分子薬学および有機プロセス研究ジャーナル

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Protective Effects of Acetyl L-Carnitine on Inhalation Anesthetic-Induced Neuronal Damage in the Nonhuman Primate

Zhang X, Liu S, Paule MG, Newport GD, Callicott R, Berridge MS, Apana SM, Slikker W Jr and Wang C

The inhalation anesthetics nitrous oxide (N2O) and isoflurane (ISO) are commonly used for general anesthesia in human infants. Combined exposures to N2O and ISO are known to cause abnormal apoptotic cell death (neurotoxicity) in pediatric animal models. Acetyl-L-carnitine (ALC), an anti-oxidant dietary supplement, has been reported to minimize neuronal damage in some models of neurotoxicity. MicroPET/CT imaging is capable of detecting and localizing changes in cellular markers of brain damage associated with developmental exposures to general anesthetics. By monitoring changes in glial activation, thought to be a marker of neuroinflammation, it should be possible to determine the intensity, duration and location of neuronal damage associated with exposure to general anesthetics. Here we assessed the uptake of 18F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA), a ligand for peripheral benzodiazepine receptors on activated glial cells. On postnatal day (PND) 5, rhesus monkeys (4/group) were exposed to a mixture of 70% N2O, 29% oxygen plus 1% ISO, or ALC (100 mg/kg given i.p.) plus this mixture for 8 hours; control monkeys with and without ALC were exposed to room air only. [18F]-FEPPA was injected intravenously and microPET/CT images were obtained one day and one and three weeks after anesthetic exposure. One day after anesthetic exposure the uptake of FEPPA was significantly increased only in the temporal lobe and one week after exposure uptake was significantly increased in only the frontal lobe. No significant differences in uptake were seen in any area after 3 weeks. Co-administration of ALC effectively blocked the increase in FEPPA uptake in both the temporal and frontal lobes. These findings suggest that microPET/CT imaging of FEPPA uptake may be useful for monitoring the time-course and location of adverse neural events that are associated with developmental exposures to general anesthetics. In addition, ALC appears to be capable of protecting against at least some of the adverse effects associated with such exposures.