Hanlon L A, Raghupathi R, Huh J W
Program in Neuroscience, Drexel University College of Medicine, Philadelphia, PA, United States.
Program in Neuroscience, Drexel University College of Medicine, Philadelphia, PA, United States; Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States; Coatesville Veteran's Administration Medical Center, Coatesville, PA, United States.
Exp Neurol. 2017 Apr;290:1-14. doi: 10.1016/j.expneurol.2016.12.010. Epub 2016 Dec 27.
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 3days 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 7days 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 9days. 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 15days 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.
小胶质细胞在发育中大脑损伤的病理生理学中的作用已得到广泛研究。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/巨噬细胞激活的标志物增加，且与更差的神经学预后相关。米诺环素是一种抗生素，可减少新生啮齿动物缺氧缺血后以及成年啮齿动物TBI后的小胶质细胞/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日龄大鼠的完整颅骨受到撞击，并用米诺环素治疗3天。米诺环素给药终止后，皮层和海马中的小胶质细胞反应性立即降低（p<0.001），同时氟玉红B染色阳性细胞数量增加（p<0.001），提示变性细胞的清除减少；然而，这种效应在损伤后7天未持续。尽管白质束中的小胶质细胞反应性降低（p<0.001），但米诺环素治疗并未减少轴突损伤或变性。在丘脑中，米诺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。损伤诱导的空间学习和记忆缺陷也不受米诺环素影响。在研究2中，为了测试延长米诺环素给药时间是否可能有必要减少持续的病理改变，另一组动物接受了9天的米诺环素治疗。治疗终止后，与接受载体的脑损伤动物相比，米诺环素治疗的脑损伤动物在所有检查区域的小胶质细胞反应性和神经变性均加重（p<0.001），这种效应仅在损伤后15天内在皮层和海马中持续（p<0.001）。虽然损伤诱导的空间学习缺陷仍不受米诺环素治疗影响，但记忆缺陷似乎明显更严重（p<0.05）。性别对损伤诱导的改变或米诺环素治疗的疗效影响最小。总体而言，这些数据证明了米诺环素在撞击伤后未成熟大脑中的不同作用，并表明米诺环素可能不是未成熟大脑TBI的有效治疗策略。
