Inflammopharmacology · 2025
Repurposing amlexanox as a topical anti-inflammatory and antioxidant intervention for diabetic foot ulcers: insights from in-silico and in-vivo studies.
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Kapoor Nishika, Dhaliwal Navneet, Dhaliwal Jatinder, Chopra Kanwaljit
Аннотация
BACKGROUND: Diabetic foot ulcers (DFUs), a debilitating manifestation of diabetes mellitus, involve persistent inflammation, oxidative stress, and impaired wound healing, largely driven by NF-κB overactivation. Amlexanox (ALX), a synthetic anti-inflammatory and antioxidant agent, was evaluated for its therapeutic potential in DFUs.
METHODS: In-silico molecular docking and pharmacokinetic studies were conducted to predict ALX's interactions with major DFU targets and to assess its topical suitability. STZ-induced diabetic rats with full-thickness foot ulcers (5 mm) received topical ALX (2.5% and 5%) or silver sulfadiazine ointments for 14 days. Wound closure, antioxidant enzymes, oxidative stress markers, connective tissue markers, pro-inflammatory markers and NF-κB expression were assessed in the wound tissue.
RESULTS: ALX demonstrated strong binding to the pathological targets (NF-κB, MMP-9, MPO, and COX-2) and displayed a favourable PK profile. Moreover, ALX topical treatment did not normalise diabetic metabolic alterations, but it dose-dependently promoted wound healing. Indeed, ALX 5% significantly accelerated wound closure (p < 0.0001) and led to marked suppression of NF-κB and MMP-9 expression (p < 0.0001). It also enhanced the levels of connective tissue markers, including hexosamine (p < 0.001), hydroxyproline, and hexuronic acid (p < 0.0001). Robust anti-inflammatory effects were also observed, as ALX reduced IL-1β, IL-6, TNF-α levels and COX-2 activity (p < 0.0001). Furthermore, ALX 5% diminished oxidative stress by lowering LPO, PCO, and MPO levels (p < 0.0001), and restoring GSH levels and SOD and CAT (p < 0.001) activities indicating its anti-oxidant properties.
CONCLUSION: Taken together, the present work highlights the mechanisms associated with ALX mediated wound healing in diabetic rats thereby demonstrating its potential as a promising strategy for DFU management.
METHODS: In-silico molecular docking and pharmacokinetic studies were conducted to predict ALX's interactions with major DFU targets and to assess its topical suitability. STZ-induced diabetic rats with full-thickness foot ulcers (5 mm) received topical ALX (2.5% and 5%) or silver sulfadiazine ointments for 14 days. Wound closure, antioxidant enzymes, oxidative stress markers, connective tissue markers, pro-inflammatory markers and NF-κB expression were assessed in the wound tissue.
RESULTS: ALX demonstrated strong binding to the pathological targets (NF-κB, MMP-9, MPO, and COX-2) and displayed a favourable PK profile. Moreover, ALX topical treatment did not normalise diabetic metabolic alterations, but it dose-dependently promoted wound healing. Indeed, ALX 5% significantly accelerated wound closure (p < 0.0001) and led to marked suppression of NF-κB and MMP-9 expression (p < 0.0001). It also enhanced the levels of connective tissue markers, including hexosamine (p < 0.001), hydroxyproline, and hexuronic acid (p < 0.0001). Robust anti-inflammatory effects were also observed, as ALX reduced IL-1β, IL-6, TNF-α levels and COX-2 activity (p < 0.0001). Furthermore, ALX 5% diminished oxidative stress by lowering LPO, PCO, and MPO levels (p < 0.0001), and restoring GSH levels and SOD and CAT (p < 0.001) activities indicating its anti-oxidant properties.
CONCLUSION: Taken together, the present work highlights the mechanisms associated with ALX mediated wound healing in diabetic rats thereby demonstrating its potential as a promising strategy for DFU management.