Homoplantaginin regulates various pharmacological pathways: Candidate drugs for multi-target relief of cognitive decline and pathological changes in Alzheimer’s disease

Alzheimer's disease is an age-associated neurodegenerative disorder with a complex pathogenesis. As a result, multi-target drug strategies have emerged in the development of anti- Alzheimer's disease medications. Natural compounds exhibit various pharmacological effects and low toxicity, making them beneficial for multifaceted intervention. Considering that NOD-like receptor protein 3 inflammasome-mediated inflammation is crucial for the treatment of Alzheimer's disease, we identified natural NOD-like receptor protein 3 inhibitors using molecular docking and a lipopolysaccharide/adenosine triphosphate-induced J774A.1 cell inflammation model. We found that homoplantaginin stably bound to NOD-like receptor protein 3, and surface plasmon resonance experiments further demonstrated that its binding affinity was 86.30 μM. Moreover, homoplantaginin effectively inhibited inflammation mediated by NOD-like receptor protein 3 inflammasome activation in J774A.1 cells by reducing the levels of interleukin-1β, interleukin-18, mature interleukin-1β (p17), and active caspase-1 (p20). Additionally, homoplantaginin treatment inhibited apoptosis and oxidative damage in L-glutamate-induced PC12 cells, as well as in aluminum chloride and D-galactose-induced Alzheimer's disease mice. The effects of homoplantaginin on Alzheimer's disease-like behavioral impairments were evaluated using the open field test, Y-maze, and Morris water maze. Results showed that there was no effect on control mice after administration of homoplantaginin once daily for 30 consecutive days, while locomotor and cognitive impairments in Alzheimer's disease mice were significantly alleviated, exhibiting superior efficacy compared with the positive drug donepezil. Importantly, consistent with the observations in J774A.1 cells, homoplantaginin inhibited the activation of the NOD-like receptor protein 3 inflammasome in the serum and brain tissues of Alzheimer's disease mice. NOD-like receptor protein 3 knockout hindered the improvement effect of homoplantaginin on cognitive deficits in Alzheimer's disease zebrafish induced by AlCl3 and D-gal, indicating that homoplantaginin enhances cognitive function by inhibiting activation of NOD-like receptor protein 3. Furthermore, homoplantaginin treatment reduced amyloid-beta deposition, oxidative stress, and apoptosis in Alzheimer's disease mice. Notably, aging is a major risk factor for Alzheimer's disease, and homoplantaginin prevented cellular senescence by regulating related biomarker levels in Alzheimer's disease mice. These results demonstrate that homoplantaginin may serve as a promising multifunctional candidate for the treatment of Alzheimer's disease.