用 Fas-阻断肽进行全身治疗可减轻脑缺血患者的细胞凋亡

Sungeun Chung, Yujong Yi, Irfan Ullah, Kunho Chung, Seongjun Park, Jaeyeoung Lim, Chaeyeon Kim, Seon-Hong Pyun, Minkyung Kim, Dokyoung Kim, Minhyung Lee, Taiyoun Rhim, Sang-Kyung Lee
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摘要

细胞凋亡在神经元损伤中起着至关重要的作用,大量证据表明 Fas 介导的细胞死亡是缺血性脑卒中的一个关键因素。为解决这一问题,抑制 Fas 信号转导已成为防止神经细胞死亡和缓解脑缺血的一种有前途的策略。然而,克服血脑屏障(BBB)的挑战阻碍了治疗药物向中枢神经系统(CNS)的有效输送。在这项研究中,我们采用了 30 个氨基酸长的瘦素肽来促进 BBB 穿透。通过使用聚乙二醇(PEG)将瘦素肽与Fas阻断肽(FBP)共轭,我们实现了全身给药后在Fas表达的脑梗塞区域的特异性蓄积。值得注意的是,在瘦素受体缺陷的 db/db 小鼠体内给药表明,瘦素促进了 FBP 肽的输送。我们发现,瘦素-PEG-FBP 的全身给药能有效抑制缺血区域由 Fas 介导的细胞凋亡,从而显著减少神经细胞死亡,缩小梗死体积,加速恢复。重要的是,瘦素和 PEG-FBP 都不会影响脑缺血中的细胞凋亡信号转导。在此,我们证明了瘦素-PEG-FBP 的全身给药是治疗脑缺血中风的一种前景广阔的可行策略。我们的方法不仅凸显了治疗潜力,还强调了克服 BBB 挑战以推进神经系统疾病治疗的重要性。
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Systemic Treatment with Fas-Blocking Peptide Attenuates Apoptosis in Brain Ischemia
Apoptosis plays a crucial role in neuronal injury, with substantial evidence implicating Fas-mediated cell death as a key factor in ischemic strokes. To address this, inhibition of Fas-signaling has emerged as a promising strategy in preventing neuronal cell death and alleviating brain ischemia. However, the challenge of overcoming the blood–brain barrier (BBB) hampers the effective delivery of therapeutic drugs to the central nervous system (CNS). In this study, we employed a 30 amino acid-long leptin peptide to facilitate BBB penetration. By conjugating the leptin peptide with a Fas-blocking peptide (FBP) using polyethylene glycol (PEG), we achieved specific accumulation in the Fas-expressing infarction region of the brain following systemic administration. Notably, administration in leptin receptor-deficient db/db mice demonstrated that leptin facilitated the delivery of FBP peptide. We found that the systemic administration of leptin-PEG-FBP effectively inhibited Fas-mediated apoptosis in the ischemic region, resulting in a significant reduction of neuronal cell death, decreased infarct volumes, and accelerated recovery. Importantly, neither leptin nor PEG-FBP influenced apoptotic signaling in brain ischemia. Here, we demonstrate that the systemic delivery of leptin-PEG-FBP presents a promising and viable strategy for treating cerebral ischemic stroke. Our approach not only highlights the therapeutic potential but also emphasizes the importance of overcoming BBB challenges to advance treatments for neurological disorders.
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