Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt.
Int J Nanomedicine. 2023 Jul 27;18:4193-4227. doi: 10.2147/IJN.S417928. eCollection 2023.
Donepezil (DPL), a specific acetylcholinesterase inhibitor, is used as a first-line treatment to improve cognitive deficits in Alzheimer's disease (AD) and it might have a disease modifying effect. Astaxanthin (AST) is a natural potent antioxidant with neuroprotective, anti-amyloidogenic, anti-apoptotic, and anti-inflammatory effects. This study aimed to prepare nanostructured lipid carriers (NLCs) co-loaded with donepezil and astaxanthin (DPL/AST-NLCs) and evaluate their in vivo efficacy in an AD-like rat model 30 days after daily intranasal administration.
DPL/AST-NLCs were prepared using a hot high-shear homogenization technique, in vitro examined for their physicochemical parameters and in vivo evaluated. AD induction in rats was performed by aluminum chloride. The cortex and hippocampus were isolated from the brain of rats for biochemical testing and histopathological examination.
DPL/AST-NLCs showed z-average diameter 149.9 ± 3.21 nm, polydispersity index 0.224 ± 0.017, zeta potential -33.7 ± 4.71 mV, entrapment efficiency 81.25 ±1.98% (donepezil) and 93.85 ±1.75% (astaxanthin), in vitro sustained release of both donepezil and astaxanthin for 24 h, spherical morphology by transmission electron microscopy, and they were stable at 4-8 ± 2°C for six months. Differential scanning calorimetry revealed that donepezil and astaxanthin were molecularly dispersed in the NLC matrix in an amorphous state. The DPL/AST-NLC-treated rats showed significantly lower levels of nuclear factor-kappa B, malondialdehyde, β-site amyloid precursor protein cleaving enzyme-1, caspase-3, amyloid beta (Aβ), and acetylcholinesterase, and significantly higher levels of glutathione and acetylcholine in the cortex and hippocampus than the AD-like untreated rats and that treated with donepezil-NLCs. DPL/AST-NLCs showed significantly higher anti-amyloidogenic, antioxidant, anti-acetylcholinesterase, anti-inflammatory, and anti-apoptotic effects, resulting in significant improvement in the cortical and hippocampal histopathology.
Nose-to-brain delivery of DPL/AST-NLCs is a promising strategy for the management of AD.
多奈哌齐（DPL）是一种特定的乙酰胆碱酯酶抑制剂，被用作改善阿尔茨海默病（AD）认知缺陷的一线治疗药物，并且可能具有疾病修饰作用。虾青素（AST）是一种天然的强效抗氧化剂，具有神经保护、抗淀粉样变性、抗细胞凋亡和抗炎作用。本研究旨在制备载有多奈哌齐和虾青素的纳米结构脂质载体（DPL/AST-NLCs），并评估其在 AD 样大鼠模型中经鼻内每日给药 30 天后的体内疗效。
采用热高剪切匀化技术制备 DPL/AST-NLCs，体外考察其理化参数，并进行体内评价。用氯化铝诱导大鼠 AD。从大鼠大脑中分离出皮质和海马，用于生化测试和组织病理学检查。
DPL/AST-NLCs 的 Z 均粒径为 149.9 ± 3.21nm，多分散指数为 0.224 ± 0.017，Zeta 电位为-33.7 ± 4.71mV，载药量为 81.25 ±1.98%（多奈哌齐）和 93.85 ±1.75%（虾青素），体外可在 24 小时内持续释放多奈哌齐和虾青素，透射电镜下呈球形形态，在 4-8±2°C 下可稳定保存 6 个月。差示扫描量热法显示，多奈哌齐和虾青素以无定形状态分子分散在 NLC 基质中。与 AD 样未治疗大鼠和多奈哌齐-NLC 治疗大鼠相比，DPL/AST-NLC 治疗大鼠的核因子-κB、丙二醛、β 位淀粉样前体蛋白裂解酶-1、半胱天冬酶-3、淀粉样β（Aβ）和乙酰胆碱酯酶水平显著降低，而谷胱甘肽和乙酰胆碱水平显著升高，皮质和海马组织。DPL/AST-NLCs 表现出更高的抗淀粉样变性、抗氧化、抗乙酰胆碱酯酶、抗炎和抗细胞凋亡作用，导致皮质和海马组织病理学显著改善。
DPL/AST-NLCs 的经鼻递药是治疗 AD 的一种有前途的策略。
