Research Article: Relevance of experimental paradigms of anesthesia induced neurotoxicity in the mouse

Date Published: March 21, 2019

Publisher: Public Library of Science

Author(s): Simon C. Johnson, Amanda Pan, Grace X. Sun, Arielle Freed, Julia C. Stokes, Rebecca Bornstein, Michael Witkowski, Li Li, Jeremy M. Ford, Christopher R. A. Howard, Margaret M. Sedensky, Philip G. Morgan, Zhongcong Xie.


Routine general anesthesia is considered to be safe in healthy individuals. However, pre-clinical studies in mice, rats, and monkeys have repeatedly demonstrated that exposure to anesthetic agents during early post-natal periods can lead to acute neurotoxicity. More concerning, later-life defects in cognition, assessed by behavioral assays for learning and memory, have been reported. Although the potential for anesthetics to damage the neonatal brain is well-documented, the clinical significance of the pre-clinical models in which damage is induced remains quite unclear. Here, we systematically evaluate critical physiological parameters in post-natal day 7 neonatal mice exposed to 1.5% isoflurane for 2–4 hours, the most common anesthesia induced neurotoxicity paradigm in this animal model. We find that 2 or more hours of anesthesia exposure results in dramatic respiratory and metabolic changes that may limit interpretation of this paradigm to the clinical situation. Our data indicate that neonatal mouse models of AIN are not necessarily appropriate representations of human exposures.

Partial Text

General anesthesia has been a key feature of modern medicine for over 150 years. Although widely used and generally safe in healthy individuals, neurotoxicity related to anesthetic exposure has been reported in multiple animal models and retrospective clinical studies (reviewed in [1–4]). These studies have linked anesthetic exposure during early post-natal periods to acute anesthesia induced neurotoxicity (AIN) and later-life defects in performance in behavioral assays for learning and memory. This data has generated substantial concern regarding the risks associated with anesthesia in human neonatal and pediatric patients [1,5–7].

Our studies demonstrate unexpected consequences of isoflurane exposure in neonatal mice. Severe derangements in respiration, blood glucose, ketones, lactate, and pH lead to a 50% mortality rate for P7 mice exposed to 1.5% isoflurane for 4 hours. Given these results, interpretation of many anesthetic neurotoxicity studies in neonatal mice must entertain confounding factors present in each study.




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