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Micropet/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: a Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity

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Micropet/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: a Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity International Scholarly Research Network ISRN Anesthesiology Volume 2012, Article ID 261640, 11 pages doi:10.5402/2012/261640 Research Article MicroPET/CT Imaging of [18F]-FEPPA in the Nonhuman Primate: A Potential Biomarker of Pathogenic Processes Associated with Anesthetic-Induced Neurotoxicity Xuan Zhang,1 Merle G. Paule,1 Glenn D. Newport,1 Fang Liu,1 Ralph Callicott,1 Shuliang Liu,1 Marc S. Berridge,2, 3 Scott M. Apana,2, 3 William Slikker Jr.,1 and Cheng Wang1 1 National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA 2 3D Imaging, LLC, Little Rock, AR 72113, USA 3 University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Correspondence should be addressed to Cheng Wang, [email protected] Received 6 August 2012; Accepted 15 September 2012 Academic Editors: J. Abraini and J.-H. Baumert Copyright © 2012 Xuan Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 (the brain growth spurt period) in the developing animal brain [1, 4–6]. Because of the similarity of the physiol- General anesthetics bring about a reversible loss of con- ogy, pharmacology, metabolism, reproductive systems, and sciousness by regulating neuronal excitability. The mecha- developmental trajectory and time course of the nonhuman nisms underlying this action include suppression of excita- primate to that of the human, they are exceptionally good tory NMDA receptor-mediated transmission and/or poten- animal models of neurodevelopment and for the detection of tiation of inhibitory GABAA receptor currents in the central potential neurodegenerative effects associated with exposure nervous system [1–3]. Nitrous oxide (N2O), a gaseous to inhaled anesthetics. In a parallel study [7], a combination inhalation anesthetic agent, is often given in combination of 70% N2O + 1% ISO was also utilized to achieve and with more powerful volatile anesthetics such as isoflurane maintain a surgical plane of anesthesia. Neonatal rhesus (ISO) to maintain general anesthesia in pregnant women, monkeys were exposed on PND 5 or 6 to N2O plus ISO for neonates and infants requiring surgery and/or other invasive 8 hours and 6 hours after termination of the exposure the or painful procedures. brains were fixed and subsequently examined for neurotoxic Experimental findings both in vitro and in vivo suggest effects. Significantly elevated neuronal damage, as indicated that general anesthetics can induce neurotoxicity during by increased numbers of caspase-3-, silver stain-, and Fluoro- the period of rapid neuronal growth and synaptogenesis Jade C-positive cells, was observed in neocortical areas, 2 ISRN Anesthesiology especially in layers II and III of the frontal cortex, temporal for physiological measurements or blood sample collections. gyrus and hippocampus. Animals in the treated group were exposed to a mixture of Theseobservationshaveheightenedconcernsabout 70% N2O/30% oxygen and 1% ISO for 8 hours. whether such effects are temporary (lasting only a few days after exposure) or long-term (lasting weeks or months) in 2.2. Experimental Procedures. Nitrous oxide (N O) and infants and children undergoing inhaled anesthetic-induced 2 oxygen were delivered using a calibrated anesthetic machine anesthesia. Additionally, recent epidemiological studies have with blender (Bird Corporation, Palm Springs, CA, USA). demonstrated a relationship between anesthesia and surgery Isoflurane (ISO) was delivered using an agent-specific vapor- in childhood and later development of behavioral abnormal- izer (E-Z Anesthesia, Palmer, PA, USA) attached to the ities and learning disabilities [8–11]. Thus, to further study anesthetic machine. To administer a specific concentration the long-term CNS effects that occur in association with of N O/oxygen/ISO in a tightly controlled environment, inhaled anesthetic-induced anesthesia, the development of 2 an anesthesia chamber (Euthanex Corp. Palmer, PA, USA) tools for the minimally invasive imaging of relevant neuronal was used. Monkeys were kept in this chamber with a damage is highly desirable. circulating water heating pad to maintain body temperature Molecular imaging using positron emission tomography at approximately 37◦C throughout the experiment. Stable gas (PET) is a leading modality for obtaining non- or minimally and volatile anesthetic concentrations were attained in the invasive in vivo measurements of multiple biological chamber within 5 min of the start of exposure. For controls, processes in various organs. The development of microPET room air was used in place of the inhalation anesthetics. imaging applications has provided the ability to collect For the treated group, the N O/oxygen/ISO mixture was sensitive and quantitative three-dimensional molecular 2 continuously delivered to the chamber for the duration of information from the living brains of a variety of animals the 8 hour exposure. A relief valve on the anesthesia chamber including nonhuman primates (NHP) [12–14]. In order to allowed escape of gases to avoid accumulation of carbon obtain sufficient data from living animals and longitudinally dioxide and waste anesthetic gas was scavenged using an assess the neurotoxic effects associated with developmental attached canister containing activated charcoal. exposures to anesthesia, we have developed a microPET During the experimental period, dextrose (5%) was protocol thought to target neuronal damage in vivo administered by stomach tube (5 mL) every 2 h to both using imaging approaches [15, 16]. Since levels of the treated and control monkeys to maintain blood glucose lev- peripheral benzodiazepine receptor (PBR) are thought to els. Glycopyrrolate (0.01 mg/kg, American Reagent, Shirley, increase in areas of neuronal injury following exposure to NY, USA) was administered intramuscularly prior to anes- neurotoxicants [17], the PBR is widely recognized as an thesia to both treated and control monkeys to reduce airway important target for imaging via PET [17–19]. In this study, secretions. Once exposures were complete, animals were [18F]-radiolabelled]-N-(2-(2-fluoroethoxy)benzyl)-N-(4- monitored in an incubator until complete recovery and then phenoxypyridin-3-yl) acetamide)([18F]-FEPPA) was utilized returned to their mothers (approximately 2 hours). Control as an imaging agent for PBRs in the central nervous system animals were kept in the exposure chambers under room air of neonatal monkeys. foratotalof10hours(8+2). 2. Materials and Methods 2.3. Monitoring of Physiological Parameters. The physiolog- ical parameters of the neonatal monkeys were monitored 2.1. Animals. All animal procedures were approved by the following procedures described previously [20, 21]Briefly, National Center for Toxicological Research (NCTR) Institu- noninvasive pulse oximetry (N-395 Pulse Oximeter, Nellcor, tional Animal Care and Use Committee and conducted in full Pleasanton, CA, USA; MouseOX Plus Vital Sign Monitor, accordance with the PHS Policy on Humane Care and Use of Starr Life Sciences, Oakmont, PA, USA), capnography (Tidal Laboratory Animals. Wave Hand-held capnography, Respironics, Murrysville, PA, All monkeys were born and housed at the FDA’s USA), and sphygmomanometry (Critikon Dynamap Vital National Center for Toxicological Research nonhuman pri- Signs Monitor, GE Healthcare, Waukesha, WI, USA), and a mate research facility. Animal procedures were designed to rectal temperature probe were used to verify the physiological minimize the number of animals required and any pain or status of subjects. Heart and respiration rates, arterial blood distress associated with the experimental procedures. O2 saturation levels, expired CO2 concentrations, and rectal A total of eight (PND 5 or 6, 460–500 g) rhesus monkeys temperatures, systolic and diastolic blood pressures were (Macaca mulatta)wereutilized.Threemaleandfivefemale recorded every one or two hours in anesthetized and control monkeyswererandomlyassignedtotreatment(n = 4, 1 animals, respectively. Venous blood (approximately
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