title: In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography.
abstract: Animals exposed to sevoflurane during development sustain neuronal cell death in their developing brains. In vivo micro-positron emission tomography (PET)/computed tomography imaging has been utilized as a minimally invasive method to detect anesthetic-induced neuronal adverse effects in animal studies.
  
  
  
  Neonatal rhesus monkeys (postnatal day 5 or 6, 3 to 6 per group) were exposed for 8 h to 2.5% sevoflurane with or without acetyl-L-carnitine (ALC). Control monkeys were exposed to room air with or without ALC. Physiologic status was monitored throughout exposures. Depth of anesthesia was monitored using quantitative electroencephalography. After the exposure, microPET/computed tomography scans using F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA) were performed repeatedly on day 1, 1 and 3 weeks, and 2 and 6 months after exposure.
  
  
  
  Critical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [F]-FEPPA in the frontal and temporal lobes was increased significantly 1 day or 1 week after exposure, respectively. Analyses of microPET images recorded 1 day after exposure showed that sevoflurane exposure increased [F]-FEPPA uptake in the frontal lobe from 0.927 ± 0.04 to 1.146 ± 0.04, and in the temporal lobe from 0.859 ± 0.05 to 1.046 ± 0.04 (mean ± SE, P < 0.05). Coadministration of ALC effectively blocked the increase in FEPPA uptake. Sevoflurane-induced adverse effects were confirmed by histopathologic evidence as well.
  
  
  
  Sevoflurane-induced general anesthesia during development increases glial activation, which may serve as a surrogate for neurotoxicity in the nonhuman primate brain. ALC is a potential protective agent against some of the adverse effects associated with such exposures.
authors.affiliation: From the Divisions of Neurotoxicology (X.Z., S.L., G.D.N., M.G.P., F.L., T.A.P., C.W.) and Bioinformatics and Biostatistics (M.P.M.) and Priority One Services (R.C., J.T.), National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, Arkansas; 3D Imaging, LLC, Little Rock, Arkansas (M.S.B., S.M.A., C.C.B.); and Center for Drug Evaluation and Research/U.S. Food and Drug Administration, Silver Spring, Maryland (J.P.H., W.S.).
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Shuliang
authors.initials: S
authors.lastname: Liu
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Newport
authors.forename: Merle G
authors.initials: MG
authors.lastname: Paule
authors.forename: Ralph
authors.initials: R
authors.lastname: Callicott
authors.forename: James
authors.initials: J
authors.lastname: Thompson
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Tucker A
authors.initials: TA
authors.lastname: Patterson
authors.forename: Marc S
authors.initials: MS
authors.lastname: Berridge
authors.forename: Scott M
authors.initials: SM
authors.lastname: Apana
authors.forename: Christina C
authors.initials: CC
authors.lastname: Brown
authors.forename: Mackean P
authors.initials: MP
authors.lastname: Maisha
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Hanig
authors.forename: William
authors.initials: W
authors.lastname: Slikker
authors.forename: Cheng
authors.initials: C
authors.lastname: Wang
mesh_terms: D000768:Anesthesia, General; D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000813:Anilides; D000818:Animals; D000831:Animals, Newborn; D064420:Drug-Related Side Effects and Adverse Reactions / Q000000981:diagnostic imaging*; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D005625:Frontal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008297:Male; D008738:Methyl Ethers / Q000009:adverse effects*; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines; D019275:Radiopharmaceuticals; D000077149:Sevoflurane; D013702:Temporal Lobe / Q000000981:diagnostic imaging / Q000378:metabolism; D014057:Tomography, X-Ray Computed
chemical_list: D018685:Anesthetics, Inhalation; D000813:Anilides; D008738:Methyl Ethers; C530438:N-(2-((N-(4-phenoxypyridin-3-yl)acetamido)methyl)phenoxy)ethyl fluoride; D011725:Pyridines; D019275:Radiopharmaceuticals; D000077149:Sevoflurane