MicroPET/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity
Background. The inhalation anesthetics nitrous oxide (N2O) and isoflurane (ISO) are used in surgical procedures for human infants. Injury to the central nervous system is often accompanied by localization of activated microglia or astrocytosis at the site of injury. The tracer that targets to the peripheral benzodiazepine receptor (PBR), [18F]N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide ([18F]-FEPPA), has been reported as a sensitive biomarker for the detection of neuronal damage/inflammation. Methods. On postnatal day (PND) 5 or 6 rhesus monkey neonates were exposed to a mixture of N2O/oxygen and ISO for 8 hours and control monkeys were exposed to room air. MicroPET/CT images with [18F]-FEPPA were obtained for each monkey 1 day, one week, three weeks, and 6 months after the anesthetic exposure. Results. The radiotracer quickly distributed into the brains of both treated and control monkeys on all scan days. One day after anesthetic exposure, the uptake of [18F]-FEPPA was significantly increased in the temporal lobe. One week after exposure, the uptake of [18F]-FEPPA in the frontal lobe of treated animals was significantly greater than that in controls. Conclusions. These findings suggest that microPET imaging is capable of dynamic detection of inhaled anesthetic-induced brain damage in different brain regions of the nonhuman primate. 1. Introduction General anesthetics bring about a reversible loss of consciousness by regulating neuronal excitability. The mechanisms underlying this action include suppression of excitatory NMDA receptor-mediated transmission and/or potentiation of inhibitory GABAA receptor currents in the central nervous system [1–3]. Nitrous oxide (N2O), a gaseous inhalation anesthetic agent, is often given in combination with more powerful volatile anesthetics such as isoflurane (ISO) to maintain general anesthesia in pregnant women, neonates and infants requiring surgery and/or other invasive or painful procedures. Experimental findings both in vitro and in vivo suggest that general anesthetics can induce neurotoxicity during the period of rapid neuronal growth and synaptogenesis (the brain growth spurt period) in the developing animal brain [1, 4–6]. Because of the similarity of the physiology, pharmacology, metabolism, reproductive systems, and developmental trajectory and time course of the nonhuman primate to that of the human, they are exceptionally good animal models of neurodevelopment and for the detection of potential neurodegenerative effects associated with exposure to inhaled anesthetics. In a parallel
References
[1]
L. L. Campbell, J. A. Tyson, E. E. Stackpole et al., “Assessment of general anaesthetic cytotoxicity in murine cortical neurones in dissociated culture,” Toxicology, vol. 283, no. 1, pp. 1–7, 2011.
[2]
M. D. Krasowski and N. L. Harrison, “General anaesthetic actions on ligand-gated ion channels,” Cellular and Molecular Life Sciences, vol. 55, no. 10, pp. 1278–1303, 1999.
[3]
C. Wang and W. Slikker Jr., “Strategies and experimental models for evaluating anesthetics: effects on the developing nervous system,” Anesthesia and Analgesia, vol. 106, no. 6, pp. 1643–1658, 2008.
[4]
V. Jevtovic-Todorovic, R. E. Hartman, Y. Izumi et al., “Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits,” Journal of Neuroscience, vol. 23, no. 3, pp. 876–882, 2003.
[5]
S. Wang, K. Peretich, Y. Zhao, G. Liang, Q. Meng, and H. Wei, “Anesthesia-induced neurodegeneration in fetal rat brains,” Pediatric Research, vol. 66, no. 4, pp. 435–440, 2009.
[6]
X. Zou, N. Sadovova, T. A. Patterson et al., “The effects of l-carnitine on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex,” Neuroscience, vol. 151, no. 4, pp. 1053–1065, 2008.
[7]
X. Zou, F. Liu, X. Zhang et al., “Inhalation anesthetic-induced neuronal damage in the developing rhesus monkey,” Neurotoxicology and Teratology, vol. 33, no. 5, pp. 592–597, 2011.
[8]
C. DiMaggio, L. S. Sun, A. Kakavouli, M. W. Byrne, and G. Li, “A retrospective cohort study of the association of anesthesia and hernia repair surgery with behavioral and developmental disorders in young children,” Journal of Neurosurgical Anesthesiology, vol. 21, no. 4, pp. 286–291, 2009.
[9]
G. K. Istaphanous and A. W. Loepke, “General anesthetics and the developing brain,” Current Opinion in Anaesthesiology, vol. 22, no. 3, pp. 368–373, 2009.
[10]
C. J. Kalkman, L. Peelen, K. G. Moons et al., “Behavior and development in children and age at the time of first anesthetic exposure,” Anesthesiology, vol. 110, no. 4, pp. 805–812, 2009.
[11]
R. T. Wilder, R. P. Flick, J. Sprung et al., “Early exposure to anesthesia and learning disabilities in a population-based birth cohort,” Anesthesiology, vol. 110, no. 4, pp. 796–804, 2009.
[12]
A. T. Hillmer, D. W. Wooten, J. Moirano, et al., “Specific α4β2 nicotinic acetylcholine receptor binding of [F-18]nifene in the rhesus monkey,” Synapse, vol. 65, no. 12, pp. 1309–1318, 2011.
[13]
M. R. Kilbourn, B. Hockley, L. Lee et al., “Positron emission tomography imaging of (2R,3R)-5-[18F]fluoroethoxybenzovesamicol in rat and monkey brain: a radioligand for the vesicular acetylcholine transporter,” Nuclear Medicine and Biology, vol. 36, no. 5, pp. 489–493, 2009.
[14]
D. W. Wooten, J. D. Moraino, A. T. Hillmer et al., “In vivo kinetics of [F-18]MEFWAY: a comparison with [C-11]WAY100635 and [F-18]MPPF in the nonhuman primate,” Synapse, vol. 65, no. 7, pp. 592–600, 2011.
[15]
X. Zhang, M. G. Paule, G. D. Newport et al., “MicroPET imaging of ketamine-induced neuronal apoptosis with radiolabeled DFNSH,” Journal of Neural Transmission, vol. 118, no. 2, pp. 203–211, 2011.
[16]
X. Zhang, M. G. Paule, G. D. Newport et al., “A minimally invasive, translational biomarker of ketamine-induced neuronal death in rats: microPET imaging using 18F-annexin V,” Toxicological Sciences, vol. 111, no. 2, pp. 355–361, 2009.
[17]
S. Lang, “The role of peripheral benzodiazepine receptors (PBRs) in CNS pathophysiology,” Current Medicinal Chemistry, vol. 9, no. 15, pp. 1411–1415, 2002.
[18]
M. K. Chen and T. R. Guilarte, “Imaging the peripheral benzodiazepine receptor response in central nervous system demyelination and remyelination,” Toxicological Sciences, vol. 91, no. 2, pp. 532–539, 2006.
[19]
A. A. Wilson, A. Garcia, J. Parkes et al., “Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors,” Nuclear Medicine and Biology, vol. 35, no. 3, pp. 305–314, 2008.
[20]
C. E. Hotchkiss, C. Wang, and W. Slikker, “Effect of prolonged ketamine exposure on cardiovascular physiology in pregnant and infant rhesus monkeys (Macaca mulatta),” Journal of the American Association for Laboratory Animal Science, vol. 46, no. 6, pp. 21–28, 2007.
[21]
W. Slikker, X. Zou, C. E. Hotchkiss et al., “Ketamine-induced neuronal cell death in the perinatal rhesus monkey,” Toxicological Sciences, vol. 98, no. 1, pp. 145–158, 2007.
[22]
M. S. Berridge, S. M. Apana, and J. M. Hersha, “Teflon radiolysis as the major source of carrier in fluorine-18,” Journal of Labelled Compounds and Radiopharmaceuticals, vol. 52, no. 13, pp. 543–548, 2009.
[23]
C. Braestrup, R. Albrechtsen, and R. F. Squires, “High densities of benzodiazepine receptors in human cortical areas,” Nature, vol. 269, no. 5630, pp. 702–704, 1977.
[24]
V. Papadopoulos, M. Baraldi, T. R. Guilarte et al., “Translocator protein (18？kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function,” Trends in Pharmacological Sciences, vol. 27, no. 8, pp. 402–409, 2006.
[25]
P. J. Schweitzer, B. A. Fallon, J. J. Mann, and J. S. D. Kumar, “PET tracers for the peripheral benzodiazepine receptor and uses thereof,” Drug Discovery Today, vol. 15, no. 21-22, pp. 933–942, 2010.
[26]
M. Hardwick, D. Fertikh, M. Culty, H. Li, B. Vidic, and V. Papadopoulos, “Peripheral-type benzodiazepine receptor (PBR) in human breast cancer: correlation of breast cancer cell aggressive phenotype with PBR expression, nuclear localization, and PBR-mediated cell proliferation and nuclear transport of cholesterol,” Cancer Research, vol. 59, no. 4, pp. 831–842, 1999.
[27]
B. O. Oke, C. A. Suarez-Quian, J. Riond, P. Ferrara, and V. Papadopoulos, “Cell surface localization of the peripheral-type benzodiazepine receptor (PBR) in adrenal cortex,” Molecular and Cellular Endocrinology, vol. 87, no. 1–3, pp. R1–R6, 1992.
[28]
J. M. M. Olson, B. J. Ciliax, W. R. Mancini, and A. B. Young, “Presence of peripheral-type benzodiazepine binding sites on human erythrocyte membranes,” European Journal of Pharmacology, vol. 152, no. 1-2, pp. 47–53, 1988.
[29]
I. Venturini, M. L. Zeneroli, L. Corsi et al., “Up-regulation of peripheral benzodiazepine receptor system in hepatocellular carcinoma,” Life Sciences, vol. 63, no. 14, pp. 1269–1280, 1998.
[30]
M. Imaizumi, E. Briard, S. S. Zoghbi et al., “Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors,” NeuroImage, vol. 39, no. 3, pp. 1289–1298, 2008.
[31]
R. B. Banati, “Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain,” British Medical Bulletin, vol. 65, pp. 121–131, 2003.
[32]
F. Ito, H. Toyama, G. Kudo et al., “Two activated stages of microglia and PET imaging of peripheral benzodiazepine receptors with [11C]PK11195 in rats,” Annals of Nuclear Medicine, vol. 24, no. 3, pp. 163–169, 2010.
[33]
A. Takeuchi, “Microglial NO induces delayed neuronal death following acute injury in the striatum,” European Journal of Neuroscience, vol. 10, no. 5, pp. 1613–1620, 1998.
[34]
E. Briard, S. S. Zoghbi, M. Imaizumi et al., “Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo,” Journal of Medicinal Chemistry, vol. 51, no. 1, pp. 17–30, 2008.
[35]
V. Papadopoulos, L. Lecanu, R. C. Brown, Z. Han, and Z. X. Yao, “Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders,” Neuroscience, vol. 138, no. 3, pp. 749–756, 2006.
[36]
J. Benavides, D. Fage, C. Carter, and B. Scatton, “Peripheral type benzodiazepine binding sites are a sensitive indirect index of neuronal damage,” Brain Research, vol. 421, no. 1-2, pp. 167–172, 1987.
[37]
N. Oku, T. Kashiwagi, and J. Hatazawa, “Nuclear neuroimaging in acute and subacute ischemic stroke,” Annals of nuclear medicine, vol. 24, no. 9, pp. 629–638, 2010.
[38]
A. C. Kuhlmann and T. R. Guilarte, “Regional and temporal expression of the peripheral benzodiazepine receptor in MPTP neurotoxicity,” Toxicological Sciences, vol. 48, no. 1, pp. 107–116, 1999.
[39]
A. C. Kuhlmann and T. R. Guilarte, “Cellular and subcellular localization of peripheral benzodiazepine receptors after trimethyltin neurotoxicity,” Journal of Neurochemistry, vol. 74, no. 4, pp. 1694–1704, 2000.
[40]
I. Bennacef, C. Salinas, G. Horvath, et al., “Comparison of [11C]PBR28 and [18F]FEPPA as CNS peripheral benzodiazepine receptor PET ligands in the pig,” Journal of Nuclear Medicine, vol. 49, p. 81, 2008.
[41]
P. M. Rusjan, A. A. Wilson, P. M. Bloomfield et al., “Quantitation of translocator protein binding in human brain with the novel radioligand 18 F-FEPPA and positron emission tomography,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 8, pp. 1807–1816, 2011.
[42]
X. Zou, T. A. Patterson, R. L. Divine et al., “Prolonged exposure to ketamine increases neurodegeneration in the developing monkey brain,” International Journal of Developmental Neuroscience, vol. 27, no. 7, pp. 727–731, 2009.
[43]
M. G. Paule, M. Li, R. R. Allen et al., “Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys,” Neurotoxicology and Teratology, vol. 33, no. 2, pp. 220–230, 2011.
[44]
Z. Xie and R. E. Tanzi, “Alzheimer's disease and post-operative cognitive dysfunction,” Experimental Gerontology, vol. 41, no. 4, pp. 346–359, 2006.
[45]
S. Rizzi, C. Ori, and V. Jevtovic-Todorovic, “Timing versus duration: determinants of anesthesia-induced developmental apoptosis in the young mammalian brain,” Annals of the New York Academy of Sciences, vol. 1199, pp. 43–51, 2010.
[46]
C. Wang, X. Zhang, F. Liu, M. G. Paule, and W. Slikker, “Anesthetic-induced oxidative stress and potential protection,” The Scientific World Journal, vol. 10, pp. 1473–1482, 2010.
