未成熟脑的创伤性损伤:炎症、氧化损伤和铁介导的损伤作为潜在的治疗靶点

Mathew B. Potts , Seong-Eun Koh , William D. Whetstone , Breset A. Walker , Tomoko Yoneyama , Catherine P. Claus , Hovhannes M. Manvelyan , Linda J. Noble-Haeusslein
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引用次数: 130

摘要

创伤性脑损伤(TBI)是儿童发病率和死亡率的主要原因,临床和实验数据表明,与成人大脑相比,未成熟的大脑对TBI的反应和脆弱性是独特的。目前儿科TBI的治疗侧重于生理紊乱,主要基于成人数据。然而,现在很明显,继发性生化扰动在儿童TBI的病理生物学中起着重要作用,并可能为头部损伤儿童的治疗提供特定的治疗靶点。在这篇综述中,我们讨论了儿童TBI继发性发病机制的三个特定组成部分——炎症、氧化损伤和铁诱导损伤——以及与它们相关的潜在治疗策略。未成熟大脑的炎症反应比成人更强烈,其特征是对血脑屏障的破坏更大,细胞因子的产生也更复杂。由于某些抗氧化分子的表达不足,与成人相比,未成熟的大脑对氧化应激的反应也较弱。此外,脑外伤引起的出血和细胞死亡后,发育中的大脑对游离铁的解毒能力较差。因此,这些过程提供了针对儿童创伤性脑损伤的潜在治疗靶点,包括抗炎剂如米诺环素,抗氧化剂如谷胱甘肽过氧化物酶和铁螯合剂去铁胺。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Traumatic Injury to the Immature Brain: Inflammation, Oxidative Injury, and Iron-Mediated Damage as Potential Therapeutic Targets

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBI – inflammation, oxidative injury, and iron-induced damage – and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

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