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

Amritpal Kaur; Shareen Singh; Manjinder Singh; Pragati Silakari; Ashi Mannan; Sukriti Vishwas; Puneet Kumar; Vetriselvan Subramaniyan; Thakur Gurjeet Singh

doi:10.1016/j.expneurol.2025.115634

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

Exp Neurol. 2026 Apr:398:115634. doi: 10.1016/j.expneurol.2025.115634. Epub 2025 Dec 31.

Authors

Amritpal Kaur¹, Shareen Singh², Manjinder Singh³, Pragati Silakari⁴, Ashi Mannan⁵, Sukriti Vishwas⁶, Puneet Kumar⁷, Vetriselvan Subramaniyan⁸, Thakur Gurjeet Singh⁹

Affiliations

¹ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: k.amritpal@chitkara.edu.in.
² Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: shareen.singh@chitkara.edu.in.
³ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: manjinder.singh@chitkara.edu.in.
⁴ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: pragati.silakari@chitkara.edu.in.
⁵ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: ashi.mannan@chitkara.edu.in.
⁶ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: sukriti.vishwas@chitkara.edu.in.
⁷ Department: Department of Pharmaceutical Sciences and Technology, Central University of Punjab, Bathinda 151001, India.
⁸ Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Selangor, Malaysia. Electronic address: vetris@sunway.edu.my.
⁹ Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India. Electronic address: gurjeet.singh@chitkara.edu.in.

PMID: 41482106
DOI: 10.1016/j.expneurol.2025.115634

Abstract

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.

Keywords: Alzheimer's disease (AD); Demethyleneberberine (DMB); In-silico; Insulin resistance; Neuroinflammation; Oxidative stress.

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides
Animals
Berberine* / analogs & derivatives
Berberine* / chemical synthesis
Berberine* / pharmacology
Berberine* / therapeutic use
Cognitive Dysfunction* / drug therapy
Diet, High-Fat / adverse effects
Disease Models, Animal
Insulin Resistance* / physiology
Male
Molecular Docking Simulation
Rats
Rats, Sprague-Dawley

Substances

Berberine
Amyloid beta-Peptides