Abstract SNACC-64

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Isoflurane-induced neuroapoptosis in Infant Non-Human Primates is prevented by Lithium co-treatment

1Brambrink A, 2Johnson S, 1Dissen G, 1Martin L, 2Kistrich L, 2Noguchi K, 2Olney J
1Oregon Health & Science University, Portland, OR, United states; 2Washington University School of Medicine, St. Louis, MO, USA

Introduction: Exposure of infant animals, including non-human primates (NHPs), to anesthetic drugs causes injury to the developing brain (1,2) and results in long-term neurodevelopmental impairment (NDI) (3). Evidence from recent retrospective human studies document that exposure of human infants to brief anesthesia is associated with a significant increase in NDI. In infant mice we have found that a single dose of lithium (Li) administered immediately prior to induction of anesthesia prevents anesthetic drugs from injuring the developing brain (4). The present study was undertaken to determine whether Li exerts neuroprotective action against anesthesia-induced neurotoxicity in the infant NHP brain.
Methods: With IACUC approval, 6 day-old rhesus macaques (n=5 per group) were exposed for 5 hrs to isoflurane (ISO), ISO plus Li, or to no drug (control). ISO anesthesia was administered as previously described (1,2) at a concentration regulated to maintain a moderate surgical plane of anesthesia. Li was administered by IV infusion at a dose regulated to maintain Li blood levels in a range that is considered therapeutic and non-toxic in the treatment of psychiatric disorders. At 8hrs from time zero, the subjects were euthanized under deep anesthesia and the brains prepared for histopathological analysis. Quantitative assessment: sections at 2mm intervals accross the entire brain; cellular profiles positive for activated caspase 3 (AC3); Stereo-Investigator; number/volume; location).
Results: ISO caused a large increase in the mean (± SEM) number of apoptotic neurons (3.36 x106 ± 0.38 x106) compared to controls (0.45 x106 ± 0.11 x106) (P< 0.001), whereas the mean number of apoptotic neurons in the ISO+Li group (0.96 x106 ± 0.05 x106) was not significantly different from controls. ISO also caused a large increase in the mean (± SEM) number of apoptotic oligodendroglia (3.04 x106 ± 0.69 x106) compared to controls (0.31 x106 ± 0.07 x106) (P< 0.01). The mean for the ISO+Li group (1.5 x106 ± 0.19 x106) was significantly reduced compared to the ISO group (p<0.05) and by Bonferroni multiple comparison test was not significantly different from the control value, although the degree of protection for oligodendroglia was less than that for neurons.
Discussion: Our findings demonstrate that intravenous administration of Li to infant rhesus macaques, while they are being exposed to a surgical plane of ISO anesthesia for 5 hrs, almost completely prevents the acute neuroapoptosis response that predictably occurs in the absence of Li co-exposure. In addition, apoptotic death of oligodendroglia, which also predictably occurs following ISO anesthesia, is significantly, but not as dramatically, reduced by Li co-exposure. It will be important in future research to determine in non-human primate subjects whether lithium not only protects against the acute brain injury induced by anesthetic drugs, but also can prevent long-term neurobehavioral disturbances that have been shown to occur (3) following anesthesia exposure of the infant primate brain.

(1) Anesthesiology 2010;112(4):834-41.
(2) Ann Neurol 2012; 72:525-535
(3) Neurotoxicol Teratol. 2011; 33: 220-30.
(4) Anesthesiology 2009; 110:862-8

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