A big concern has recently arisen regarding the safety of anesthesia in infants and children based on the profoundly increasing preclinical evidences in rodents and nonhuman primates that the commonly used anesthetics in clinic are neurotoxic to the developing brain and may cause long-term neurobehavioral abnormalities. Hence, the clinical relevance of anesthetic neurotoxicity as well as the development of biomarkers for early detection of anesthetic-induced neuronal injury is an urgent matter of public health. Since the diversified neuronal lipids play specific roles in the nervous system, small disturbance in the brain could result in changes of lipids in the brain, cerebrospinal fluid (CSF), and plasma. General anesthetics, due to their lipid solubility, readily enter the brain, dissolve into cellular membranes, penetrate organelle, disturb dynamics of neuronal lipidome, and leave far-reaching effects on the developing nervous system (neurotoxicity). We hypothesized that perturbation of brain lipids with anesthetics is manifest in brain tissues, CSF, and/or plasma of patients at a very early stage of anesthetic-induced brain injury, and these changed lipids can serve as biomarker(s) for early detection of anesthetic neurotoxicity. We believe the changes of lipids induced with anesthetic exposure can be detected at a very early stage of brain injury by our enabling technology, shotgun lipidomics, which we have recently pioneered with the support of NIH funding. The power of this technology has been demonstrated in discovery of altered lipids in CSF and plasma in accompanying the changes in brain tissues of Alzheimer's disease. In the application, we will take the advantages of an existing research project in which our collaborators at the FDA are conducting studies on the anesthetic- induced neuronal injury in the developing monkey model, which has proved to be invaluable for informing aspects of human pharmacology, physiology, toxicology, etc. Our hypothesis is strongly supported by the preliminary studies showing that numerous lipid classes were significantly changed in brain, CSF, and plasma of monkeys exposed to anesthetics. To further test our hypothesis, we will (1) identify that the changes of lipid content in monkey brain tissues occur at a much earlier stage (i.e., shorter duration) of anesthetic exposure in comparison to that revealed from the enhanced neuronal cell death and/or changes in gene expression; (2) determine that altered lipids in both CSF and plasma of monkeys which are exposed to anesthetic(s) occurs at the stage parallel to that detected with the changes of lipid content and/or composition in brain tissues; and (3) verify that the altered lipids manifest in CSF and plasma of monkeys exposed to anesthetic(s) can be served as biomarkers for early detection of anesthetic-induced neurotoxicity. The proposed studies hold tremendous promise for the discovery of a panel of specific and sensitive lipid biomarkers for detection of anesthetic neurotoxicity at its early stage in CSF and/or plasma, which can be used for future translational studies. This study might also provide insight into the biochemical mechanism underlying general anesthetic neurotoxicity.
An urgent matter of public health is to elucidate the clinical relevance of anesthetic neurotoxicity and develop sensitive biomarkers for early detection of anesthetic-induced neuronal damage in pediatric patients. We will use our expertise, enabling technologies, and an informative and cost-effective monkey model to (a) identify that the changes of lipid signatures in developing monkey brain tissues occur at a much earlier stage of anesthetic exposure relative to other biological changes; (b) determine if changed lipid signatures in CSF and plasma of monkeys after anesthetic exposure occurs at the stage parallel to that in brain tissues; and (c) verify that the altered lipids manifest in CSF and plasma of perinatal monkeys can be served as biomarkers for early detection of anesthetic neurotoxicity.
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