Danish Syed Mohammad, Gupta Anshul, Khan Urooj Ahmad, Hasan Nazeer, Ahmad Farhan Jalees, Warsi Musarrat Husain, Ali Ahmed M Abdelhaleem, Zafar Ameeduzzafar, Jain Gaurav Kumar
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Department of Pharmaceutics, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India.
Pharmaceutics. 2022 Mar 30;14(4):756. doi: 10.3390/pharmaceutics14040756.
Cerium oxide nanoparticles (CNPs), owing to their antioxidant property, have recently emerged as therapeutic candidate for Alzheimer's disease (AD). However, intravenous CNPs are limited due to their poor physicochemical properties, rapid blood clearance and poor blood-brain penetration. Thus, we developed intranasal CNPs and evaluated its potential in experimental AD. CNPs were synthesized using homogenous precipitation method and optimized through Box-Behnken Design. The formation of CNPs was confirmed by UV spectroscopy and FTIR. The optimized CNP were spherical, small (134.0 ± 3.35 nm), uniform (PDI, 0.158 ± 0.0019) and stable (ZP, -21.8 ± 4.94 mV). The presence of Ce in CNPs was confirmed by energy-dispersive X-ray analysis. Further, the X-ray diffraction spectra revealed that the CNPs were nano-crystalline. The DPPH assay showed that at concentration of 50 µg/mL, the percentage radical scavenging was 95.40 ± 0.006%. Results of the in vivo behavioral studies in the scopolamine-induced Alzheimer rat model showed that intranasal CNPs dose dependently reversed cognitive ability. At dose of 6 mg/kg the morris water maze results (escape latency, path length and dwell time) and passive avoidance results (retention latency) were significantly different from untreated group but not significantly different from positive control group (rivastigmine patch, 13.3 mg/24 h). Further, biochemical estimation showed that intranasal CNP upregulated the levels of SOD and GSH in brain. In conclusion, intranasal CNPs, through its antioxidant effect, could be a prospective therapeutics for the treatment of cognitive impairment in AD.
氧化铈纳米颗粒（CNPs）因其抗氧化特性，最近已成为阿尔茨海默病（AD）的治疗候选物。然而，静脉注射的CNPs由于其不良的物理化学性质、快速的血液清除率和较差的血脑通透性而受到限制。因此，我们开发了鼻内给药的CNPs，并评估了其在实验性AD中的潜力。采用均匀沉淀法合成CNPs，并通过Box-Behnken设计进行优化。通过紫外光谱和傅里叶变换红外光谱确认了CNPs的形成。优化后的CNPs呈球形，尺寸小（134.0±3.35 nm），均匀（多分散指数，0.158±0.0019）且稳定（zeta电位，-21.8±4.94 mV）。通过能量色散X射线分析确认了CNPs中铈的存在。此外，X射线衍射光谱显示CNPs为纳米晶体。二苯基苦味酰基自由基（DPPH）测定表明，在浓度为50μg/mL时，自由基清除率为95.40±0.006%。在东莨菪碱诱导的阿尔茨海默病大鼠模型中的体内行为学研究结果表明，鼻内给药的CNPs剂量依赖性地逆转了认知能力。在6 mg/kg的剂量下，莫里斯水迷宫实验结果（逃避潜伏期、路径长度和停留时间）和被动回避实验结果（记忆潜伏期）与未治疗组有显著差异，但与阳性对照组（卡巴拉汀贴片，13.3 mg/24 h）无显著差异。此外，生化评估表明，鼻内给药的CNPs上调了大脑中超氧化物歧化酶（SOD）和谷胱甘肽（GSH）的水平。总之，鼻内给药的CNPs通过其抗氧化作用，可能是治疗AD认知障碍的一种有前景的疗法。
