Exposure to Morphine and Caffeine Induces Apoptosis and Mitochondrial Dysfunction in a Neonatal Rat Brain.
Exposure to Morphine and Caffeine Induces Apoptosis and Mitochondrial Dysfunction in a Neonatal Rat Brain.
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DOI：
10.3389/fped.2020.00593
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发表时间：
2020
影响因子：
2.6
通讯作者：
Gulati A
中科院分区：
文献类型：
--
作者：
Kasala S;Briyal S;Prazad P;Ranjan AK;Stefanov G;Donovan R;Gulati A
背景：早产儿出生后早期大脑发育迅速，对作用于中枢神经系统的药物易感。吗啡用于早产儿止痛，咖啡因用于早产儿呼吸暂停。同时使用吗啡和咖啡因在新生儿重症监护病房很常见。先前的研究已经显示了这种组合的急性神经毒性，然而，关于调节神经毒性作用的机制的信息很少。本研究旨在探讨吗啡和咖啡因单独及联合作用对新生大鼠脑线粒体功能障碍(Drp1和Mfn2)、神经细胞凋亡(Bcl2、Bax和细胞损伤)及内皮素(ET)受体(ETA和ETB)的影响。方法：将雄性和雌性幼鼠按不同处理分为4个亚组：生理盐水(Control)、吗啡(MoR)、咖啡因(Caff)和吗啡+咖啡因(M+C)。MOR组于出生后第3~6天皮下注射吗啡2 mg/kg，Caff组给予咖啡因100 mg/kg，M+C组同时给予吗啡2 mg/kg和咖啡因100 mg/kg，分别于出生后第7、14、28天处死动物。分离大脑，通过免疫荧光和免疫印迹分析线粒体功能障碍、细胞损伤和ET受体的表达。结果：在雌性仔鼠PND 7，14，28和雄性仔鼠PND 7，14，14时，M+C组Bax的表达显著高于Caff或Mor组(p<；0.05)。在PND7、14、28与对照组相比，所有治疗组的DRp1、Bax的表达均显著增加(p<；0.05)，而Mfn2、Bcl2的表达均受到抑制(p<；0.05)。在PND 7、14和28天，雌雄幼鼠ETA和ETB受体的表达无显著差异。结论：与单独使用咖啡因和咖啡因相比，在生命的第一周同时使用吗啡和咖啡因会增加发育中大脑的细胞凋亡和细胞损伤。
Background: Preterm infants experience rapid brain growth during early post-natal life making them vulnerable to drugs acting on central nervous system. Morphine is administered to premature neonates for pain control and caffeine for apnea of prematurity. Simultaneous use of morphine and caffeine is common in the neonatal intensive care unit. Prior studies have shown acute neurotoxicity with this combination, however, little information is available on the mechanisms mediating the neurotoxic effects. The objective of this study was to determine the effects of morphine and caffeine, independently and in combination on mitochondrial dysfunction (Drp1 and Mfn2), neural apoptosis (Bcl-2, Bax, and cell damage) and endothelin (ET) receptors (ETA and ETB) in neonatal rat brain. Methods: Male and female rat pups were grouped separately and were divided into four different subgroups on the basis of treatments–saline (Control), morphine (MOR), caffeine (CAFF), and morphine + caffeine (M+C) treatment. Pups in MOR group were injected with 2 mg/kg morphine, CAFF group received 100 mg/kg caffeine, and M+C group received both morphine (2 mg/kg) and caffeine (100 mg/kg), subcutaneously on postnatal days (PND) 3–6. Pups were euthanized at PND 7, 14, or 28. Brains were isolated and analyzed for mitochondrial dysfunction, apoptosis markers, cell damage, and ET receptor expression via immunofluorescence and western blot analyses. Results: M+C showed a significantly higher expression of Bax compared to CAFF or MOR alone at PND 7, 14, 28 in female pups (p < 0.05) and at PND 7, 14 in male pups (p < 0.05). Significantly (p < 0.05) increased expression of Drp1, Bax, and suppressed expression of Mfn2, Bcl-2 at PND 7, 14, 28 in all the treatment groups compared to the control was observed in both genders. No significant difference in the expression of ETA and ETB receptors in male or female pups was seen at PND 7, 14, and 28. Conclusion: Concurrent use of morphine and caffeine during the first week of life increases apoptosis and cell damage in the developing brain compared to individual use of caffeine and morphine.
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影响因子：
2.5
作者：
Duehrsen, Lasse;Simons, Sinno H. P.;Felderhoff-Mueser, Ursula
通讯作者：
Felderhoff-Mueser, Ursula
影响因子：
168.9
作者：
Anand, KJS;Hall, RW;Barton, BA
通讯作者：
Barton, BA
影响因子：
5.1
作者：
Borenstein-Levin, Iron;Synnes, Anne;Shah, Prakesh S.
通讯作者：
Shah, Prakesh S.
影响因子：
8.3
作者：
Back, Stephen A.;Riddle, Art;McClure, Melissa M.
通讯作者：
McClure, Melissa M.
影响因子：
5.3
作者：
Craig, A;Luo, NL;Back, SA
通讯作者：
Back, SA