Enhancing mitochondrial functions in neuroinflammatory mouse model using isoflavones-loaded nanoparticles: A potential approach for Alzheimer's disease treatment

• Published in: Journal of drug delivery science and technology 2024-11, Vol.101, p.106252, Article 106252
• Main Authors: Gad, Alaa A., Tammam, Salma N., Ilyas, Shaista, Mansour, Samar, Youssef, Yomna A., Farag, Karin S., Abdel-Kader, Reham M., Mathur, Sanjay
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Daidzein; Mitochondrial biogenesis; Nanoparticles; Neuroinflammatory animal model; PLGA
• ISSN: 1773-2247
• DOI: 10.1016/j.jddst.2024.106252

A significant reduction in mitochondrial functions, coupled with increased oxidative stress, is believed to trigger the histological changes associated with the Alzheimer's disease (AD). Daidzein (DEZ) and Daidzin (DZ), natural isoflavones, exhibit anti-oxidant properties and enhance mitochondrial biogenesis. However, their low solubility presents challenges for drug circulation and adversely affecting their bioavailability. Novel drug-delivery modalities capable of overcoming these limitations and facilitating brain delivery could enhance therapeutic outcomes. In this work, Tween 80-coated PLGA-NPs and chitosan-coated PLGA-NPs (CS-PLGA-NPs) loaded with DEZ and DZ were evaluated for their ability to enhance cognition in a neuroinflammatory mouse model. The hydrodynamic diameter and zeta potential were measured to be 62 ± 13 nm and −16.8 ±1 mV for PLGA-NPs and to 159 ± 5 nm and +31 ± 5 mV for CS-PLGA-NPs. Biodistribution studies revealed accumulation of both PLGA-NPs and CS-PLGA-NPs in the brain following intravenous administration to animals with neuroinflammation induced by lipopolysaccharides (LPS). Administration of drug-loaded NPs improved cognitive functions compared to untreated animals, in contrast to unloaded NPs or free DEZ and DZ. Animals treated with DEZ-CS-PLGA-NPs and DZ-CS-PLGA-NPs showed significant reductions in superoxide dismutase levels compared to those receiving LPS, suggesting a role in mitigating oxidative stress. When compared to animals receiving LPS, concentrations of Amyloid-β were markedly reduced and complex I activity and ATP levels were significantly increased in animals receiving drug-loaded NPs, unloaded NPs and free drugs, indicating enhanced mitochondrial functions. For drug delivery, CS-PLGA-NPs outperformed PLGA-NPs due sustained drug-release resulting in higher drug concentrations in the brain. [Display omitted]