BACKGROUND Preclinical studies suggest that exposures of infant animals to general anesthetics cause acute neurotoxicity and affect their neurobehavioral development representing a potential risk to human infants undergoing anesthesia. Alternative or mitigating strategies to counteract such adverse effects are desirable. Dexmedetomidine (DEX) is a clinically established sedative with potential neuroprotective properties. DEX ameliorates experimental brain injury as well as neurotoxicity caused by anesthetic doses of sevoflurane (SEVO) or other general anesthetics in infant animals. However, it is unknown whether DEX also is beneficial when given together with lower doses of these drugs. Here we tested the hypothesis that DEX co-administration with a sub-anesthetic dose of SEVO reduces responsiveness to external stimuli while also protecting against SEVO-induced brain cell apoptosis. METHOD Rats were exposed on postnatal day 7 for 6 h to SEVO 1.1, 1.8, or 2.5% and were given intraperitoneal injections of saline or DEX at different doses (1-25 μg/kg) three times during the exposure. Responsiveness to external stimuli, respiratory rates, and blood gases were assessed. Apoptosis was determined in cortical and subcortical brain areas by activated caspase-3 immunohistochemistry. RESULTS Rats exposed to SEVO 1.1% alone were sedated but still responsive to external stimuli whereas those exposed to SEVO 1.8% reached complete unresponsiveness. SEVO-induced brain cell apoptosis increased dose-dependently, with SEVO 1.1% causing a small increase in apoptosis above that in controls. Co-administration of DEX at 1 μg/kg did not alter the responsiveness to stimuli nor the apoptosis induced by SEVO 1.1%. In contrast, co-administration of DEX at 5 μg/kg or higher with SEVO 1.1% reduced responsiveness but potentiated apoptosis. CONCLUSIONS In the neonatal rat model, co-administration of a clinically relevant dose of DEX (1 μg/kg) with a sub-anesthetic dose of SEVO (1.1%) does not affect the neurotoxicity of the anesthetic while co-administration of higher doses of DEX with SEVO 1.1% potentiates it.

中文翻译：

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亚麻醉剂量的七氟醚和右美托咪定对新生大鼠的神经毒性。

背景技术临床前研究表明，将婴儿动物暴露于全身麻醉下会引起急性神经毒性，并影响其神经行为发育，这代表了正在接受麻醉的人类婴儿的潜在风险。期望有替代或减轻策略来抵消这种不利影响。右美托咪定（DEX）是临床上建立的具有潜在神经保护作用的镇静剂。DEX改善了麻醉剂量的七氟醚（SEVO）或其他婴儿麻醉剂引起的实验性脑损伤以及神经毒性。然而，未知的是当与低剂量的这些药物一起使用时，DEX是否也有益。在这里，我们测试了这样的假设，即DEX与亚麻醉剂量的SEVO并用会降低对外部刺激的反应性，同时还能防止SEVO诱导的脑细胞凋亡。方法大鼠在出生后第7天接受SEVO 1.1％，1.8％或2.5％暴露6小时，并在暴露期间腹膜内注射不同剂量（1-25μg/ kg）的盐水或DEX 3次。评估对外界刺激，呼吸频率和血气的反应。通过激活的caspase-3免疫组织化学测定皮质和皮质下脑区域的凋亡。结果单独暴露于SEVO 1.1％的大鼠被镇静，但仍对外部刺激有反应，而暴露于SEVO 1.8％的大鼠则完全无反应。SEVO诱导SEVO诱导的脑细胞凋亡呈剂量依赖性增加。1％导致细胞凋亡略高于对照组。以1μg/ kg的DEX共同给药不会改变对刺激的反应性，也不会改变SEVO 1.1％诱导的细胞凋亡。相反，以5μg/ kg或更高的DEX与SEVO 1.1％共同给药可降低反应性，但可增强细胞凋亡。结论在新生大鼠模型中，临床上相关剂量的DEX（1μg/ kg）与亚麻醉剂量的SEVO（1.1％）并用不会影响麻醉剂的神经毒性，而同时并用较高剂量SEVO 1.1％的DEX可以增强效果。1％降低反应性，但增强细胞凋亡。结论在新生大鼠模型中，临床上相关剂量的DEX（1μg/ kg）与亚麻醉剂量的SEVO（1.1％）并用不会影响麻醉剂的神经毒性，而同时并用较高剂量SEVO 1.1％的DEX可以增强效果。1％降低反应性，但增强细胞凋亡。结论在新生大鼠模型中，临床上相关剂量的DEX（1μg/ kg）与亚麻醉剂量的SEVO（1.1％）并用不会影响麻醉剂的神经毒性，而同时并用较高剂量SEVO 1.1％的DEX可以增强效果。