Department of Pediatrics, Division of Neonatology, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ, USA.
Department of Pediatrics, Division of Neonatology, Feinstein Institute for Medical Research, Manhasset, NY, USA.
J Neuroinflammation. 2020 Dec 1;17(1):365. doi: 10.1186/s12974-020-02031-9.
Periventricular leukomalacia (PVL), a devastating brain injury affecting premature infants, is the most common cause of cerebral palsy. PVL is caused by hypoxia ischemia (HI) and is characterized by white matter necrotic lesions, microglial activation, upregulation of NF-κB, and neuronal death. The microglia is the main cell involved in PVL pathogenesis. The goal of this study was to investigate the role of microglial NF-κB activity and its prophylactic inhibition in a neonate mouse model of HI.
Transgenic mice with specific knockout NF-κB in microglia and colony stimulating factor 1 receptor Cre with floxed IKKβ (CSF-1R Cre + IKKβ ) were used. Postnatal day 5 (P5) mice underwent sham or bilateral temporary carotid artery ligation followed by hypoxia. After HI insult, inflammatory cytokines, volumetric MRI, histopathology, and immunohistochemistry for oligodendroglia and microglial activation markers were analyzed. Long-term neurobehavioral assessment, including grip strength, rotarod, and open field testing, was performed at P60.
We demonstrate that selective inhibition of NF-κB in microglia decreases HI-induced brain injury by decreasing microglial activation, proinflammatory cytokines, and nitrative stress. Rescue of oligodendroglia is evidenced by immunohistochemistry, decreased ventriculomegaly on MRI, and histopathology. This selective inhibition leads to attenuation of paresis, incoordination, and improved grip strength, gait, and locomotion.
We conclude that NF-κb activation in microglia plays a major role in the pathogenesis of hypoxic ischemic injury of the immature brain, and its prophylactic inhibition offers significant neuroprotection. Using a specific inhibitor of microglial NF-κB may offer a new prophylactic or therapeutic alternative in preterm infants affected by HI and possibly other neurological diseases in which microglial activation plays a role.
脑室周围白质软化症（PVL）是一种影响早产儿的毁灭性脑损伤，是脑瘫的最常见原因。PVL 由缺氧缺血（HI）引起，其特征是白质坏死病变、小胶质细胞激活、NF-κB 上调和神经元死亡。小胶质细胞是 PVL 发病机制中的主要细胞。本研究旨在探讨小胶质细胞 NF-κB 活性及其在新生鼠 HI 模型中的预防性抑制作用。
使用具有特异性 NF-κB 在小胶质细胞中敲除和集落刺激因子 1 受体 Cre 与 floxed IKKβ（CSF-1R Cre + IKKβ）的转基因小鼠。出生后第 5 天（P5）的小鼠接受假手术或双侧暂时性颈总动脉结扎，随后缺氧。HI 损伤后，分析炎症细胞因子、体积 MRI、组织病理学和少突胶质细胞和小胶质细胞激活标志物的免疫组织化学。在 P60 时进行长期神经行为评估，包括握力、转棒和旷场测试。
我们证明，小胶质细胞中 NF-κB 的选择性抑制通过减少小胶质细胞激活、促炎细胞因子和硝化应激来减少 HI 诱导的脑损伤。免疫组织化学、MRI 上脑室扩大减少和组织病理学证明少突胶质细胞的挽救。这种选择性抑制导致瘫痪、协调障碍减轻，握力、步态和运动能力改善。
我们得出结论，小胶质细胞中 NF-κB 的激活在未成熟脑缺氧缺血损伤的发病机制中起主要作用，其预防性抑制可提供显著的神经保护作用。使用小胶质细胞 NF-κB 的特异性抑制剂可能为受 HI 影响的早产儿和其他可能涉及小胶质细胞激活的神经疾病提供新的预防或治疗选择。
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