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Numerous animal models have been used to study developmental neurotoxicity associated with short-term or prolonged exposure of common general anesthetics at clinically relevant concentrations. Pediatric anesthesia models using the nonhuman primate (NHP) may more accurately reflect the human condition because of their phylogenetic similarity to humans with regard to reproduction, development, neuroanatomy, and cognition. Although they are not as widely used as other animal models, the contribution of NHP models in the study of anesthetic-induced developmental neurotoxicity has been essential. In this review, we discuss how neonatal NHP animals have been used for modeling pediatric anesthetic exposure; how NHPs have addressed key data gaps and application of the NHP model for the studies of general anesthetic-induced developmental neurotoxicity. The appropriate application and evaluation of the NHP model in the study of general anesthetic-induced developmental neurotoxicity have played a key role in enhancing the understanding and awareness of the potential neurotoxicity associated with pediatric general anesthetics.

The brain is highly enriched in lipids. A growing body of research has shown that brain lipid content and composition change in various neurological disorders. In addition to brain tissues, lipid changes have been detected in cerebrospinal fluid and blood in animal models of various central nervous system diseases and patients. Altered lipid metabolism has also been observed to contribute to the development and progression of sevoflurane-induced neurotoxicity. Analyses of lipid profiles have provided significant insights into the underlying mechanisms of central nervous system diseases. Assessing changes in lipid profiles in the cerebrospinal fluid and blood may provide additional information on the status of the brain in clinical settings. This mini-review summarizes the recent updates on lipids in diverse neurological conditions and discusses the application of lipid analysis to neurotoxicity assessment studies.

Neurotoxicity assessments are generally performed using laboratory animals. However, as in vitro neurotoxicity models are continuously refined to reach adequate predicative concordance with in vivo responses, they are increasingly used for some endpoints of neurotoxicity. In this study, gestational day 80 fetal rhesus monkey brain tissue was obtained for neural stem cells (NSCs) isolation. Cells from the entire hippocampus were harvested, mechanically dissociated, and cultured for proliferation and differentiation. Immunocytochemical staining and biological assays demonstrated that the harvested hippocampal cells exhibited typical NSC phenotypes in vitro: (1) cells proliferated vigorously and expressed NSC markers nestin and sex-determining region Y-box 2 (SOX2) and (2) cells differentiated into neurons, astrocytes, and oligodendrocytes, as confirmed by positive staining with class III β-tubulin, glial fibrillary acidic protein, and galactocerebroside, respectively. The NSC produced detectable responses following neurotoxicant exposures (e.g. trimethyltin and 3-nitropropionic acid). Our results indicated that non-human primate NSCs may be a practical tool to study the biology of neural cells and to evaluate the neurotoxicity of chemicals in vitro, thereby providing data that are translatable to humans and may also reduce the number of animals needed for developmental neurotoxicological studies.

With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5–7) were randomly assigned to each of two groups: Group A ( n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B ( n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1β at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.

Carnitine is an essential metabolite that is absorbed from the diet and synthesized in the kidney, liver, and brain. It ferries fatty acids across the mitochondrial membrane to undergo β-oxidation. Carnitine has been studied as a therapy or protective agent for many neurological diseases and neurotoxicity (e.g., prolonged anesthetic exposure-induced developmental neurotoxicity in preclinical models). Preclinical and clinical data support the notion that carnitine or acetyl carnitine may improve a patient's quality of life through increased mitochondrial respiration, release of neurotransmitters, and global gene expression changes, showing the potential of carnitine beyond its approved use to treat primary and secondary carnitine deficiency. In this review, we summarize the beneficial effects of carnitine or acetyl carnitine on the central nervous system, highlighting protective effects against neurotoxicity-induced damage caused by various chemicals and encouraging a thorough evaluation of carnitine use as a therapy for patients suffering from neurotoxicant exposure.

OBJECTIVE To identify possible radiographic predictors markers of dynamic instability including disc height (DH), disc degeneration, and spondylosis in the setting of degenerative spondylolisthesis (DS). METHODS A retrospective review with prospectively collected data was performed on 125 patients with L4-5 DS who underwent decompression and fusion. Patients were divided into groups with dynamic instability and those without. Radiographs of the lumbar spine in neutral, flexion, and extension were used to determine degree of slip, DH, translational motion, angular motion, spondylotic changes, and lumbar lordosis. Magnetic resonance imaging (MRI) scans were reviewed to assess disc degeneration. RESULTS Thirty-one percent of the patients met criteria for dynamic instability. Significant correlations (p < 0.05) were found between preserved DH and dynamic instability; increased spondylotic changes and decreased translational motion; as well as advanced MRI-based disc degeneration scores with decreased angular motion, respectively. Six radiographic parameters were utilized to create a predictive model for dynamic instability, and a receiver operating characteristic curve was able to validate the predictive model (area = 0.891, standard error = 0.034, p < 0.001). CONCLUSION In DS patients, preserved DH was significantly related to dynamic instability. This finding may represent a greater potential for slip progression over time in these patients. In contrast, disc degeneration on MRI, and spondylotic changes were inversely related to dynamic instability and may represent restabilization mechanisms that decrease the chance of future slip progression in DS.

et al., There is an evolution and increasing need for the utilization of emerging cellular, molecular and in silico technologies and novel approaches for safety assessment of food, drugs, and personal care products. Convergence of these emerging technologies is also enabling rapid advances and approaches that may impact regulatory decisions and approvals. Although the development of emerging technologies may allow rapid advances in regulatory decision making, there is concern that these new technologies have not been thoroughly evaluated to determine if they are ready for regulatory application, singularly or in combinations. The magnitude of these combined technical advances may outpace the ability to assess fit for purpose and to allow routine application of these new methods for regulatory purposes. There is a need to develop strategies to evaluate the new technologies to determine which ones are ready for regulatory use. The opportunity to apply these potentially faster, more accurate, and cost-effective approaches remains an important goal to facilitate their incorporation into regulatory use. However, without a clear strategy to evaluate emerging technologies rapidly and appropriately, the value of these efforts may go unrecognized or may take longer. It is important for the regulatory science field to keep up with the research in these technically advanced areas and to understand the science behind these new approaches. The regulatory field must understand the critical quality attributes of these novel approaches and learn from each other's experience so that workforces can be trained to prepare for emerging global regulatory challenges. Moreover, it is essential that the regulatory community must work with the technology developers to harness collective capabilities towards developing a strategy for evaluation of these new and novel assessment tools.

Background Open injuries communicating with the wrist joint are essential to detect to facilitate timely, appropriate treatment. While the saline load test to detect traumatic arthrotomy has been well studied in the knee and ankle, it has not been studied in the wrist, and therefore the appropriate volume of saline infusion to detect traumatic arthrotomy is not known. Purpose The purpose of this study was to utilize wrist arthroscopy to determine the saline infusion volume necessary to achieve 99% sensitivity in detecting traumatic arthrotomy. Methods Twenty consecutive patients undergoing elective wrist arthroscopy were prospectively enrolled. A 5-mm arthrotomy was established between the third and fourth dorsal extensor compartments. An 18-gauge needle was inserted into the 6R portal on the radial side of the extensor carpi ulnaris. Sterile normal saline was injected into the wrist joint through the needle at a rate of 0.1 mL per second until extravasation from the 3–4 portal was visualized. Saline volumes required for extravasation were analyzed. Results The mean saline volume required for extravasation was 0.8 mL. The volume of saline needed to achieve sensitivities of 50, 90, 95, and 99% were 0.4, 2.2, 2.3, and 2.5 mL respectively. Conclusions The saline infusion volume required to detect a dorsal radiocarpal arthrotomy with 99% sensitivity was 2.5 mL. We recommend using at least 2.5 mL when performing the saline load test to rule out a potential arthrotomy to the wrist in the traumatic setting. Level of Evidence: This is a Level II, diagnostic study.

Nanotechnology and more particularly nanotechnology-based products and materials have provided a huge potential for novel solutions to many of the current challenges society is facing. However, nanotechnology is also an area of product innovation that is sometimes developing faster than regulatory frameworks. This is due to the high complexity of some nanomaterials, the lack of a globally harmonised regulatory definition and the different scopes of regulation at a global level. Research organisations and regulatory bodies have spent many efforts in the last two decades to cope with these challenges. Although there has been a significant advancement related to analytical approaches for labelling purposes as well as to the development of suitable test guidelines for nanomaterials and their safety assessment, there is a still a need for greater global collaboration and consensus in the regulatory field. Furthermore, with growing societal concerns on plastic litter and tiny debris produced by degradation of littered plastic objects, the impact of micro- and nanoplastics on humans and the environment is an emerging issue. Despite increasing research and initial regulatory discussions on micro- and nanoplastics, there are still knowledge gaps and thus an urgent need for action. As nanoplastics can be classified as a specific type of incidental nanomaterials, current and future scientific investigations should take into account the existing profound knowledge on nanotechnology/nanomaterials when discussing issues around nanoplastics. This review was conceived at the 2019 Global Summit on Regulatory Sciences that took place in Stresa, Italy, on 24–26 September 2019 (GSRS 2019) and which was co-organised by the Global Coalition for Regulatory Science Research (GCRSR) and the European Commission's (EC) Joint Research Centre (JRC). The GCRSR consists of regulatory bodies from various countries around the globe including EU bodies. The 2019 Global Summit provided an excellent platform to exchange the latest information on activities carried out by regulatory bodies with a focus on the application of nanotechnology in the agriculture/food sector, on nanoplastics and on nanomedicines, including taking stock and promoting further collaboration. Recently, the topic of micro- and nanoplastics has become a new focus of the GCRSR. Besides discussing the challenges and needs, some future directions on how new tools and methodologies can improve the regulatory science were elaborated by summarising a significant portion of discussions during the summit. It has been revealed that there are still some uncertainties and knowledge gaps with regard to physicochemical properties, environmental behaviour and toxicological effects, especially as testing described in the dossiers is often done early in the product development process, and the material in the final product may behave differently. The harmonisation of methodologies for quantification and risk assessment of nanomaterials and micro/nanoplastics, the documentation of regulatory science studies and the need for sharing databases were highlighted as important aspects to look at., Highlights • Overview on current regulatory framework of various regulatory bodies on nanotechnology and nanoplastics. • Main regulatory challenges are the lack of global standardisation of nomenclature, test methods or characterisation. • Research on micro-/nanoplastics to be intensified taking into account results available in the area of nanomaterials. • Urgent need for standards (documentary, materials, methods) especially for micro-/nanoplastics. • Urgent need to understand environmental contamination, human exposure and possible risks from small plastic particles.

Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).

We have described that prolonged sevoflurane exposure at a clinically-relevant concentration of 2.5 % caused neuronal cell death in the developing monkey brain. Postnatal day 5 or 6 rhesus monkeys (n = 3) were exposed to 2.5 % sevoflurane for 8 h. Monkeys kept at environmental conditions in the procedure room served as controls (n = 3). Brain tissues were harvested four hours after sevoflurane exposure for histological analysis, and RNA or protein extraction. MicroRNA (miRNA) profiling on the frontal cortex of monkey brains was performed using next-generation sequencing. 417 miRNAs were identified in the frontal cortex, where most neuronal cell death was observed. 7 miRNAs were differentially expressed in frontal cortex after sevoflurane exposure. Five of these were expressed at significantly lower levels than controls and the other two miRNAs were expressed significantly higher. These differentially expressed miRNAs (DEMs) were then loaded to the Ingenuity Pathway Analysis database for pathway analysis, in which targeting information was available for 5 DEMs. The 5 DEMs target 2,919 mRNAs which are involved in pathways that contribute to various cellular functions. Of note, 78 genes that are related to axon guidance signaling were targeted, suggesting that development of the neural circuit may be affected after sevoflurane exposure. Such changes may have long-term effects on brain development and function. These findings are supplementary to our previous observations and provide more evidence for better understanding the adverse effects of sevoflurane on the developing brain after an 8 -h exposure.

Background: Whether long-term methylphenidate (MPH) results in any changes in cardiovascular function or structure can only be properly addressed through a randomized trial using an animal model which permits elevated dosing over an extended period of time. Methods: We studied 28 male rhesus monkeys (M. mulatta) approximately seven years of age who had been randomly assigned to one of three MPH dosages: vehicle control (0 mg/kg, bid, n = 9), low-dose (2.5 mg/kg, bid, n = 9), or high-dose (12.5 mg/kg, bid, n = 10). Dosage groups were compared on serum cardiovascular and inflammatory biomarkers, electrocardiograms (ECG), echocardiograms, myocardial biopsies, and clinical pathology parameters following five years of uninterrupted dosing. Results: With the exception of serum myoglobin, there were no statistical differences or apparent dose response trends in clinical pathology, cardiac inflammatory biomarkers, ECG’s echocardiograms, or myocardial biopsies. The high-dose MPH group had a lower serum myoglobin concentration (979 ng/ml) than either the low dose (1882 ng/ml) or control group (2182 ng/ml). The dose response was inversely proportional to dosage (P = .0006). Conclusions: Although the findings cannot be directly generalized to humans, chronic MPH exposure is unlikely to be associated with increased cardiovascular risk in healthy children.

Although numerous studies have raised public concerns regarding the safety of anesthetics including sevoflurane in children, the biochemical mechanisms leading to anesthetics-induced neurotoxicity remain elusive. Moreover, potential biomarker(s) for early detection of general anesthetics-induced brain injury are urgent for public health. We employed an enabling technology of shotgun lipidomics and analyzed nearly 20 classes and subclasses of lipids present in the blood serum of postnatal day (PND) 5 or 6 rhesus monkeys temporally collected after exposure to sevoflurane at a clinically relevant concentration or room-air as control. Lipidomics analysis revealed numerous significant anesthetic-induced changes of serum lipids and their metabolites as well as short chain acylcarnitines in the brain and cerebrospinal fluid after anesthetic exposure. These include decreased carnitine and acylcarnitines, unchanged triacylglycerol mass but accumulation of 16:0 and 18:1 fatty acyl chains in the triacylglycerol pool, losses of polyunsaturated fatty acids in both non-esterified fatty acid and phospholipid pools, and increased 4-hydroxynonenal content as early as 2 h after sevoflurane exposure. Importantly, the amounts of short chain acylcarnitines in the brain and cerebrospinal fluid were also significantly reduced after anesthetic exposure. We propose that this serum lipidomic profile can serve as indicative of neuronal damage. Our results reveal that sevoflurane exposure induces an energy deficient state in the brain evidenced by reduced free and acyl carnitine contents, as well as the presence of a pro-inflammatory state in the exposed animals, providing deep insights into the underlying mechanisms responsible for anesthetic-induced neurotoxicity.

Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18-20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

Neurotoxicity has been linked with exposure to a number of common drugs and chemicals, yet efficient, accurate, and minimally invasive methods to detect it are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid have great potential due to the relative ease of sampling but at present, data on their expression and translation are lacking or inconsistent. In this pilot study using a trimethyl tin rat model of central nervous system toxicity, we have applied state-of-the-art assessment techniques to identify potential individual biomarkers and patterns of biomarkers in serum, plasma, urine or cerebral spinal fluid that may be indicative of nerve cell damage and degeneration. Overall changes in metabolites and microRNAs were observed in biological fluids that were associated with neurotoxic damage induced by trimethyl tin. Behavioral changes and magnetic resonance imaging T2 relaxation and ventricle volume changes served to identify animals that responded to the adverse effects of trimethyl tin. Impact statement These data will help design follow-on studies with other known neurotoxicants to be used to assess the broad applicability of the present findings. Together this approach represents an effort to begin to develop and qualify a set of translational biochemical markers of neurotoxicity that will be readily accessible in humans. Such biomarkers could prove invaluable for drug development research ranging from preclinical studies to clinical trials and may prove to assist with monitoring of the severity and life cycle of brain lesions.

Ketamine, a noncompetitive NMDA receptor antagonist, is used as a general anesthetic and recent data suggest that general anesthetics can cause neuronal damage when exposure occurs during early brain development. To elucidate the underlying mechanisms associated with ketamine-induced neurotoxicity, stem cell-derived models, such as rodent neural stem cells harvested from rat fetuses and/or neural stem cells derived from human induced pluripotent stem cells (iPSC) can be utilized. Prolonged exposure of rodent neural stem cells to clinically-relevant concentrations of ketamine resulted in elevated NMDA receptor levels as indicated by NR1subunit over-expression in neurons. This was associated with enhanced damage in neurons. In contrast, the viability and proliferation rate of undifferentiated neural stem cells were not significantly affected after ketamine exposure. Calcium imaging data indicated that 50μM NMDA did not cause a significant influx of calcium in typical undifferentiated neural stem cells; however, it did produce an immediate elevation of intracellular free Ca2+ [Ca2+]i in differentiated neurons derived from the same neural stem cells. This paper reviews the literature on this subject and previous findings suggest that prolonged exposure of developing neurons to ketamine produces an increase in NMDA receptor expression (compensatory up-regulation) which allows for a higher/toxic influx of calcium into neurons once ketamine is removed from the system, leading to neuronal cell death likely due to elevated reactive oxygen species generation. The absence of functional NMDA receptors in cultured neural stem cells likely explains why clinically-relevant concentrations of ketamine did not affect undifferentiated neural stem cell viability.

The number of Individuals that use dietary supplements and herbal medicine products are continuous to increase in many countries. The context of usage of a dietary supplement varies widely from country-to-country; in some countries supplement use is just limited to general health and well-being while others permit use for medicinal purposes. To date, there is little consensus from country to country on the scope, requirements, definition, or even the terminology in which dietary supplement and herbal medicines categories could be classified. Transparent science-based quality standards for the ingredients across these regulatory frameworks/definitions becomes even more important given the international supply chain. Meanwhile, there has been a rapid advancement in emerging technologies and data science applied to the field. This review was conceived at the Global Summit on Regulatory Sciences that took place in Beijing on September 2018 (GSRS2018) which is organized by Global Coalition for Regulatory Science Research (GCRSR) that consists of the global regulatory agencies from over ten countries including the European Union. This review summarizes a significant portion of discussions relating to a longitudinal comparison of the status for dietary supplements and herbal medicines among the different national jurisdictions and to the extent of how new tools and methodologies can improve the regulatory application.

Early life exposure to general anesthetics can have neurotoxic consequences. Evidence indicates that xenon, a rare noble gas with anesthetic properties, may lessen neuronal damage under certain conditions. However, its potential neuroprotective properties, when used alone or in combination with other anesthetics, remain largely unknown. While it is difficult to verify the adverse effects of long duration anesthetic exposure in infants and children, the utilization of relevant non-clinical models (i.e., human-derived neural stem cells) may serve as a “bridging” model for evaluating the vulnerability of the nervous system. Neural stem cells, purchased from PhoenixSongs Biologicals, Inc., were guided to differentiate into neurons, astrocytes, and oligodendrocytes, which were then exposed to propofol (50 μM) for 16 h in the presence or absence of xenon (33%). Differentiation into cells of the neural lineage was confirmed by labelling with cell-specific markers, β-tubulin for neurons, glial fibrillary acidic protein (GFAP) for astrocytes, and galactocerebroside (GALC) for oligodendrocytes after 5 days of differentiation. The presence and severity of neural damage induced by anesthetic exposures were assessed by several methods, including the TUNEL assay, and immuno-histochemical measurements. Our data demonstrate that prolonged exposure to propofol results in a significant increase in the number of TUNEL-positive cells, indicating increased neural apoptosis. No significant changes were detected in the number of GFAP-positive astrocytes or GALC-positive oligodendrocytes. However, the number of β-tubulin-positive neurons was substantially reduced in the propofol-exposed cultures. Co-administration of xenon effectively blocked the propofol-induced neuronal damage/loss. No significant effects were observed when xenon was administered alone. The data indicate that prolonged exposure to propofol during development produces elevated levels of neuronal apoptosis in a human neural stem cell-derived model. However, sub-clinical, non-anesthetic concentrations of xenon, when used in combination with propofol, can prevent or ameliorate the toxic effects associated with prolonged anesthetic exposure. This is important as a more complete understanding of the neurotoxic mechanisms associated with a variety of clinically relevant anesthetic combinations becomes available. Protective approaches are critical for developing sound guidance on best practices for the use of these agents in the pediatric setting.

BackgroundAnimals 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.MethodsNeonatal 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 18F-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.ResultsCritical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [18F]-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 [18F]-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.ConclusionsSevoflurane-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.

Methylphenidate (MPH) is a psychostimulant commonly used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD). Since the long-term effects of this drug on the central nervous system (CNS) are not well understood, we conducted microPET/CT scans on young adult male rhesus monkeys (n=4/group) to gather information on brain metabolism using the uptake of [(18)F]Fluoro-2-deoxy-2-d-glucose (FDG) as a marker. Approximately two-year old, male rhesus monkeys were treated orally with MPH twice per day, five days per week (M-F) over a 6-year period. Subjects received MPH at either 2.5 or 12.5mg/kg/dose or vehicle (Prang). To minimize the acute effects of MPH on FDG uptake, microPET/CT scans were scheduled on Mondays before their first daily dosing of the week (approximately 68h since their last treatment). FDG (370±8.88MBq) was injected intravenously and 30min later microPET/CT images were obtained over 60min. Radiolabeled tracer accumulation in regions of interest (ROIs) in the prefrontal cortex, temporal cortex, striatum and cerebellum were converted into Standard Uptake Values (SUVs). Compared to the control group, the uptake of FDG in the cerebellum was significantly decreased in both the low and high dose groups. These preliminary data demonstrate that microPET imaging is capable of distinguishing differences in retention of FDG in the brains of NHPs treated chronically with MPH and suggests that this approach may provide a minimally invasive biomarker for exploring the effects of chronic MPH treatment on aspects of brain function.