Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment

- Anesthetics induce widespread apoptosis in the immature brain.
- Low dose carbon monoxide (CO) exerts anti-apoptotic properties in the brain.
- CO inhibits isoflurane-induced apoptosis in a dose-dependent manner.
- CO incompletely prevented isoflurane-induced defects in neurodevelopment.
- Anesthesia-induced neurotoxicity may not be mediated solely by apoptosis.

BackgroundCommonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment.MethodsC57Bl/6 mouse pups underwent 1-hour exposure to 0 ppm (air), 5 ppm, or 100 ppm CO in air with or without isoflurane on postnatal day 7. Cohorts were evaluated 5-7 weeks post exposure with T-maze cognitive testing followed by social behavior assessment. Brain size, whole brain cellular content, and neuronal density in primary somatosensory cortex and hippocampal CA3 region were measured as secondary outcomes 1-week or 5-7 weeks post exposure along with 7-day old, unexposed controls.ResultsIsoflurane impaired memory acquisition and resulted in abnormal social behavior. Low concentration CO abrogated anesthetic-induced defects in memory acquisition, however, it also resulted in impaired spatial reference memory and social behavior abnormalities. Changes in brain size, cellular content, and neuronal density over time related to the age of the animal and were unaffected by either isoflurane or CO.ConclusionsAnti-apoptotic concentrations of CO incompletely prevented isoflurane-induced defects in neurodevelopment, lacked concentration-dependent effects, and only provided protection in certain domains suggesting that anesthesia-related neurotoxicity is not solely mediated by activation of the mitochondrial apoptosis pathway.