Department of Neonatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
Department of Neonatology, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang 317500, China.
Brain Res. 2020 Nov 15;1747:147046. doi: 10.1016/j.brainres.2020.147046. Epub 2020 Aug 5.
Dl-3-n-butylphthalide (NBP) has been demonstrated to exert neuroprotective effects in experimental models and human patients. This study was performed to assess the therapeutic effects and the underlying molecular mechanisms of NBP in a neonatal hypoxic-ischemic rat model. The results showed that NBP treatment significantly reduced the infarct volume, improved histological recovery, decreased neuronal cell loss, enhanced neuronal cell rehabilitation, promoted neurite growth and decreased white matter injury. In addition, NBP treatment effectively improved long-term neurobehavioral development and prognosis after HI injury. We further demonstrated an inhibitory effect of NBP on endoplasmic reticulum (ER) stress-induced apoptosis, evidenced by reduction in ER stress-related protein expressions (GRP78, XBP-1, PDI and CHOP), decrease in TUNEL-positive cells, down-regulation in pro-apoptosis protein (Bax and cleaved caspase-3), up-regulation in anti-apoptosis protein (Bcl-2). Moreover, NBP exerted a protective effect in blood-brain barrier disruption, which ameliorated brain edema and reduced the degeneration of the tight junction proteins (Occludin and Claudin-5) and adherens junction proteins (P120-Catenin, VE-Cadherin and β-Catenin). Overall, our findings demonstrated that NBP treatment attenuated HI brain injury through inhibiting ER stress-induced apoptosis and alleviating blood-brain barrier disruption in newborn rats. This work provides an effective therapeutic strategy to reduce brain damage and enhance recovery after neonatal HI brain injury.
二丁基苯酞（NBP）已被证明在实验模型和人类患者中具有神经保护作用。本研究旨在评估 NBP 在新生大鼠缺氧缺血模型中的治疗效果及其潜在的分子机制。结果表明，NBP 治疗可显著减少梗死体积，改善组织学恢复，减少神经元细胞丢失，促进神经元细胞修复，促进神经突生长，减轻白质损伤。此外，NBP 治疗可有效改善 HI 损伤后的长期神经行为发育和预后。我们进一步证明了 NBP 对内质网（ER）应激诱导的细胞凋亡具有抑制作用，这表现在 ER 应激相关蛋白（GRP78、XBP-1、PDI 和 CHOP）表达减少、TUNEL 阳性细胞减少、促凋亡蛋白（Bax 和 cleaved caspase-3）下调、抗凋亡蛋白（Bcl-2）上调。此外，NBP 对血脑屏障破坏具有保护作用，可改善脑水肿并减少紧密连接蛋白（Occludin 和 Claudin-5）和黏着连接蛋白（P120-Catenin、VE-Cadherin 和 β-Catenin）的变性。综上所述，我们的研究结果表明，NBP 通过抑制 ER 应激诱导的细胞凋亡和减轻新生大鼠的血脑屏障破坏，减轻 HI 脑损伤。这项工作为减少新生儿 HI 脑损伤后的脑损伤和促进恢复提供了一种有效的治疗策略。
