-0.55); P < .001), Bax (Sevo vs Sevo-Vit-D: 0.61 (0.6-0.63) versus 0.34 (0.32-0.36); P < .001) and c-Fos (Sevo vs Sevo-Vit-D: 0.64 (0.62-0.66) vs 0.42 (0.4-0.43); P < .001) in the hippocampus at PN7. Furthermore, vitamin D improved the mean (95% CI) expression levels of antiapoptotic and neuroprotective proteins, such as Bcl-2 (Sevo vs Sevo-Vit-D: 0.46 (0.45-0.47) versus 0.56 (0.54-0.58); P < .001), BDNF (Sevo vs Sevo-Vit-D: 0.37 (0.34-0.39) vs 0.64 (0.63-0.65); P < .001), Olig2 (Sevo vs Sevo-Vit-D: 0.38 (0.36-0.39) vs 0.56 (0.54-0.58); P < .001) in the hippocampus at PN7. These changes also occurred in the prefrontal cortex at PN7 and PN45. EM images supported these data. No significant difference was found in behavioral tests between the groups. CONCLUSIONS Our findings suggested that maternal sevoflurane exposure could cause neurotoxicity in the offspring mice. Vitamin D can protect against the negative effects of sevoflurane.