Bichler Edyta K, Elder Courtney C, García Paul S
Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia;
Anesthesiology and Research Divisions, Atlanta VA Medical Center, Decatur, Georgia; and.
J Neurophysiol. 2017 Jan 1;117(1):93-103. doi: 10.1152/jn.00134.2016. Epub 2016 Oct 12.
Antibiotics are used in the treatment and prevention of bacterial infections, but effects on neuron excitability have been documented. A recent study demonstrated that clarithromycin alleviates daytime sleepiness in hypersomnia patients (Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. J Psychopharmacol 28: 697-702, 2014). To explore the potential application of clarithromycin as a stimulant, we performed whole cell patch-clamp recordings in rat pyramidal cells from the CA3 region of hippocampus. In the presence of the antibiotic, rheobase current was reduced by 50%, F-I relationship (number of action potentials as a function of injected current) was shifted to the left, and the resting membrane potential was more depolarized. Clarithromycin-induced hyperexcitability was dose dependent; doses of 30 and 300 μM clarithromycin significantly increased the firing frequency and membrane potential compared with controls (P = 0.003, P < 0.0001). We hypothesized that clarithromycin enhanced excitability by reducing GABA receptor activation. Clarithromycin at 30 μM significantly reduced (P = 0.001) the amplitude of spontaneous miniature inhibitory GABAergic currents and at 300 μM had a minor effect on action potential width. Additionally, we tested the effect of clarithromycin in an ex vivo seizure model by evaluating its effect on spontaneous local field potentials. Bath application of 300 μM clarithromycin enhanced burst frequency twofold compared with controls (P = 0.0006). Taken together, these results suggest that blocking GABAergic signaling with clarithromycin increases cellular excitability and potentially serves as a stimulant, facilitating emergence from anesthesia or normalizing vigilance in hypersomnia and narcolepsy. However, the administration of clarithromycin should be carefully considered in patients with seizure disorders.
NEW & NOTEWORTHY: Clinical administration of the macrolide antibiotic clarithromycin has been associated with side effects such as mania, agitation, and delirium. Here, we investigated the adverse effects of this antibiotic on CA3 pyramidal cell excitability. Clarithromycin induces hyperexcitability in single neurons and is related to a reduction in GABAergic signaling. Our results support a potentially new application of clarithromycin as a stimulant to facilitate emergence from anesthesia or to normalize vigilance.
抗生素用于治疗和预防细菌感染，但已证明其对神经元兴奋性有影响。最近一项研究表明，克拉霉素可减轻发作性睡病患者的日间嗜睡（Trotti LM, Saini P, Freeman AA, Bliwise DL, García PS, Jenkins A, Rye DB. 《精神药理学杂志》28: 697 - 702, 2014）。为探究克拉霉素作为一种兴奋剂的潜在应用，我们在来自海马体CA3区的大鼠锥体细胞中进行了全细胞膜片钳记录。在存在该抗生素的情况下，基强度电流降低了50%，电流-频率关系（动作电位数量作为注入电流的函数）向左移动，静息膜电位更去极化。克拉霉素诱导的兴奋性过高是剂量依赖性的；与对照组相比，30 μM和300 μM的克拉霉素剂量显著增加了放电频率和膜电位（P = 0.003，P < 0.0001）。我们推测克拉霉素通过减少GABA受体激活来增强兴奋性。30 μM的克拉霉素显著降低了（P = 0.001）自发性微小抑制性GABA能电流的幅度，300 μM时对动作电位宽度有轻微影响。此外，我们通过评估其对自发性局部场电位的影响，在离体癫痫模型中测试了克拉霉素的作用。与对照组相比，浴加300 μM克拉霉素使爆发频率增加了两倍（P = 0.0006）。综上所述，这些结果表明，用克拉霉素阻断GABA能信号传导会增加细胞兴奋性，并有可能作为一种兴奋剂，促进从麻醉中苏醒或使发作性睡病和发作性睡病患者的警觉恢复正常。然而，对于患有癫痫疾病的患者，应谨慎考虑使用克拉霉素。
大环内酯类抗生素克拉霉素的临床应用与诸如躁狂、激动和谵妄等副作用有关。在此，我们研究了这种抗生素对CA3锥体细胞兴奋性的不良影响。克拉霉素在单个神经元中诱导兴奋性过高，并且与GABA能信号传导的减少有关。我们的结果支持克拉霉素作为一种兴奋剂促进从麻醉中苏醒或使警觉恢复正常的潜在新应用。
