Hypoxic-ischemic (HI) brain injury in neonatal encephalopathy triggers a wave of neuroinflammatory events attributed to causing the progressive degeneration and functional deficits seen weeks after the primary damage. The cellular processes mediating this prolonged neurodegeneration in HI injury are not sufficiently understood. Consequently, current therapies are not fully protective. In a recent study, we found significant improvements in neurologic outcomes when a small molecule antagonist for Activin-Like Kinase 5 (ALK5), a transforming growth factor beta (TGF-β) receptor was used as a therapeutic in a rat model of moderate term HI. Here, we have extended those studies to a mouse preterm pup model of HI. For these studies, postnatal day 7 (P7) CD1 mice of both sexes were exposed to 35-40 minutes of HI. Beginning 3 days later, SB505124, the ALK5 receptor antagonist, was administered systemically through intraperitoneal injections performed every 12 hours for 5 days. When evaluated 23 days later, SB505124-treated mice had ~2.5-fold more hippocampal area and ~2-fold more thalamic tissue. Approximately ~90% of the ipsilateral hemisphere (ILH) was preserved in the SB505124-treated HI mice compared to the vehicle-treated HI mice, where the ILH was ~60% of its normal size. SB505124 also preserved the subcortical white matter. SB505124 treatment preserved levels of aquaporin-4 and n-cadherin, key proteins associated with blood-brain-barrier function. Importantly, SB505124 administration improved sensorimotor function as assessed by a battery of behavioral tests. Altogether these data lend additional support to the conclusion that SB505124 is a candidate neuroprotective molecule that could be an effective treatment for HI-related encephalopathy in moderately injured preterm infants.

中文翻译：

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延迟 TGF-β1 受体拮抗剂给药对围产期缺氧缺血性脑损伤的神经保护作用。

新生儿脑病中的缺氧缺血性（HI）脑损伤会引发一波神经炎症事件，其原因是导致原发性损伤几周后出现的进行性退化和功能缺陷。HI 损伤中介导这种长期神经变性的细胞过程尚未得到充分了解。因此，目前的疗法并不能完全起到保护作用。在最近的一项研究中，我们发现，当使用激活素样激酶 5 (ALK5)（一种转化生长因子 β (TGF-β) 受体）的小分子拮抗剂作为中期大鼠模型的治疗剂时，神经系统结果显着改善你好。在这里，我们将这些研究扩展到小鼠早产儿 HI 模型。在这些研究中，出生后第 7 天 (P7) 的两性 CD1 小鼠均暴露于 35-40 分钟的 HI。3天后开始，SB505124，ALK5 受体拮抗剂通过腹膜内注射进行全身给药，每 12 小时进行一次，持续 5 天。23 天后进行评估时，SB505124 治疗的小鼠的海马面积增加了约 2.5 倍，丘脑组织增加了约 2 倍。与媒介物治疗的 HI 小鼠相比，SB505124 治疗的 HI 小鼠保留了约 90% 的同侧半球 (ILH)，其中 ILH 约为正常大小的 60%。SB505124还保留了皮质下白质。SB505124 治疗保留了水通道蛋白 4 和 n-钙粘蛋白（与血脑屏障功能相关的关键蛋白质）的水平。重要的是，通过一系列行为测试评估，SB505124 给药改善了感觉运动功能。