Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity.
Caffeine combined with sedative/anesthetic drugs triggers widespread neuroapoptosis in a mouse model of prematurity.
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DOI：
10.1080/14767058.2016.1261400
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Noguchi KK
中科院分区：
文献类型：
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作者：
Cabrera OH;O'Connor SD;Swiney BS;Salinas-Contreras P;Manzella FM;Taylor GT;Noguchi KK
咖啡因（CAF）和镇静/麻醉药物（SAD）经常共同管理的早产儿在新生儿重症监护病房（NICU）。虽然SAD在发育中的大脑中的神经毒性已经得到了很好的证实，但尚不完全清楚CAF是否与SAD相互作用以及这种相互作用是否有害。使用早产小鼠模型，我们假设CAF与SAD共同给药时会增加凋亡神经毒性。在用6 mg/kg咪达唑仑、40 mg/kg氯胺酮或40 μg/kg芬太尼攻击之前，用媒介物或80 mg/kg CAF处理出生后第3天的小鼠。6小时后，处死幼仔进行活化半胱天冬酶3（AC 3）免疫组织化学，并分析新皮质、海马、尾状核、丘脑和丘中每mm 3 AC 3阳性细胞的数量。当与咪达唑仑（p = 0.002）、氯胺酮（p = 0.014）或芬太尼（p <0.001）共同给药时，CAF引起AC 3阳性细胞的统计学显著增加。我们的复合数据集表明，在这些SAD中添加CAF具有超累加效应，导致比预期更多的神经毒性。CAF可能通过触发早产儿发育中大脑的广泛凋亡来增强NICU中用于新生儿镇静/麻醉的SAD的神经毒性作用。
Caffeine (CAF) and sedative/anesthetic drugs (SADs) are often coadministered to premature infants in the neonatal intensive care unit (NICU). While SAD neurotoxicity in the developing brain is well established, it is not fully clear whether CAF interacts with SADs and whether this interaction is detrimental. Using a mouse model of prematurity, we hypothesized that CAF would increase apoptotic neurotoxicity when coadministered with SADs. Postnatal day 3 mice were treated with vehicle or 80 mg/kg CAF prior to challenge with 6 mg/kg midazolam, 40 mg/kg ketamine, or 40 μg/kg fentanyl. Six hours later, pups were sacrificed for activated caspase 3 (AC3) immunohistochemistry, and number of AC3 positive cells per mm3 throughout neocortex, hippocampus, caudate, thalamus, and colliculi was analyzed. CAF caused a statistically significant increase in AC3 positive cells when coadministered with midazolam (p = 0.002), ketamine (p = 0.014), or fentanyl (p <0.001). Our composite dataset suggests that the addition of CAF to these SADs has a supra-additive effect, causing more neurotoxicity than expected. CAF may augment the neurotoxic action of SADs indicated for neonatal sedation/anesthesia in the NICU by triggering widespread apoptosis in the developing brains of premature infants.