Minocycline blocks acute bilirubin-induced neurological dysfunction in jaundiced Gunn rats
Minocycline blocks acute bilirubin-induced neurological dysfunction in jaundiced Gunn rats
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DOI：
10.1159/000103740
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发表时间：
2007-01-01
期刊：
影响因子：
2.5
通讯作者：
Shapiro, Steven M.
中科院分区：
文献类型：
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作者：
Geiger, Angela S.;Rice, Ann C.;Shapiro, Steven M.
背景：极度高胆红素血症可通过双倍容量换血治疗，可能需要数小时才能开始。可以立即施用的神经保护剂可能在临床上有用。米诺环素是一种抗炎和抗凋亡的半合成四环素，可预防高胆红素血症引起的 Gunn 大鼠小脑发育不全。给 16 天大的黄疸 Gunn 大鼠服用磺胺二甲氧嘧啶，将胆红素转移到包括大脑在内的组织中后，会出现急性脑干听觉诱发电位 (BAEP) 异常。目的：评估米诺环素在急性胆红素脑病模型中是否具有神经保护作用。方法：我们记录了基线和注射磺胺二甲氧嘧啶后 6 小时的 BAEP。在磺胺二甲氧嘧啶治疗前 15 分钟（0 小时）给予米诺环素 0.5 mg/kg（n = 4）、5 mg/kg（n = 9）、50 mg/kg（n = 9）或 500 mg/kg（n = 3，全部死亡）。对照组接受生理盐水，然后接受磺胺二甲氧嘧啶 (n = 13) 或生理盐水 (n = 7)。结果：6 小时时，所有磺胺二甲氧嘧啶注射组的血浆总胆红素从 10.84 +/- 0.88 mg/dl（平均值 +/- SD）下降至 0.70 +/- 0.35 mg/dl（p < 10(-9)）。 6 小时时，50 mg/kg 米诺环素对 BAEP 波 II 和 III 波幅降低以及 I-II 和 I-III 波间间隔增加（对应于人类 I - III 和 I - V 的脑干传导时间）有完全保护作用，而较低剂量则有部分保护作用。结论：在通常产生急性胆红素神经毒性的干预前 15 分钟给予米诺环素 50 mg/kg，对黄疸 Gunn 幼鼠具有神经保护作用。需要进一步的研究来调查神经保护的时间过程和机制。立即施用米诺环素在临床上可用于治疗新生儿极度高胆红素血症和预防核黄疸。我们相信我们的模型提供了一种有效的体内模型来筛选和评估对胆红素毒性和核黄疸具有神经保护作用的新药物。版权所有 (C) 2007 S. Karger AG，巴塞尔。
Background : Extreme hyperbilirubinemia is treated with double volume exchange transfusion, which may take hours to commence. A neuroprotective agent that could be administered immediately might be clinically useful. Minocycline, an anti-inflammatory and anti-apoptotic semisynthetic tetracycline, prevents hyperbilirubinemia-induced cerebellar hypoplasia in Gunn rats. Acute brainstem auditory evoked potential (BAEP) abnormalities occur after giving sulfadimethoxine to 16-day-old jaundiced Gunn rats to displace bilirubin into tissue including brain. Objective : To assess whether minocycline is neuroprotective in this model of acute bilirubin encephalopathy. Methods : We recorded BAEPs at baseline and 6 h after injecting sulfadimethoxine. Minocycline 0.5 mg/kg (n = 4), 5 mg/kg ( n = 9), 50 mg/kg ( n = 9) or 500 mg/kg ( n = 3, all died) was administered 15 min before sulfadimethoxine ( 0 h). Controls received saline followed by either sulfadimethoxine ( n = 13) or saline ( n = 7). Results : At 6 h total plasma bilirubin decreased from 10.84 +/- 0.88 mg/dl ( mean +/- SD) to 0.70 +/- 0.35 mg/dl ( p < 10(-9)) in all sulfadimethoxine-injected groups. At 6 h, there was complete protection against decreased amplitudes of BAEP waves II and III and increased I-II and I-III interwave intervals (brainstem conduction times corresponding to I - III and I - V in humans) with 50 mg/kg minocycline, and partial protection with lower doses. Conclusions : Minocycline 50 mg/kg 15 min prior to an intervention that normally produces acute bilirubin neurotoxicity is neuroprotective in jaundiced Gunn rat pups. Further studies are needed to investigate the temporal course and mechanism of neuroprotection. Minocycline, administered immediately, may be clinically useful in treating extreme neonatal hyperbilirubinemia and preventing kernicterus. We believe our model provides an efficient in vivo model to screen and evaluate new agents that are neuroprotective against bilirubin toxicity and kernicterus. Copyright (C) 2007 S. Karger AG, Basel.