Department of Neonatology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
Endowed Professorship of Immunotechnology, Institute of Biochemistry and Biology, University of Potsdam, Campus Golm, Karl-Liebknechtstraße 24-25, 14476, Potsdam - Golm, Germany.
Neurotox Res. 2018 Aug;34(2):173-187. doi: 10.1007/s12640-018-9872-8. Epub 2018 Feb 7.
In preterm infants, phenobarbital is the first-line antiepileptic drug for neonatal seizures while caffeine is used for the treatment of apnea. Data from experimental animals suggest that phenobarbital and other anticonvulsants are toxic for the developing brain, while neuroprotective effects have been reported for caffeine both in newborn rodents and preterm human infants. To characterize the interaction of phenobarbital and caffeine in the hippocampus of the developing rodent brain, we examined the effects of both drugs given separately or together on postnatal neurogenesis after administration to neonatal rats throughout postnatal day (P) 4 to P6. Phenobarbital treatment (50 mg/kg) resulted in a significant decrease of proliferative capacity in the dentate gyrus. Phenobarbital also reduced expression of neuronal markers (doublecortin (DCX), calretinin, NeuN), neuronal transcription factors (Pax6, Sox2, Tbr1/2, Prox1), and neurotrophins (NGF, BDNF, NT-3) up to 24 h after the last administration. The phenobarbital-mediated impairment of neurogenesis was largely ameliorated by preconditioning with caffeine (10 mg/kg). In contrast, caffeine alone reduced proliferative capacity and expression of the neuronal markers DCX and NeuN at 6 h, but increased expression of neurotrophins and neuronal transcription factors at 6 and 12 h. These results indicate that administration of phenobarbital during the vulnerable phase of brain development negatively interferes with neuronal development, which can be prevented in part by co-administration of caffeine.
在早产儿中，苯巴比妥是治疗新生儿癫痫发作的一线抗癫痫药物，而咖啡因则用于治疗呼吸暂停。实验动物的数据表明，苯巴比妥和其他抗惊厥药对发育中的大脑有毒性，而咖啡因对新生啮齿动物和早产儿都有神经保护作用。为了描述苯巴比妥和咖啡因在发育中啮齿动物大脑海马体中的相互作用，我们研究了这两种药物在新生大鼠出生后第 4 至第 6 天期间分别或同时给药对出生后神经发生的影响。苯巴比妥治疗（50mg/kg）导致齿状回的增殖能力显著下降。苯巴比妥还降低了神经元标志物（双皮质素 (DCX)、钙视网膜蛋白、神经元核抗原 (NeuN)）、神经元转录因子（Pax6、Sox2、Tbr1/2、Prox1）和神经营养因子（NGF、BDNF、NT-3）的表达，直到最后一次给药后 24 小时。在最后一次给药前用咖啡因（10mg/kg）预处理可大大减轻苯巴比妥介导的神经发生损伤。相比之下，咖啡因单独给药在 6 小时时降低了增殖能力和神经元标志物 DCX 和 NeuN 的表达，但在 6 和 12 小时时增加了神经营养因子和神经元转录因子的表达。这些结果表明，在大脑发育的脆弱阶段给予苯巴比妥会对神经元发育产生负面影响，而部分可以通过联合给予咖啡因来预防。
