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<p>Type 2 diabetes mellitus (T2DM) increases the risk of hippocampal neurodegeneration and cognitive decline. Berberine and metformin independently activate AMPK and may engage Nrf2-mediated antioxidant defenses, yet their combined neuroprotective interaction has not been formally quantified using validated synergy frameworks, nor has its pharmacokinetic basis been verified. Streptozotocin–nicotinamide diabetic rats were allocated to twelve groups (<i>n</i> = 13/group) receiving berberine (50, 100, 150&#xa0;mg/kg/day) or metformin (100, 200, 300&#xa0;mg/kg/day) monotherapy, fixed-ratio 1:2 combinations, or vehicle controls (including a non-diabetic combination group) orally for six weeks. The novel object recognition (NOR) discrimination index served as the predefined primary endpoint for Chou–Talalay combination index (CI) analysis. Hippocampal mechanistic (<i>n</i> = 6/group) and satellite LC–MS/MS pharmacokinetic (<i>n</i> = 6/group) analyses were performed. Diabetes impaired NOR discrimination index (37.2 ± 3.8% vs. 68.4 ± 3.2%; <i>p</i> &lt; 0.001). The reference combination (100 + 200&#xa0;mg/kg) restored NOR to 67.1 ± 3.6% with CI = 0.65 (95% CI: 0.43–0.91), synergism maintained across the full effect range. All six neuroinflammatory endpoints achieved Benjamini–Hochberg-corrected significance (<i>p</i>_adj = 0.006–0.043; Tier 2). Non-diabetic combination animals showed reduced AMPK activation magnitude (1.53 vs. 2.31-fold; <i>P</i>_adj = 0.067; Tier 3, hypothesis-generating). LC–MS/MS verified bioequivalent drug exposure. Berberine–metformin co-treatment is associated with CI-quantified supra-additive recognition memory recovery in diabetic encephalopathy, with neuroinflammatory suppression as the most statistically robust mechanistic correlate. Pharmacokinetic findings are consistent with a pharmacodynamic rather than pharmacokinetic basis. Causal involvement of the AMPK–Nrf2 axis remains correlative pending direct loss-of-function validation.</p> Graphical abstract <p></p>

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Supra-additive neuroprotective effects of berberine–metformin combination in diabetic encephalopathy: Chou–Talalay synergy quantification, AMPK–Nrf2 axis modulation, and pharmacokinetic verification

  • 期刊论文

  • 发表日期：

    2026年7月2日

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  • Wessam M. Filfilan,
  • Mohamed E. Elbeeh

摘要

Type 2 diabetes mellitus (T2DM) increases the risk of hippocampal neurodegeneration and cognitive decline. Berberine and metformin independently activate AMPK and may engage Nrf2-mediated antioxidant defenses, yet their combined neuroprotective interaction has not been formally quantified using validated synergy frameworks, nor has its pharmacokinetic basis been verified. Streptozotocin–nicotinamide diabetic rats were allocated to twelve groups (n = 13/group) receiving berberine (50, 100, 150 mg/kg/day) or metformin (100, 200, 300 mg/kg/day) monotherapy, fixed-ratio 1:2 combinations, or vehicle controls (including a non-diabetic combination group) orally for six weeks. The novel object recognition (NOR) discrimination index served as the predefined primary endpoint for Chou–Talalay combination index (CI) analysis. Hippocampal mechanistic (n = 6/group) and satellite LC–MS/MS pharmacokinetic (n = 6/group) analyses were performed. Diabetes impaired NOR discrimination index (37.2 ± 3.8% vs. 68.4 ± 3.2%; p < 0.001). The reference combination (100 + 200 mg/kg) restored NOR to 67.1 ± 3.6% with CI = 0.65 (95% CI: 0.43–0.91), synergism maintained across the full effect range. All six neuroinflammatory endpoints achieved Benjamini–Hochberg-corrected significance (p_adj = 0.006–0.043; Tier 2). Non-diabetic combination animals showed reduced AMPK activation magnitude (1.53 vs. 2.31-fold; P_adj = 0.067; Tier 3, hypothesis-generating). LC–MS/MS verified bioequivalent drug exposure. Berberine–metformin co-treatment is associated with CI-quantified supra-additive recognition memory recovery in diabetic encephalopathy, with neuroinflammatory suppression as the most statistically robust mechanistic correlate. Pharmacokinetic findings are consistent with a pharmacodynamic rather than pharmacokinetic basis. Causal involvement of the AMPK–Nrf2 axis remains correlative pending direct loss-of-function validation.

Graphical abstract