title: Melatonin elevates apoptosis in human platelets via ROS mediated mitochondrial damage.
abstract: Melatonin is a pineal hormone that regulates circadian and seasonal rhythms. The chronobiotic role of melatonin corresponds with a repertoire of pharmacological properties. Besides, it has a wide range of therapeutic applications. However, recent studies have demonstrated its direct interaction with platelets: at physiological concentration it promotes platelet aggregation; on the other hand, at pharmacological doses it raises intracellular Ca(2+) leading to platelet activation, thrombus formation and cardiovascular disorders. In order to further probe its effects on platelets, the current study targeted platelet apoptosis and melatonin was found to stimulate apoptosis. The mitochondrial pathway of apoptosis was mainly investigated because of its susceptibility to oxidative stress-inducing factors including therapeutic and dietary elements. Melatonin significantly increased the generation of intracellular ROS and Ca(2+), facilitating mitochondrial membrane depolarization, cytochrome c release, caspase activation, protein phosphorylation and phosphatidylserine externalization. Further, the overall toxicity of melatonin on platelets was confirmed by MTT and lactate dehydrogenase assays. The elevated rate of platelet apoptosis has far reaching consequences including thrombocytopenia. Besides, platelets undergoing apoptosis release microparticles, which fuel thrombus formation and play a significant role in the pathophysiology of a number of diseases. In many parts of the world melatonin is an over-the-counter dietary supplement and alternative medicine. Since, melatonin displays platelet proapoptotic effect at a concentration attainable through therapeutic dosage, the present study sends a warning signal to the chronic use of melatonin as a therapeutic drug and questions its availability without a medical prescription.
authors.affiliation: Department of Studies in Biochemistry, University of Mysore, Mysore 570006, India. ksgbaboo@gmail.com
authors.forename: Kesturu Subbaiah
authors.initials: KS
authors.lastname: Girish
authors.forename: Manoj
authors.initials: M
authors.lastname: Paul
authors.forename: Ram Mohan
authors.initials: RM
authors.lastname: Thushara
authors.forename: Mahadevappa
authors.initials: M
authors.lastname: Hemshekhar
authors.forename: Mahalingam
authors.initials: M
authors.lastname: Shanmuga Sundaram
authors.forename: Kanchugarakoppal Subbegowda
authors.initials: KS
authors.lastname: Rangappa
authors.forename: Kempaiah
authors.initials: K
authors.lastname: Kemparaju
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008550:Melatonin / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D063306:Mitophagy / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D008550:Melatonin
keywords: Caspases; Intracellular calcium; Melatonin; Mitochondrial damage; Platelet apoptosis