Bioavailability enhancement and neuropharmacological effects of Dauricine under intranasal administration to improve cognitive impairment via PI3K/AKT/mTOR pathway.

Alzheimer's disease (AD) is a neurodegenerative disorder strongly associated with aging, and Dauricine (DAU) has demonstrated significant neuropharmacological properties for AD treatment. However, its bioavailability is significantly limited when administered orally, leaving the mechanisms underlying its effects on AD largely unexplored. In this study, a DAU-loaded thermosensitive gel was formulated for delivery via the nasal-nerve route, and its potential to enhance the bioavailability of DAU in rat plasma and cerebrospinal fluid (CSF) was assessed through a pharmacokinetic study. The anti-Alzheimer's disease (AD) mechanism of DAU was investigated using network pharmacology approaches, molecular docking, and dynamics simulations, complemented by in vivo experimental validation. DAU can be effectively incorporated into a thermosensitive gel and administered to the brain within 30 min via intranasal delivery. Following nasal administration, the pharmacokinetic parameters of DAU in cerebrospinal fluid and plasma were significantly elevated compared to oral administration (P < 0.01), indicating a substantial improvement in bioavailability at equivalent doses. Behavioral studies demonstrated that DAU (dose of 1 mg/kg and 2 mg/kg in gel) enhanced cognitive function in intracerebroventricular-streptozotocin (ICV-STZ) rats and decelerated aging processes by reversing oxidative stress and mitigating neuronal apoptosis. Additionally, DAU contributed to lowering blood glucose levels, increasing insulin-like growth factor 1 (IGF-1) content, and reducing insulin resistance. Network pharmacological analysis, molecular docking, molecular dynamics simulations, and in vivo experiments collectively suggested that DAU exerted significant therapeutic effects on Alzheimer's disease by inhibiting the PI3K/AKT/mTOR pathway. Our study demonstrates a significant enhancement in the bioavailability of DAU in the brain via nasal-nerve delivery route and also this research is the first to report that DAU ameliorates cognitive impairment in ICV-STZ rats through the PI3K/AKT/mTOR pathway. Our findings contribute to the scientific understanding of DAU's potential in Alzheimer's disease treatment and offer a novel experimental foundation for the development of anti-Alzheimer's drugs.