<i>In Vivo</i>Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography

Zhang, Xuan; Liu, Shuliang; Newport, Glenn D.; Paule, Merle G.; Callicott, Ralph; Thompson, J. Will; Fang, Liu; Patterson, Tucker A.; Berridge, Marc S.; Apana, Scott M.; Brown, Christina C.; Maisha, Mackean; Hanig, Joseph P.; Slikker, William; Wang, Cheng

doi:10.1097/aln.0000000000001154

Cited by 59 publications

(51 citation statements)

References 96 publications

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“…Several studies have also reported that L-carnitine, and particularly ALCAR can protect the developing brain from deleterious effects of exposure to clinically used anesthetic agents [154–157]. Treatment with ALCAR protected from neuroinflammation and apoptosis resulting from anesthesia [154–157]. It is particularly important that some of these studies used newborn or very young nonhuman primates [154, 155, 157].…”

Section: Neuroprotection By Acetyl-l-carnitine (Alcar)mentioning

confidence: 99%

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l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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L-Carnitine functions to transport long chain fatty acyl CoAs into the mitochondria for degradation by β-oxidation. Treatment with L-carnitine can ameliorate metabolic imbalance in many inborn errors of metabolism. In recent years there has been considerable interest in the therapeutic potential of L-carnitine and its acetylated derivative acetyl-L-carnitine (ALCAR) for neuroprotection in a number of disorders including hypoxia-ischemia, traumatic brain injury, Alzheimer’s disease and in conditions leading to central or peripheral nervous system injury. There is compelling evidence from preclinical studies that L-carnitine and ALCAR can improve energy status, decrease oxidative stress and prevent subsequent cell death in models of adult, neonatal and pediatric brain injury. ALCAR can provide an acetyl moiety that can be oxidized for energy, used as a precursor for acetylcholine, or incorporated into glutamate, glutamine and GABA, or into lipids for myelination and cell growth. Administration of ALCAR after brain injury in rat pups improved long-term functional outcomes, including memory. Additional studies are needed to better explore the potential of L-carnitine and ALCAR for protection of developing brain as there is an urgent need for therapies that can improve outcome after neonatal and pediatric brain injury.

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Section: Neuroprotection By Acetyl-l-carnitine (Alcar)mentioning

confidence: 99%

“…Treatment with ALCAR protected from neuroinflammation and apoptosis resulting from anesthesia [154–157]. It is particularly important that some of these studies used newborn or very young nonhuman primates [154, 155, 157]. …”

Section: Neuroprotection By Acetyl-l-carnitine (Alcar)mentioning

confidence: 99%

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

2017

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“…The observed sevoflurane-induced developmental neurotoxicity has yet to be associated with subsequent functional effects in the nonhuman primate as it has with other species [33] but studies looking into this phenomenon are underway [34]. The sevoflurane-induced developmental neurotoxicity that has been demonstrated in previous animal studies [33,35] and in the present work should lead to increased vigilance regarding its use in patients of an age most likely to be susceptible to the adverse effects of general anesthetics [36].…”

Section: Discussionmentioning

confidence: 78%

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

Liu¹,

Zhang²,

Liu³

et al. 2017

J Drug Alcohol Res

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Background. In studies on anesthetic-induced developmental neurotoxicity, the animals' physiological status and the depth of anesthesia during anesthesia need to be monitored. In addition, blood borne indicators of prolonged sevoflurane exposure have yet to be explored. The nonhuman primate model could have more advantages over rodent model in these aspects. Methods. Twentyseven rhesus monkeys [postnatal day (PND) 5 or 6] were monitored for their physiological status during the eight-hour exposures to 2.5% sevoflurane or room air. Plasma samples collected during the exposures were analyzed for proinflammatory mediators. Tissue from the frontal cortex was examined via electron microscopy (EM) four hours following the exposure in a subgroup of animals. Micro-positron emission tomography (microPET) using the radiolabeled ligand [ 18 F]FEPPA, which binds to activated microglia and astrocytes in the central nervous system (CNS), was performed one day following the exposure. Results. Key physiological metrics observed in PND 5/6 monkeys undergoing anesthesia were not altered significantly in comparison with those for control animals. Sevoflurane-induced neural damage was confirmed by EM observations. Increased production of interleukin (IL)-6 and CCL-2 was detected in plasma at the end of the eight-hour sevoflurane exposure, and enhanced uptake of [ 18 F]FEPPA was observed in the frontal cortical region the day following anesthesia. The coincident increase in proinflammatory mediators in the peripheral circulation suggested that this sevofluraneinduced response may be used as an indicator of anesthetic-induced developmental neurotoxicity. Conclusions. The valuable information obtained in these studies demonstrates the usefulness of the nonhuman primate model in the evaluation of anesthetic-induced developmental neurotoxicity. The elevation of IL-6 and CCL-2 may be the useful indicator of anesthetic-induced developmental neurotoxicity.

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“…MicroPET/CT is a minimally invasive molecular imaging multimodality that was broadly used in both preclinical and clinical research [34]. These data, plus data from studies by others [56], indicate that dopamine receptors do not mediate the immobility or altered MAC produced by inhaled anesthetics, including sevofl urane, and that D2/D3 receptors in striatum have no contribution to sevofl urane-induced behavioral disturbance and sevofl uraneinduced neurotoxicity [14,54].…”

Section: Discussionmentioning

confidence: 99%

“…There are substantial data indicating that prolonged exposure to sevofl urane can induce neurotoxicity in both rodents and nonhuman primates developing brains [13,14]. Signifi cant behavioral research has also shown that exposure of neonatal mammalian animals to sevofl urane for a long period and/or multiple times will impair performance in the Morris water maze (MWM), a novel-object recognition test (NOR), social behaviors, fear conditioning and recognition memory at all ages [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Dopamine Receptor Integrity after Sevofl urane Exposure in Neonatal Rat Brain Using Positron Emission Tomography

Yin¹,

Paule²,

Patterson³

et al. 2018

Glob J Anesth

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Aims: The volatile general anesthetic sevofl urane is commonly used across all ages in the clinic. Sevofl urane-induced neurotoxic effects on the developing dopaminergic system are still unclear. The aim of this study was to evaluate the integrity of the D2/D3 receptor in developing rat brain utilizing molecular imaging techniques. Method: Positron Emission Tomography (PET) coupled with Computerized Tomography (CT) approaches were used to evaluate the effects of developmental sevofl urane exposure on D2/D3 receptors in rat pups. The PET radiotracer, [ 18 F]-fallypride, was used to examine whether dopamine receptors were affected by prolonged sevofl urane-exposure during the brain growth spurt. Six postnatal day (PND) 7 rats in the experimental group were exposed to sevofl urane at the clinically-relevant concentration of 2.5% (v/v) for 8 hours, and an equal number of control animals were exposed to room air for 8 hours. MicroPET/ CT scans were sequentially collected on PNDs 14, 21, 28, and 35. Results: No signifi cant differences in the retention of [ 18 F]-fallypride in striatum were detected between sevofl urane-exposed and control animals at any of the scan times. D2/D3 receptors are not affected by prolonged sevofl urane-induced general anesthesia during development. Conclusions: Sevofl urane-induced neurotoxicity in the developing rodent brain was not associated with apparent derangements in dopamine D2/D3 receptors.

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In VivoMonitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography

Cited by 59 publications

References 96 publications

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

l-Carnitine and Acetyl-l-carnitine Roles and Neuroprotection in Developing Brain

The Utility of a Nonhuman Primate Model for Assessing Anesthetic-Induced Developmental Neurotoxicity

Evaluation of Dopamine Receptor Integrity after Sevofl urane Exposure in Neonatal Rat Brain Using Positron Emission Tomography

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