The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

Author(s): Shuliang Liu, Xuan Zhang, Fang Liu, Merle G Paule, Ralph Callicott, Glenn D Newport, Syed F Ali, Tucker A Patterson, Scott M Apana, Marc S Berridge, Mackean P Maisha, Joseph P Hanig, William Slikker Jr., and Cheng Wang


Background. In studies on anesthetic-induced developmental neurotoxicity, the animals’ physiological status and the depth of anesthesia during anesthesia need to be monitored. In addition, blood borne indicators of prolonged sevoflurane exposure have yet to be explored. The nonhuman primate model could have more advantages over rodent model in these aspects. Methods. Twentyseven rhesus monkeys [postnatal day (PND) 5 or 6] were monitored for their physiological status during the eight-hour exposures to 2.5% sevoflurane or room air. Plasma samples collected during the exposures were analyzed for proinflammatory mediators. Tissue from the frontal cortex was examined via electron microscopy (EM) four hours following the exposure in a subgroup of animals. Micro-positron emission tomography (microPET) using the radiolabeled ligand [18F]FEPPA, which binds to activated microglia and astrocytes in the central nervous system (CNS), was performed one day following the exposure. Results. Key physiological metrics observed in PND 5/6 monkeys undergoing anesthesia were not altered significantly in comparison with those for control animals. Sevoflurane-induced neural damage was confirmed by EM observations. Increased production of interleukin (IL)-6 and CCL-2 was detected in plasma at the end of the eight-hour sevoflurane exposure, and enhanced uptake of [18F]FEPPA was observed in the frontal cortical region the day following anesthesia. The coincident increase in proinflammatory mediators in the peripheral circulation suggested that this sevofluraneinduced response may be used as an indicator of anesthetic-induced developmental neurotoxicity. Conclusions. The valuable information obtained in these studies demonstrates the usefulness of the nonhuman primate model in the evaluation of anesthetic-induced developmental neurotoxicity. The elevation of IL-6 and CCL-2 may be the useful indicator of anesthetic-induced developmental neurotoxicity.


image 10.4303/jdar/236011

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