Real-Time Fast Scan Cyclic Voltammetry Detection and Quantification of Exogenously Administered Melatonin in Mice Brain

Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

Melatonin has been shown to protect against oxidative stress in various, highly divergent experimental systems. There are many reasons for its remarkable protective potential. Signaling effects comprise the upregulation of antioxidant enzymes, such as superoxide dismutases, peroxidases, and enzymes of glutathione supply, down-regulation of prooxidant enzymes, such as nitric oxide synthases and lipoxygenases, and presumably also the control of quinone reductase 2. Other mechanisms are based on direct interactions with several reactive oxygen and nitrogen species. Among these reactions, the capacity of easily undergoing single-electron transfer reactions is of particular importance. Electron donation by melatonin is not only an aspect of direct radical scavenging, but additionally represents the basis for formation of the protective metabolites AFMK (N1-ace-tyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine). Recent investigations on mitochondrial metabolism indicate that melatonin as well as AMK are capable of supporting the electron flux through the respiratory chain, of preventing the breakdown of the mitochondrial membrane potential, and of decreasing electron leakage, thereby reducing the formation of superoxide anions. Radical avoidance is a new line of investigation, which exceeds mitochondrial actions and also comprises antiexcitatory effects and contributions to the maintenance of internal circadian phase relationships.

Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.