This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Alpha-Lipoic Acid and Metformin Combination Therapy Synergistically Activate Nrf2-AMPK Signaling Pathways to Ameliorate Cognitive Dysfunction in Type 2 Diabetic Encephalopathy: A Preclinical Study
1
Genetic and Molecular Biology Central Laboratory (GMCL), Department of Biology, Jamoum University College, Umm Al-Qura University, Makkah 2203, Saudi Arabia
2
Department of Biology, Jamoum University College, Umm Al-Qura University, Makkah 2203, Saudi Arabia
3
Department of Zoology, Faculty of Science, Mansoura University, Mansoura 35516, Egypt
*
Author to whom correspondence should be addressed.
Biology 2025, 14(7), 885; https://doi.org/10.3390/biology14070885
Submission received: 22 June 2025
/
Revised: 11 July 2025
/
Accepted: 17 July 2025
/
Published: 18 July 2025
(This article belongs to the Special Issue Animal Models of Neurodegenerative Diseases)
Simple Summary
Diabetic encephalopathy, affecting over 40% of diabetic patients globally, represents a critical unmet medical need with limited therapeutic options. This study investigated whether combining alpha-lipoic acid (ALA), an FDA-approved antioxidant, with metformin, the first-line diabetes medication, could provide superior neuroprotection through synergistic pathway activation. Using a clinically relevant type 2 diabetes rat model, we demonstrated that combination therapy produces statistically validated synergistic effects (combination index < 1.0) across molecular, cellular, and behavioral endpoints. The combination restored brain energy metabolism (92% ATP recovery), normalized antioxidant defenses, and dramatically improved cognitive performance approaching control levels. Since both drugs are already safely used clinically, these findings support immediate translation to human trials for diabetic cognitive decline prevention.
Abstract
Diabetic encephalopathy affects over 40% of diabetic patients globally, yet effective treatments remain critically limited. This study investigated the synergistic neuroprotective potential of alpha-lipoic acid (ALA) and metformin through the coordinated activation of Nrf2 and AMPK signaling pathways in type 2 diabetes mellitus (T2DM)-induced encephalopathy. Using a clinically relevant streptozotocin-nicotinamide-induced T2DM rat model, sixty male Sprague–Dawley rats were randomly assigned to five groups: control, diabetic, ALA-treated (300 mg/kg), metformin-treated (50 mg/kg), and combination-treated groups over eight weeks. Combination therapy produced statistically validated synergistic effects with significant interaction terms (p < 0.01) across all evaluated parameters. Nuclear Nrf2 translocation increased 3.9-fold and AMPK phosphorylation rose 3.2-fold compared to monotherapies, surpassing mathematical additivity. Mitochondrial function was remarkably restored, with ATP production increasing to 92% of control levels. Cognitive performance was normalized, with spatial memory approaching control values. Combination index analysis (CI < 1.0) confirmed true synergistic interactions across molecular, cellular, and behavioral endpoints. These findings establish a novel convergent mechanism providing compelling evidence for combination ALA–metformin therapy as an innovative treatment strategy for diabetes-associated neurodegeneration.
