Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat
Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat
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DOI：
10.1002/jnr.20623
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发表时间：
2005-10-01
影响因子：
4.2
通讯作者：
Cai, ZW
中科院分区：
文献类型：
--
作者：
Fan, LW;Pang, Y;Cai, ZW
新生大鼠脑内注射内毒素脂多糖（LPS）引起的优先脑白质损伤和髓鞘形成不足已被定性为与小胶质细胞的激活有关。为了检查抑制小胶质细胞活化是否可以提供针对 LPS 诱导的脑损伤和行为缺陷的保护，在出生后第 5 天 (P5) 的 Sprague-Dawley 大鼠脑内注射 LPS (1 mg/kg) 之前和之后 12 小时，腹腔内注射米诺环素 (45 mg/kg)，然后每 24 小时注射一次，持续 3 天。出生后第21天检查脑损伤和髓鞘形成，P3至P21进行神经行为毒性测试。 LPS 给药导致严重的白质损伤、脑室扩大、海马缺陷、少突胶质细胞和酪氨酸羟化酶神经元损失、轴突和树突损伤以及髓鞘形成受损，如 P21 大鼠脑中髓磷脂碱性蛋白免疫染色减少所示。 LPS 给药还显着影响身体发育（体重）和神经行为表现，例如翻正反射、钢丝悬挂动作、悬崖回避、运动活动、步态分析以及高架十字迷宫和被动回避任务中的反应。米诺环素治疗显着减轻了脂多糖引起的脑损伤并改善了神经行为表现。米诺环素的保护作用与其减弱 LPS 诱导的小胶质细胞活化的能力有关。这些结果表明，米诺环素抑制小胶质细胞活化可能对新生儿大脑中感染引起的脑损伤和相关神经功能障碍具有长期保护作用。 (C) 2005 Wiley-Liss, Inc.
Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat. (C) 2005 Wiley-Liss, Inc.