Abstract

Quercetin (QU) and rosmarinic acid (RA) were loaded in phosphatidic acid-liposomes (QU/RA-PA-liposomes) with surface apolipoprotein E (ApoE) using a process of thin-film hydration, followed by covalent crosslinking to activate biological pathways for penetrating the blood–brain barrier (BBB) and redeeming the neuronal apoptosis from attack of β-amyloid 1-42 (Aβ_1-42) and neurofibrillary tangles. The conjugation of liposomes with PA improved the activity of QU and RA against neurotoxicity of Aβ_1-42. The fluorescent images of brain capillaries revealed that surface modification with ApoE improved the permeation ability of QU/RA-PA-ApoE-liposomes across the BBB. In addition, the highest therapeutic efficacy was obtained in the case of QU/RA-PA-ApoE-liposomes, compared to other QU/RA formulations studied using in vivo Aβ_1-42-insulted rats mimicking Alzheimer’s disease (AD). The cellular and molecular evidence from AD rats included the decrease in Aβ_1-42 plaque formation and interleukin-6 secretion, increase in the neuronal count in Nissl staining, and reduction in the expression of phosphorylated extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, p38 kinase and tau protein at serine 202 as well as caspase-3. The use of PA-ApoE-liposomes as a dual targeting formulation enhances the QU and RA ability to infiltrate the BBB, docks Aβ_1-42 plaques and can be a potent approach to rescue degenerated neurons from AD.

 抽象的

使用薄膜水合过程将槲皮素 (QU) 和迷迭香酸 (RA) 负载到具有表面载脂蛋白 E (ApoE) 的磷脂酸脂质体 (QU/RA-PA-脂质体) 中，然后进行共价交联以激活生物途径用于穿透血脑屏障 (BBB) 并挽救因 β-淀粉样蛋白 1-42 (Aβ _1-42 ) 和神经原纤维缠结攻击而导致的神经元凋亡。脂质体与 PA 的结合提高了 QU 和 RA 对抗 Aβ _1-42神经毒性的活性。脑毛细血管的荧光图像显示，ApoE 的表面修饰提高了 QU/RA-PA-ApoE-脂质体穿过 BBB 的渗透能力。此外，与使用模拟阿尔茨海默氏病（AD）的体内Aβ _1-42受害大鼠研究的其他 QU/RA 制剂相比，QU/RA-PA-ApoE-脂质体获得了最高的治疗效果。 AD 大鼠的细胞和分子证据包括 Aβ _1-42斑块形成​​和白细胞介素 6 分泌减少、尼氏染色神经元计数增加以及磷酸化细胞外信号调节激酶 1/2、c 表达减少-Jun N 末端激酶、p38 激酶和丝氨酸 202 处的 tau 蛋白以及 caspase-3。使用 PA-ApoE-脂质体作为双重靶向制剂可增强 QU 和 RA 渗透 BBB、对接 Aβ _1-42斑块的能力，并且可以成为拯救 AD 退化神经元的有效方法。