Light-enabled identification of the neural substrates for alkylphenol anesthesia

University Of Pennsylvania, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): This project serves to contribute to our understanding of the pharmacology of the general anesthetic propofol through the use of a photoactive analogue, meta-azi-propofol. The mechanisms of propofol-induced hypnosis remain unclear on both molecular and systems neuroscience levels. Further, propofol and other general anesthetics are becoming increasingly recognized as mediators of neurodevelopmental and neurodegenerative risks with the potential for causing irreversible phenotypes. Meta-azi-propofol contains a diazirine moiety that undergoes photolysis when exposed to long wave ultraviolet light (~370 nm) to create a reactive carbene intermediate. Novel techniques involving localized stimulation of meta-azi-propofol in vivo will elucidate brain regions that contribute to the unconsciousness produced by this general anesthetic. Comprehensive in vitro proteomic experiments with meta-azi-propofol will uncover molecular substrates that potentially contribute to alkylphenol anesthesia and the acute and long-term side effects associated with these anesthetic compounds. Further, the identification of protein binding sites of meta-azi-propofol through photolabeling and tandem mass spectrometry techniques will provide insight into binding specificity in order to improve our understanding of drug action by these small hydrophobic molecules. By addressing these aims, the knowledge gained will add to our appreciation for the widespread impact of general anesthetics within the central nervous system and will generate areas for future research to minimize the harmful potential of these widely used drugs. PUBLIC HEALTH RELEVANCE: Every year general anesthetics are administered to millions of people in America and abroad despite a clear understanding of the mechanisms that govern their clinical usefulness. Additionally, concern has risen regarding the ability of these compounds to cause developmental deficiencies in the central nervous system of the young and to accelerate neurodegenerative processes in the elderly. The optimal usage of currently available drugs and the prospect for the development of improved general anesthetics relies on our ability to discern the pharmacology of these compounds.