Demethyleneberberine attenuates combined cognitive and metabolic dysfunctions in an insulin-resistance-induced Alzheimer's disease rat model: Synthesis, in-silico and in-vivo insights.

In this study, we evaluated the therapeutic potential of DMB, a berberine derivative known for its enhanced bioavailability and reduced toxicity. DMB was synthesized and administered orally at doses of 5 and 10 mg/kg in an in vivo rat model of insulin resistance-induced Alzheimer's disease (AD). This model was established using a combination of a high-fat diet (HFD), streptozotocin (35 mg/kg; intraperitoneally), and amyloid-β25-35. In-silico docking studies revealed that DMB exhibits a high binding affinity for key proteins implicated in both AD and diabetes, including insulin receptors, leptin receptors, protein tyrosine phosphatase 1B (PTP1B), HMG-CoA reductase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Molecular dynamics simulations confirmed the stable binding and inhibitory potential of Demethyleneberberine (DMB) against Insulin Receptor Tyrosine Kinase and AChE. Pharmacological network analysis indicated that DMB modulates multiple pathways involved in metabolic and cognitive decline, suggesting its promise as a therapeutic candidate for insulin resistance-induced AD. Neurobehavioral assessments demonstrated that DMB significantly (p < 0.001) improved cognitive function, ameliorated metabolic disruptions (elevated blood glucose and insulin levels), and normalized pro-inflammatory markers (Tumor Necrosis Factor-alpha (TNF-α), Interleukin 1-beta (IL-1β)) and oxidative stress parameters (Thiobarbituric Acid Reactive Substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). Additionally, DMB reduced levels of AD-related biomarkers, including BACE-1 (β-secretase 1), amyloid-β, and acetylcholinesterase, indicating its capacity to mitigate oxidative stress and amyloidogenesis. This multidisciplinary approach, integrating in vivo and in-silico methodologies, provides a comprehensive understanding of DMB's neuroprotective effects and underscores its potential as a therapeutic agent for both AD and diabetes.