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聚山梨酯 80 表面修饰的福莫特罗固体脂质纳米粒可抑制帕金森病小鼠模型中 SNCA 基因和线粒体氧化应激。

Polysorbate 80 surface modified SLNs of formoterol suppress SNCA gene and mitochondrial oxidative stress in mice model of Parkinson's disease.

机构信息

Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, 643001, Tamil Nadu, India.

出版信息

Sci Rep. 2023 Nov 15;13(1):19942. doi: 10.1038/s41598-023-46511-3.

DOI:10.1038/s41598-023-46511-3
PMID:37968340
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10651909/
Abstract

The present study hypothesises that the selective brain β2 receptor activation through β2-adrenoreceptor agonist (β2ARA), Formoterol (FMT), suppresses SNCA gene expression, a pathological hallmark of Parkinson's disease (PD) in brain. Further, it is also hypothesized that brain targeted delivery of Formoterol via polysorbate-80 surface modified solid lipid nanoparticles of Formoterol (FMT-SLNs-PS80) can improve its stability, therapeutic efficacy and avoid/reduce peripheral off-target side effects. FMT-SLNs-PS80 was prepared by solvent injection method, the formulation was optimized by using Box-Behnken design and characterized by measuring drug content, entrapment efficacy, particle size, zeta potentials and poly dispersibility. The FMT-SLNs-PS80, significantly decreases the SNCA expression, mitochondrial membrane damage and rotenone induced changes in oxidative (SOD, CAT, GSH and ROS) stress markers in SH-SY5Y cell lines. The ex vivo permeation study of the formulation using everted chicken ileum exhibited a steady state flux. The pharmacokinetic and tissue distribution studies of the formulation in rats showed a significant improvement in the kinetic parameters when compared to naïve FMT, further the formulation also improved the brain bioavailability of FMT. The anti-Parkinson's efficacy studies of the formulation in mice showed a significant neuroprotection against rotenone-induced changes in behavioural and biochemical parameters. Further, the histopathological analysis of mice brain confirms a significant neuroprotective benefit. The present study successfully establishes the brain targeted delivery and anti-Parkinson's therapeutic efficacy of FMT-SLNs-PS80.

摘要

本研究假设通过β2-肾上腺素受体激动剂（β2ARA）、福莫特罗（FMT）选择性激活大脑β2 受体，可抑制帕金森病（PD）大脑中 SNCA 基因的表达，这是 PD 的病理标志。此外，还假设通过聚山梨醇酯 80 表面修饰的福莫特罗固体脂质纳米粒（FMT-SLNs-PS80）将福莫特罗靶向递送至大脑，可以提高其稳定性、治疗效果，并避免/减少外周脱靶副作用。采用溶剂注入法制备 FMT-SLNs-PS80，采用 Box-Behnken 设计优化配方，并通过测定药物含量、包封率、粒径、Zeta 电位和多分散性进行表征。FMT-SLNs-PS80 可显著降低 SH-SY5Y 细胞系中 SNCA 表达、线粒体膜损伤和鱼藤酮诱导的氧化应激标志物（SOD、CAT、GSH 和 ROS）的变化。该制剂的外翻鸡肠体外渗透研究显示出稳定的通量。制剂在大鼠中的药代动力学和组织分布研究表明，与原始 FMT 相比，动力学参数有显著改善，进一步提高了 FMT 的脑生物利用度。该制剂在小鼠中的抗帕金森病疗效研究表明，对鱼藤酮诱导的行为和生化参数变化具有显著的神经保护作用。此外，小鼠大脑的组织病理学分析证实了其具有显著的神经保护作用。本研究成功建立了 FMT-SLNs-PS80 的脑靶向递送和抗帕金森治疗效果。

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