Minimally invasive biomarkers of general anesthetic-induced developmental neurotoxicity

The association of general anesthesia with developmental neurotoxicity, while nearly impossible to study in pediatric populations, is clearly demonstrable in a variety of animal models from rodents to nonhuman primates. Nearly all general anesthetics tested have been shown to cause abnormal brain cell death in animals when administered during periods of rapid brain growth. The ability to repeatedly assess in the same subjects adverse effects induced by general anesthetics provides significant power to address the time course of important events associated with exposures. Minimally-invasive procedures provide the opportunity to bridge the preclinical/clinical gap by providing the means to more easily translate findings from the animal laboratory to the human clinic. Positron Emission Tomography or PET is a tool with great promise for realizing this goal. PET for small animals (microPET) is providing valuable data on the life cycle of general anesthetic induced neurotoxicity. PET radioligands (annexin V and DFNSH) targeting apoptotic processes have demonstrated that a single bout of general anesthesia effected during a vulnerable period of CNS development can result in prolonged apoptotic signals lasting for several weeks in the rat. A marker of cellular proliferation (FLT) has demonstrated in rodents that general anesthesia-induced inhibition of neural progenitor cell proliferation is evident when assessed a full 2 weeks after exposure. Activated glia express Translocator Protein (TSPO) which can be used as a marker of presumed neuroinflammatory processes and a PET ligand for the TSPO (FEPPA) has been used to track this process in both rat and nonhuman primate models. It has been shown that single bouts of general anesthesia can result in elevated TSPO expression lasting for over a week. These examples demonstrate the utility of specific PET tracers to inform, in a minimally-invasive fashion, processes associated with general anesthesia-induced developmental neurotoxicity. The fact that PET procedures are also used clinically suggests an opportunity to confirm in humans what has been repeatedly observed in animals.