Melatonin: new applications in clinical and veterinary medicine, plant physiology and industry.

Novel functions of melatonin continue to be uncovered. Those summarized in this report include actions at the level of the peripheral reproductive organs and include functions as an antioxidant to protect the maturing oocyte in the vesicular follicle and during ovulation, melatonin actions on the developing fetus particularly in relation to organizing the circadian system, its potential utility in combating the consequences of pre-eclampsia, reducing intrauterine growth restriction, suppressing endometriotic growths and improving the outcomes of in vitro fertilization/embryo transfer. The inhibitory effects of melatonin on many cancer types have been known for decades. Until recently, however, melatonin had not been tested as a protective agent against exocrine pancreatic tumors. This cancer type is highly aggressive and 5 year survival rate in individuals with pancreatic cancer is very low. Recent studies with melatonin indicate it may have utility in the treatment of these otherwise almost untreatable pancreatic cancers. The discovery of melatonin in plants has also opened a vast new field of research which is rapidly being exploited although the specific functions(s) of melatonin in plant organs remains enigmatic. Finally, the described application of melatonin's use as a chemical reductant in industry could well serve as a stimulus to further define the utility of this versatile molecule in new industrial applications.

The use of melatonin to combat mustard toxicity. REVIEW.

Among the most readily available chemical warfare agents, sulfur mustard (SM) has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Oxidative stress is the first and key event in the pathogenesis of SM toxicity. The involvement of inducible nitric oxide (iNOS) in SM toxicity, however, also leads to elevated nitrosative stress; thus, the damage caused by SM is nitro-oxidative stress because of peroxynitrite (ONOO-) production. Once ONOO- is formed, it activates nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) leading to pro-inflammatory gene expression thereby promoting inflammation; additionally, ONOO- directly exerts harmful effects by damaging all biomolecules including lipids, proteins and DNA within cells. DNA damage is sensed by an important DNA repair enzyme, poly (ADP-ribose) polymerase (PARP); this enzyme repairs molecular damage by using nicotinamide adenine dinucleotide (NAD+) as a substrate. Over-activation of PARP, due to severe DNA damage, consumes vast amounts of the respiratory coenzyme NAD+ leading to a cellular energy crisis. This pathophysiologic mechanism eventually results in cellular dysfunction, apoptosis or necrosis. Therefore, classic antioxidants may have limited beneficial effects on SM toxicity. Melatonin is a multifunctional indolamine which counteracts virtually all pathophysiologic steps and displays significant beneficial effects against ONOO--induced cellular toxicity. Melatonin has the capability of scavenging both oxygen and nitrogen-based reactants including ONOO- and blocking transcriptional factors which induce pro-inflammatory cytokines. The delayed toxicity of SM, however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Therefore, as a putative epigenetic modulator, melatonin may also be beneficial to subjects with delayed toxicity of SM.

Melatonin reduces oxidative/nitrosative stress due to drugs, toxins, metals, and herbicides.

The purpose of this brief review is to introduce the reader to the vast amount of published literature related to the free radical scavenging and antioxidative activity of melatonin. However, this review summarizes only a few of the many conditions in which melatonin has been found to be protective against oxidative/nitrosative damage. Melatonin ameliorates the extensive free radical-mediated damage that ensues following exposure to a wide variety of environmental insults. Concisely reviewed in this report are the protective effects of melatonin against toxic prescription drugs, neural toxins, herbicides and metals. The findings have clear implications for the utility of melatonin in toxicology.

Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites.

N-acetyl-5-methoxytryptamine (melatonin) is an endogenous indoleamine produced by all vertebrate organisms. Its production in the pineal gland has been extensively investigated but other organs also synthesize this important amine. Melatonin's functions in organisms are diverse. The actions considered in the current review relate to its ability to function in the reduction of oxidative stress, i.e., molecular damage produced by reactive oxygen and reactive nitrogen species. Numerous publications have now shown that not only is melatonin itself an efficient scavenger of free radicals and related reactants, but so are its by-products cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and others. These derivatives are produced sequentially when each functions in the capacity of a free radical scavenger. These successive reactions are referred to as the antioxidant cascade of melatonin. That melatonin has this function within cells has been observed in studies employing time lapse conventional, confocal and multiphoton fluorescent microscopy coupled with the use of appropriate mitochondrial-targeted fluorescent probes. The benefits of melatonin and its metabolites have been described in the brain where they are found to be protective in models of Parkinson's disease, Alzheimer's disease and spinal cord injury. The reader is reminded, however, that data not covered in this review has documented beneficial actions of these amines in every organ where they have been tested. The outlook for the use of melatonin in clinical trials looks encouraging given its low toxicity and high efficacy.

Melatonin: reducing molecular pathology and dysfunction due to free radicals and associated reactants.

Endogenously produced metabolites of ground state oxygen are highly reactive and destructive to intracellular and extracellular molecules. The resulting damage, referred to as oxidative stress, leads to molecular and cellular dysfunction. The destruction of essential macromolecules by oxygen-based reactants is the basis of some diseases and is believed to be involved in the processes of aging. Free radical scavengers and antioxidants neutralize and/or metabolically remove reactive species from cells before they carry out their destructive activities. Melatonin is a highly ubiquitous direct free radical scavenger and indirect antioxidant. This brief report summarizes the interactions of melatonin with reactive species and identifies the resulting products. The paper also defines the melatonin antioxidant cascade wherein not only melatonin but at least one of the products, i.e., N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, formed as a result of melatonin scavenging hydrogen peroxide is also a potent scavenger. The review summarizes the data which shows that melatonin is not only a pharmacologically useful free radical scavenger but that it functions in this capacity at physiological concentrations as well. Finally, this report identifies high oxidative stress situations in humans where melatonin has proven effective in reducing the severity of the disease state. In the last decade there have been hundreds of publications documenting melatonin's protective actions against a vast array of conditions, e.g., ischemia/reperfusion injury, toxin exposure, lipopolysaccharide exposure, etc., where free radical damage is a component of the condition.