Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, FCFRP-USP, Ribeirão Preto, SP, Brazil.
Peptides. 2018 Jun;104:24-34. doi: 10.1016/j.peptides.2018.04.012. Epub 2018 Apr 20.
Venom small peptides that target neurotrophin receptors might be beneficial in neurodegeneration, including Parkinsońs disease (PD). Their small size, ease of synthesis, structural stability and target selectivity make them important tools to overcome the limitations of endogenous neurotrophins as therapeutic agents. Additionally, they might be optimized to improve resistance to enzymatic degradation, bioavailability, potency and, mainly, lipophilicity, important to cross the blood brain barrier (BBB). Here, we evaluated the neuroprotective effects and mechanisms of the synthetic snake-venom-based peptide p-BTX-I (Glu-Val-Trp) in PC12 cells treated with MPP (1-methyl-4-phenylpyridinium), a dopaminergic neurotoxin that induces Parkinsonism in vivo. The peptide p-BTX-I induced neuritogenesis, which was reduced by (i) k252a, antagonist of the NGF-selective receptor, trkA (tropomyosin receptor kinase A); (ii) LY294002, inhibitor of the PI3 K/AKT pathway and (iii) U0126, inhibitor of the MAPK-ERK pathway. Besides that, p-BTX-I also increased the expression of GAP-43 and synapsin, which are molecular markers of axonal growth and synaptic communication. In addition, the peptide increased the viability and differentiation of cells exposed to MPP, known to inhibit neuritogenesis. Altogether, our findings suggest that the synthetic peptide p-BTX-I protects PC12 cells from MPP toxicity by a mechanism that mimics the neurotrophic action of NGF. Therefore, the molecular structure of p-BTX-I might be relevant in the development of drugs aimed at restoring the axonal connectivity in neurodegenerative processes.
靶向神经营养因子受体的毒液小肽在神经退行性疾病中可能是有益的，包括帕金森病（PD）。它们的体积小、合成容易、结构稳定且具有靶向选择性，使其成为克服内源性神经营养因子作为治疗剂的局限性的重要工具。此外，它们可以被优化以提高对酶降解、生物利用度、效力的抗性，主要是脂溶性，这对于穿过血脑屏障（BBB）很重要。在这里，我们评估了基于蛇毒液的合成肽 p-BTX-I（Glu-Val-Trp）在 MPP（1-甲基-4-苯基吡啶）处理的 PC12 细胞中的神经保护作用和机制，MPP 是一种多巴胺能神经毒素，可在体内诱导帕金森病。肽 p-BTX-I 诱导神经突生成，这被（i）k252a 减少，k252a 是 NGF 选择性受体 trkA（原肌球蛋白受体激酶 A）的拮抗剂；（ii）LY294002，PI3K/AKT 通路抑制剂；（iii）U0126，MAPK-ERK 通路抑制剂。此外，p-BTX-I 还增加了 GAP-43 和突触素的表达，GAP-43 和突触素是轴突生长和突触通讯的分子标志物。此外，该肽还增加了暴露于 MPP 的细胞的活力和分化，已知 MPP 抑制神经突生成。总之，我们的研究结果表明，合成肽 p-BTX-I 通过模拟 NGF 的神经营养作用来保护 PC12 细胞免受 MPP 毒性。因此，p-BTX-I 的分子结构可能与开发旨在恢复神经退行性过程中轴突连接的药物有关。
