Possible role of the mitochondrial pyruvate dehydrogenase in ketorolac mediated onset and progression of gastric ulcers in male Wistar rats: Protection by melatonin.

Ketorolac tromethamine (KT), a nonsteroidal anti-inflammatory drug, is widely used to treat pain. However, its use is often associated with gastric ulceration, which is attributed to cyclooxygenase-1 inhibition. This study investigates the effect of KT on energy metabolism enzymes in gastric mucosae, revealing a novel mechanism of pyruvate dehydrogenase (PDH) inhibition. Furthermore, our preliminary findings led us to extensively characterize the enzyme PDH using a multi-technique approach, comprising PCR for expressional analysis, CD spectroscopy for structural evaluation, isothermal titration calorimetry for thermodynamic characterization and kinetic studies for functional assessment. Our findings demonstrate that KT directly interacts with PDH, disrupting the glycolysis-Krebs' cycle link, reducing ATP production, and increasing free radical species generation. Pre-treatment with melatonin mitigates KT-induced gastric ulceration and prevents alterations in energy metabolism enzymes. This study provides new insights into the molecular mechanisms underlying KT-induced gastric ulceration, highlighting a potential therapeutic strategy.