Parkinson's disease (PD) is a neurodegenerative condition that results in dyskinesia, with oxidative stress playing a pivotal role in its progression. Antioxidant peptides may thus present therapeutic potential for PD. In this study, a novel cathelicidin peptide (Cath-KP; GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV) was identified from the skin of the Asiatic painted frog ( Kaloula pulchra). Structural analysis using circular dichroism and homology modeling revealed a unique αββ conformation for Cath-KP. In vitro experiments, including free radical scavenging and ferric-reducing antioxidant analyses, confirmed its antioxidant properties. Using the 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine cell line and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice, Cath-KP was found to penetrate cells and reach deep brain tissues, resulting in improved MPP +-induced cell viability and reduced oxidative stress-induced damage by promoting antioxidant enzyme expression and alleviating mitochondrial and intracellular reactive oxygen species accumulation through Sirtuin-1 (Sirt1)/Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation. Both focal adhesion kinase (FAK) and p38 were also identified as regulatory elements. In the MPTP-induced PD mice, Cath-KP administration increased the number of tyrosine hydroxylase (TH)-positive neurons, restored TH content, and ameliorated dyskinesia. To the best of our knowledge, this study is the first to report on a cathelicidin peptide demonstrating potent antioxidant and neuroprotective properties in a PD model by targeting oxidative stress. These findings expand the known functions of cathelicidins, and hold promise for the development of therapeutic agents for PD.
帕金森病（PD）是一种以运动障碍为主要临床表现的的神经退行性疾病。这种运动障碍通常由氧化应激损伤导致，这表明抗氧化肽可能具有治疗帕金森病的潜力。在该研究中，我们从 Kaloula pulchra青蛙的皮肤中鉴定出一种名为Cath-KP （GCSGRFCNLFNNRRPGRLTLIHRPGGDKRTSTGLIYV）的新型 Cathelicidin 多肽。圆二色谱和同源建模分析表明，Cath-KP 具有独特的 αββ结构；自由基清除实验和铁还原抗氧化分析的体外实验证实了其抗氧化特性。我们使用1-甲基-4-苯基吡啶离子 （MPP +）诱多巴胺神经元细胞系（MN9D）构建PD细胞模型，和使用1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理C57小鼠构建PD动物模型。实验表明，Cath -KP可内化至细胞内并递送至深部脑组织，提高MPP +诱导的细胞活力，并通过激活Sirt1/Nrf2抗氧化通路，促进抗氧化酶的表达，减轻线粒体损伤和细胞内活性氧的积累，缓解细胞氧化应激损伤。FAK和p38也在其调节中发挥作用。最终，使用Cath-KP 治疗PD小鼠可以提高黑质区域酪氨酸羟化酶 (TH) 阳性神经元的数量和纹状体TH的表达，并改善小鼠的运动行为障碍。据我们所知，这是第一个通过作用氧化应激在PD模型中展示出有效的抗氧化和神经保护特性的Cathelicidin家族多肽。这些发现扩展了Cathelicidins的已知功能，并为开发新的PD治疗药物带来了希望。.
Keywords: Cath-KP; Neuroprotection; Oxidative stress; Parkinson’s disease; Peptide.