Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity
Dopaminergic neuronal injury in the adult rat brain following neonatal exposure to lipopolysaccharide and the silent neurotoxicity
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DOI：
10.1016/j.bbi.2010.09.020
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发表时间：
2011-02-01
影响因子：
15.1
通讯作者：
Cai, Zhengwei
中科院分区：
文献类型：
--
作者：
Fan, Lir-Wan;Tien, Lu-Tai;Cai, Zhengwei
我们以前的研究表明，新生大鼠暴露于脂多糖（LPS）导致运动功能障碍和多巴胺能神经元损伤的幼年大鼠脑。为了进一步检查新生儿LPS暴露是否对成年大鼠具有持续影响，从出生后第7天（P7）至P70检查运动行为，并在P5 Sprague-Dawley雄性大鼠脑内注射LPS（1 mg/kg）后测定P70大鼠的脑损伤。尽管新生儿LPS暴露导致运动和刻板任务的过度活跃以及其他运动行为障碍，但受损的运动功能在P70时自发恢复。另一方面，新生儿LPS诱导的多巴胺能系统的损伤，如树突的损失和黑质酪氨酸羟化酶免疫反应性降低持续在P70大鼠。新生儿LPS暴露也导致P70大鼠脑中持续的炎症反应，如大鼠脑中活化的小胶质细胞数量增加和白细胞介素-1 β和白细胞介素-6含量升高所示。此外，当用甲基苯丙胺（METH，0.5 mg/kg）皮下攻击时，与新生儿LPS暴露的大鼠相比，在甲基苯丙胺诱导的运动和刻板行为的反应显着增加。这些结果表明，虽然新生儿LPS诱导的神经行为损害是自发恢复的，LPS刺激诱导的多巴胺能系统的持续损伤和慢性炎症可能代表存在无声的神经毒性。我们的数据进一步表明，树突状线粒体功能受损可能至少部分导致了无声的神经毒性。(C)2010年爱思唯尔公司All rights reserved.
Our previous studies have shown that neonatal exposure to lipopolysaccharide (LPS) resulted in motor dysfunction and dopaminergic neuronal injury in the juvenile rat brain. To further examine whether neonatal LPS exposure has persisting effects in adult rats, motor behaviors were examined from postnatal day 7 (P7) to P70 and brain injury was determined in P70 rats following an intracerebral injection of LPS (1 mg/kg) in P5 Sprague-Dawley male rats. Although neonatal LPS exposure resulted in hyperactivity in locomotion and stereotyped tasks, and other disturbances of motor behaviors, the impaired motor functions were spontaneously recovered by P70. On the other hand, neonatal LPS-induced injury to the dopaminergic system such as the loss of dendrites and reduced tyrosine hydroxylase immunoreactivity in the substantia nigra persisted in P70 rats. Neonatal LPS exposure also resulted in sustained inflammatory responses in the P70 rat brain, as indicated by an increased number of activated microglia and elevation of interleukin-1 beta and interleukin-6 content in the rat brain. In addition, when challenged with methamphetamine (METH, 0.5 mg/kg) subcutaneously, rats with neonatal LPS exposure had significantly increased responses in METH-induced locomotion and stereotypy behaviors as compared to those without LPS exposure. These results indicate that although neonatal LPS-induced neurobehavioral impairment is spontaneously recoverable, the LPS exposure-induced persistent injury to the dopaminergic system and the chronic inflammation may represent the existence of silent neurotoxicity. Our data further suggest that the compromised dendritic mitochondrial function might contribute, at least partially, to the silent neurotoxicity. (C) 2010 Elsevier Inc. All rights reserved.