Highly pleiotropic compound

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Highly pleiotropic compound

Highly pleiotropic compound

The indoleamine melatonin (N-acetyl-5-methoxytryptamine), once discovered as a pineal hormone with skin lightening properties in fish and amphibia, later identified as a major regulator of seasonal and circadian rhythms, is now known to represent a highly pleiotropic compound produced in various tissues and exerting numerous, highly divergent effects.

This remarkable diversity appears to be the consequence of a progressive gain of functions, from a primary, ancient protection against reactive intermediates to the more recently acquired regulation of circadian, immunological, reproductive and neurobiological mechanisms that have ended up, in vertebrates, in an orchestrating, highly versatile role. Therefore, it seems important to perceive melatonin neither only in its chronobiotic function nor simply as a radical scavenger, but rather as a compound acting in a complex manner at different levels of integration.

As will be outlined in this review, part of this complexity is reflected by melatonin’s multiple interactions with reactive nitrogen species (RNS). This comprises chemical reactions with various nitrogen-containing compounds and regulatory influences as well, at the levels of organelles, especially mitochondria, of cells and tissues.

These control mechanisms are also of considerable pathophysiological interest. Moreover, melatonin should be seen in relation to its metabolites. Especially one of its kynuramine derivatives, N1- acetyl-5-methoxykynuramine (AMK), displays properties as a potent regulator and scavenger of nitric oxide (NO).

The ensemble of modulatory effects exerted by melatonin and AMK seems to substantially contribute to the avoidance of dysfunctions at mitochondrial and cellular levels, including possible consequences for apoptosis, inflammation- related necrosis and, presumably, also parthanatos and autophagy.

Prevention of NO-dependent Ca2+ overload and NO-promoted mitochondrial dysfunction by the indoleamine and its metabolite should be perceived in its significance for attenuation of free radical generation in more general terms, including the formation of organic, oxygen and carbonate radicals. From a pathophysiological point of view, the importance of radical avoidance exceeds by far the solely biochemical aspects of damaged biomolecules to be replaced or repaired. Partial blockades within the mitochondrial electron transport chain (ETC), which lead to electron leakage and, thus, secondarily augmented radical formation, also cause ATP deficiency and, eventually, cytochrome c release that initiates apoptosis.

Especially in neurons, ETC malfunction can change the mitochondrial fragmentation/fission balance, which ultimately leads to losses of peripheral mitochondria, synaptic function and connectivity. Tyrosine nitration, another consequence of enhanced NO formation, is potentiated especially in conjunction with high CO2/HCO3– levels, which are normally present in mitochondria, but may become relevant in the cytosol or body fluids during hypoxia/hypercapnia because of impaired blood flow and also in ischemia/reperfusion.

This type of protein modification can result, among other effects, in dysfunctional reuptake of neurotransmitters that further promotes neuronal overexcitation, or, in the circulation, to modified atherosclerotic plaque proteins which are more resistant to degradation.

These scenarios shed light on the potential value of compounds that allow NO synthases (NOS) to operate at low or moderately enhanced activities, but are, on the other hand, capable of preventing extreme, disadvantageous rises of NO with its deleterious consequences. Melatonin seems to fulfill these requirements.

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