Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat.
Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat.
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DOI：
10.1016/j.expneurol.2016.12.010
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发表时间：
2017-04
影响因子：
5.3
通讯作者：
Huh JW
中科院分区：
文献类型：
--
作者：
Hanlon LA;Raghupathi R;Huh JW
小胶质细胞在发育中的脑损伤病理生理中的作用已被广泛研究。在4岁以下遭受创伤性脑损伤（TBI）的儿童中，脑脊液中小胶质细胞/巨噬细胞激活标记物增加，并与较差的神经系统预后相关。二甲胺四环素是一种抗生素，可降低新生啮齿动物缺氧缺血和成年啮齿动物TBI后的小胶质/巨噬细胞激活，从而减少神经变性和行为缺陷。在研究1中，11天大的大鼠对完整的颅骨进行撞击，并用二甲胺四环素治疗3天。终止二甲胺四环素治疗后，皮质和海马的小胶质细胞反应性立即降低（p<0.001），并伴有氟- jade B谱数量的增加（p<0.001），提示退行性细胞的清除减少；然而，这种影响在损伤后7天没有持续。尽管白质束的小胶质细胞反应性降低（p<0.001），二甲胺四环素治疗并没有减少轴突损伤或变性。在丘脑中，二甲胺四环素治疗不影响小胶质细胞反应性、轴突损伤和变性以及神经变性。二甲胺四环素也不影响损伤性空间学习和记忆缺陷。在研究2中，为了测试是否需要延长二甲胺四环素的剂量来减少正在进行的病理改变，另一组动物服用二甲胺四环素9天。在治疗结束后，与接受载药治疗的脑损伤动物相比，二甲胺四环素治疗的脑损伤动物的所有区域的小胶质细胞反应性和神经退行性均加重（p<0.001），这种影响仅在损伤后15天内在皮质和海马中持续（p<0.001）。米诺环素治疗后，损伤性空间学习缺陷未受影响，但记忆缺陷明显加重（p<0.05）。性别对损伤引起的改变或二甲胺四环素治疗效果的影响很小。总的来说，这些数据证明了二甲胺四环素在未成熟脑外伤后的不同作用，并表明二甲胺四环素可能不是未成熟脑外伤的有效治疗策略。
The role of microglia in the pathophysiology of injury to the developing brain has been extensively studied. In children under the age of 4 who have sustained a traumatic brain injury (TBI), markers of microglial/macrophage activation were increased in the cerebrospinal fluid and were associated with worse neurologic outcome. Minocycline is an antibiotic that decreases microglial/macrophage activation following hypoxic-ischemia in neonatal rodents and TBI in adult rodents thereby reducing neurodegeneration and behavioral deficits. In study 1, 11-day-old rats received an impact to the intact skull and were treated for 3 days with minocycline. Immediately following termination of minocycline administration, microglial reactivity was reduced in the cortex and hippocampus (p<0.001) and was accompanied by an increase in the number of fluoro-Jade B profiles (p<0.001) suggestive of a reduced clearance of degenerating cells; however, this effect was not sustained at 7 days post-injury. Although microglial reactivity was reduced in the white matter tracts (p<0.001), minocycline treatment did not reduce axonal injury or degeneration. In the thalamus, minocycline treatment did not affect microglial reactivity, axonal injury and degeneration, and neurodegeneration. Injury-induced spatial learning and memory deficits were also not affected by minocycline. In study 2, to test whether extended dosing of minocycline may be necessary to reduce the ongoing pathologic alterations, a separate group of animals received minocycline for 9 days. Immediately following termination of treatment, microglial reactivity and neurodegeneration in all regions examined were exacerbated in minocycline-treated brain-injured animals compared to brain-injured animals that received vehicle (p<0.001), an effect that was only sustained in the cortex and hippocampus up to 15 days post-injury (p<0.001). Whereas injury-induced spatial learning deficits remained unaffected by minocycline treatment, memory deficits appeared to be significantly worse (p<0.05). Sex had minimal effects on either injury-induced alterations or the efficacy of minocycline treatment. Collectively, these data demonstrate the differential effects of minocycline in the immature brain following impact trauma and suggest that minocycline may not be an effective therapeutic strategy for TBI in the immature brain.