Interface potential-induced natural antioxidant mimic system for the treatment of Alzheimer’s disease

Alzheimer's disease (AD), a leading cause of dementia, is characterized by mitochondrial dysfunction, central nervous system inflammation, and imbalanced antioxidant capacity. While antioxidant therapy is a preferred treatment approach, existing methods face limitations due to single mechanisms of action, insufficient bioavailability, and blood-brain barrier penetration challenges. The human body's antioxidant defense system comprises both enzymatic (SOD, catalase, GSH-Px) and non-enzymatic (vitamin C, glutathione, tocopherols, etc.) components. This research aimed to overcome existing limitations by creating a synergistic antioxidant system mimicking this natural defense mechanism. The researchers hypothesized that combining the enzymatic activity of a MOF with the non-enzymatic properties of curcumin would lead to a more effective treatment for AD.

The literature review extensively covers the existing antioxidant therapies for AD and their limitations. It highlights the inadequacy of single-agent antioxidant therapies and emphasizes the need for synergistic approaches that combine enzymatic and non-enzymatic antioxidants to mimic the body's natural defense mechanisms. The review also mentions the challenges associated with bioavailability and blood-brain barrier penetration, which are critical considerations in the development of effective AD treatments.

The researchers synthesized a ZnBTC MOF using a hydrothermal method, characterized by SEM, TEM, XRD, and N2 adsorption-desorption experiments. Curcumin was then loaded into ZnBTC using a solvent adsorption method to create CUR@ZnBTC. The characterization included analysis of morphology, crystallinity, surface area, pore size, and thermal properties. Drug release studies were conducted under various pH conditions to assess the release profile of curcumin from the MOF. The antioxidant activity of CUR@ZnBTC was evaluated using ABTS and DPPH radical scavenging assays, and the SOD-like activity was determined using pyrogallol autoxidation inhibition assays. Finally, the therapeutic effect of CUR@ZnBTC on AD was investigated using 5xFAD mice through behavioral tests (grip strength, hanging wire, and transfer tests) and immunohistochemical analysis of Aβ plaques in the hippocampus.

CUR@ZnBTC nanoparticles were successfully synthesized, showing a rod-like morphology. The loading efficiency of curcumin in ZnBTC was approximately 47.3%. Drug release studies revealed a slower release rate at physiological pH (7.4), suggesting sustained release. CUR@ZnBTC exhibited significant ABTS and DPPH radical scavenging activity and SOD-like enzyme activity. In vivo studies using 5xFAD mice demonstrated that CUR@ZnBTC significantly improved grip strength, reduced Aβ plaque deposition in the hippocampus, and enhanced cognitive and motor function compared to the control and single-agent groups. Importantly, the treatment showed no apparent toxicity to major organs.

The findings demonstrate the successful creation and validation of a synergistic antioxidant system for AD treatment. The combination of ZnBTC's SOD-like activity and curcumin's non-enzymatic antioxidant and anti-inflammatory properties resulted in a superior therapeutic effect compared to individual components. The sustained release of curcumin from the MOF at physiological pH is crucial for maintaining therapeutic levels in the brain. The positive behavioral outcomes and reduced Aβ plaque deposition in 5xFAD mice strongly suggest the potential of this approach as a new therapeutic strategy for AD. The lack of toxicity further supports the safety and efficacy of CUR@ZnBTC.

This study successfully developed CUR@ZnBTC, a synergistic antioxidant system for AD treatment. The combination of ZnBTC and curcumin resulted in improved Aβ scavenging, reduced oxidative stress, and enhanced cognitive function in AD mice, showing promise for the development of safe and effective AD therapeutics. Future research may focus on optimizing the MOF structure and exploring other potential synergistic combinations to further enhance efficacy.

The study utilized a mouse model of AD, which may not fully replicate the complex pathophysiology of human AD. Further studies in larger animal models and clinical trials are needed to confirm the findings. The long-term effects of CUR@ZnBTC and potential side effects require further investigation.