Department of Studies in Biochemistry, University of Mysore, Mysore 570006, India.
Biochem Biophys Res Commun. 2013 Aug 16;438(1):198-204. doi: 10.1016/j.bbrc.2013.07.053. Epub 2013 Jul 20.
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.
褪黑素是一种调节昼夜节律和季节性节律的松果腺激素。褪黑素的chronobiotic 作用与一系列药理学特性相对应。此外，它有广泛的治疗应用。然而，最近的研究表明它与血小板直接相互作用：在生理浓度下，它促进血小板聚集；另一方面，在药理剂量下，它会提高细胞内 Ca(2+)，导致血小板激活、血栓形成和心血管疾病。为了进一步研究其对血小板的影响，本研究针对血小板凋亡，发现褪黑素刺激凋亡。由于其易受氧化应激诱导因素（包括治疗和饮食因素）的影响，主要研究了凋亡的线粒体途径。褪黑素显著增加了细胞内 ROS 和 Ca(2+)的产生，促进了线粒体膜去极化、细胞色素 c 释放、半胱天冬酶激活、蛋白磷酸化和磷脂酰丝氨酸外化。此外，通过 MTT 和乳酸脱氢酶测定进一步证实了褪黑素对血小板的整体毒性。血小板凋亡率的升高会导致严重后果，包括血小板减少症。此外，正在凋亡的血小板释放微粒，这些微粒会促进血栓形成，并在许多疾病的病理生理学中发挥重要作用。在世界上许多地方，褪黑素是一种非处方膳食补充剂和替代药物。由于褪黑素在可通过治疗剂量达到的浓度下显示出促血小板凋亡作用，因此本研究向长期使用褪黑素作为治疗药物发出了警告信号，并对其在没有处方的情况下的可用性提出了质疑。
