Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies

Volatile anesthetics are widely used in human medicine and generally considered to be safe in healthy individuals. In recent years, the safety of volatile anesthesia in pediatric patients has been questioned following reports of anesthetic induced neurotoxicity in pre-clinical studies. These studies in mice, rats, and primates have demonstrated that exposure to anesthetic agents during early post-natal periods can cause acute neurotoxicity, as well as later-life cognitive defects including deficits in learning and memory. In recent years, the focus of many pre-clinical studies has been on identifying candidate pathways or potential therapeutic targets through intervention trials. These reports have shed light on the mechanisms underlying anesthesia induced neurotoxicity as well as highlighting the challenges of pre-clinical modeling of anesthesia induced neurotoxicity in mice. Here, we summarize the data derived from intervention studies in neonatal mouse models of anesthetic exposure and provide an overview of mechanisms proposed to mediate anesthesia induced neurotoxicity in mice based on these reports. The majority of these studies implicate one of three mechanisms: reactive oxygen species (ROS) mediated stress and signaling, growth/nutrient signaling, or direct neuronal modulation.