Understanding the role of mTOR activation causing neurotoxicity following pediatric exposure to volatile anesthetics
Since their discovery, volatile anesthetics have been viewed as benign inhibitors of the central nervous system. While there are acknowledged risks associated with the use of anesthesia, there has been no previous indication that central nervous system damage could arise. However, recent experimental studies have seriously challenged this belief, causing an astonishing paradigm shift in the field of anesthesiology, in particular regarding the care of infants undergoing general anesthesia. Since more than a million children undergo general anesthesia each year in the U.S., even small effects from anesthesia during a critical window of vulnerability have potentially large implications to current care of children.
Work conducted by Drs. Sedensky and Morgan examines long-term damage that can arise in children following exposure to general anesthetics. Previous work has shown that general anesthetics trigger apoptotic neuronal degeneration in neonatal rodents and in primates, resulting in learning defects that persisted into adulthood. Since it is impossible to eliminate exposure of neonates to general anesthesia in emergency situations, it is critical to develop a better mechanistic understanding of the process of anesthetic induced neurotoxicity (AIN) to help prevent or cure it.
Through testing isoflurane exposure in C. elegans, Drs. Sedensky and Morgan have discovered that AIN operates via an ancient mechanism, one that is conserved across the animal kingdom, and is mediated by two intersecting pathways. One is downstream of mitochondrial stress and induces the unfolded protein response in the endoplasmic reticulum (UPRER). The second pathway (known as the daf-2 pathway) induces a protective response to stress; its activation eliminates AIN. Identification of these two pathways led to the hypothesis that signaling via the transcription factor, hypoxia inducible factor 1 (HIF-1), and the mechanistic target of rapamycin (mTOR), are central in the AIN process. Activation of these pathways is monitored using a green fluorescent protein that reveals ER-stress.
While rapamycin is sparingly used on pediatric patients given an array of side effects, its efficacy at reducing AIN in pre-clinical models gives hope that interventions both before and after anesthesia are achievable. Moving forward, Drs. Sedensky and Morgan hope to understand the role of mTOR activation and ER-stress following isoflurane exposure in mouse models, and to conduct high throughput screens to find additional inhibitors of AIN.
Stage of Development
- Pre-clinical in vivo
- Collaborative research opportunity
- Sponsored research agreement
- Consultation agreement
- Kayser E, Sedensky M, Morgan P. Region-Specific Defects of Respiratory Capacities in the Ndufs4(KO) Mouse Brain. PLoS ONE. 2016;11(1):e0148219.
- Gentry K, Steele L, Sedensky M, Morgan P. Early Developmental Exposure to Volatile Anesthetics Causes Behavioral Defects in Caenorhabditis elegans. Anesthesia & Analgesia. 2013;116(1):185-189.
- Quintana A, Morgan P, Kruse S, Palmiter R, Sedensky M. Altered Anesthetic Sensitivity of Mice Lacking Ndufs4, a Subunit of Mitochondrial Complex I. PLoS ONE. 2012;7(8):e42904.
- Singaram V, Somerlot B, Falk S, Falk M, Sedensky M, Morgan P. Optical Reversal of Halothane-Induced Immobility in C. elegans. Current Biology. 2011;21(24):2070-2076.
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