Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies

Abstract

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.

Figure 1:. Neurotoxicity of anesthesia appears to occur at both extremes of age.

Anesthetics are associated with neuronal death and adverse cognitive effects in both pediatric and geriatric populations. While the precise mechanisms of anesthesia induced neurotoxicity are unclear, data suggests that anesthetics have some neurotoxicity at all ages. In pediatric patients, this neurotoxicity disrupts normal neurodevelopment, and neonates are highly sensitive to as a result of their relatively high number of young neurons. Conversely, sensitivity to anesthesia in geriatric patients appears to result from age-related deficits in neurogenesis which exacerbate the functional impact of neuron loss due to anesthesia exposure.

Figure 2:. Interventions and mechanisms reported in mouse models of AIN.

Intervention studies in mouse AIN models have identified a wide variety of candidate targets and compounds. The majority of these can be grouped into one of three major categories: oxidative stress, ROS signaling, and energetics; growth/nutrient signaling; and direct modulation of neuronal activity. Additional candidates, such as epigenetic factors, are less clearly defined.

Figure 3:. Growth and nutrient sensing signaling pathways at the interface between intra- and extra-cellular stimulus.

Growth and nutrient signaling pathways involve soluble signaling factors, membrane bound receptors at the cell surface, intracellular sensors, and intracellular kinases which mediate signal transduction and amplification. Growth and nutrient signaling pathways, such as the canonical PI3K/AKT/mTOR pathway, play critical roles in neuron survival, differentiation, metabolism, and cellular organization.

Figure 4:. Sources of variability in pre-clinical anesthesia induced neurotoxicity literature.

Pre-clinical models of anesthesia induced neurotoxicity have identified a variety of pathways involved in AIN, but a global assessment of these studies is hampered by the high variability in experimental conditions. Confounding factors include anesthetic dose, frequency, duration, and various aspects of physiological maintenance. In addition, measured outcomes vary widely between studies. Future work in pre-clinical AIN would benefit from standardization of anesthetic protocols and experimental methods used to assess AIN.