Since their discovery volatile anesthetics have been viewed as benign inhibitors of the central nervous system. However, recent experimental studies have seriously challenged this dogma, causing an astonishing paradigm shift in the field of anesthesiology, in particular in regard to the care of infants undergoing general anesthesia. Since more than a million children undergo general anesthesia each year in the U.S., even small developmental defects from their use during a critical window of vulnerability have potentially large implications for our current care of children. General anesthetics have now been shown to cause neurotoxicity in nematodes, rodents and primates. Histologic changes in the CNS are accompanied by behavioral defects that persist into adulthood. It is now established that volatile anesthetics in isolation are capable of inducing neurodegeneration in the developing nervous systems of multiple organisms. We propose to carry our findings in nematodes into a direct exploration aiming to prevent anesthetic induced neurotoxicity (AIN) in mammals. It remains unclear how great a risk normal anesthetic exposure poses to the newborn human. Retrospective studies have raised the possibility that significant learning defects may exist in children who have had multiple anesthetic exposures but other studies have failed to find such an effect. While it is clearly important to determine the overall significance of AIN in humans, an equally important question is how do anesthetics cause this toxicity. Using a tractable model (C. elegans), we have identified two intersecting pathways that mediate AIN. One of these pathways induces a stress pathway leading to activation of the unfolded protein response in the endoplasmic reticulum (UPRER). The second pathway (known as the daf-2 pathway) induces a protective response to stress and its activation eliminates AIN. Discovering these two mechanisms led to the identification of signaling molecules, the transcription factor hypoxia inducible factor1 (HIF-1) and the mechanistic target of rapamycin (mTOR), as central in mediating AIN. We can completely eliminate AIN in the nematode by manipulating these pathways. We propose to discover whether mTOR and ER-stress mediate AIN in mammals, and to prevent AIN in mice by inhibiting mTOR. We will continue to exploit the nematode to perform a high throughput screen to discover other molecules capable of eliminating ER stress, and test their effects on AIN in C. elegans.
Our Specific Aims are: SA1. A. Test the effects of isoflurane on mTOR activation and ER-stress in the mouse. B. Test rapamycin in mice for prevention of AIN. SA2. Perform a high throughput small molecule screen for inhibitors of AIN.
Little is known about mechanisms underlying the potential harmful effects of anesthetics on infants. We have identified two interacting molecular pathways important in this response in the nematode, C. elegans, which have clear counterparts in mammals. Our goal is to now identify treatments in mammals that alleviate the neurotoxic effects of anesthetics.
| Johnson, Simon C; Pan, Amanda; Li, Li et al. (2018) Neurotoxicity of anesthetics: Mechanisms and meaning from mouse intervention studies. Neurotoxicol Teratol 71:22-31 |
| van der Bliek, Alexander M; Sedensky, Margaret M; Morgan, Phil G (2017) Cell Biology of the Mitochondrion. Genetics 207:843-871 |
