Melatonin attenuates hyperglycemia-induced platelet dysfunction by preserving redox balance and mitochondrial...

Hyperglycemia is a characteristic feature of diabetes mellitus and is strongly associated with thrombotic risks due to platelet hyperreactivity contributing significantly to morbidity and mortality. Oxidative stress-driven platelet activation, mitochondrial dysfunction, and metabolic dysregulation are key mechanisms contributing to platelet dysfunction in hyperglycemia. Therefore, preventing platelet dysfunction could be a promising therapeutic approach to reduce thrombotic risk and mortality in patients with diabetes. In this study, we investigated the effects of high glucose on platelet activation, aggregation, and apoptosis and evaluated the protective effects of melatonin against high glucose-induced platelet dysfunction, with a particular focus on the underlying molecular mechanisms. The results suggest that exposure to high glucose primes platelets for activation, aggregation, and apoptosis. Mechanistic studies have shown that high glucose promote oxidative stress by increasing aldose reductase and NADPH oxidase activities while reducing glutathione reductase activity, resulting in disruption of redox homeostasis. Furthermore, oxidative stress-triggered mitochondrial dysfunction, endoplasmic reticulum stress, and cytoskeletal remodelling are crucial mechanisms that promote platelet dysfunction. Interestingly, melatonin as a redox modulator, markedly counteracted high glucose-induced oxidative stress by suppressing ROS generation, restoring intracellular calcium and redox homeostasis, preserving mitochondrial function, and alleviating endoplasmic reticulum stress, thereby preventing platelet activation, aggregation, and apoptosis. These protective effects of melatonin are predominantly mediated through melatonin receptor 1 signaling in platelets. Together, these findings demonstrate that hyperglycemia promotes oxidative stress-mediated platelet dysfunction, whereas melatonin represents a potential therapeutic strategy to attenuate oxidative stress, platelet hyperreactivity, and diabetes-associated thrombotic complications.