Melatonin has long been recognized as the central modulator of circadian rhythms. More recently, as highlighted a number of times in recent editions of TherapeuticAdvances, this neurotransmitter is also involved in vascular and neuroimmunological function. The involvement of melatonin in vascular (patho)physiology is due, at least in part, to its potent antioxidant activity and its direct free radical scavenging ability. Hence melatonin or its mimics may offer a therapeutic approach to ischemia. This possibility was recently demonstrated by researchers who reported a dramatic improvement in the survival rate of rats with coronary artery occlusion. This was paralleled by a reduction in infarct size, superoxide anion production and neutrophil infiltration. Likewise, pretreatment with melatonin protects against focal cerebral ischemia. In related studies, researchers have demonstrated that melatonin may exert its anti-ischemic activity through a reduction in apoptosis. This may be of importance not only to acute neural cell death but also those diseases associated with more long-term neurodegeneration such as Alzheimer's disease. Indeed melatonin has been shown to reduce beta amyloid-induced apoptosis. As well as having direct scavenging activity, melatonin is able to evoke MT(1), MT(2), and MT(3) receptor as well as nuclear receptor mediated events. The MT(1) receptor has been implicated in tumorigenesis, and in particular breast cancer progression. Subcutaneous injections of melatonin have been shown to inhibit, and pinealectomy to enhance, the development of mammary tumors in rats. Furthermore, breast cancer patients have low levels of serum melatonin and those patients with higher levels have an improved prognosis. On the other hand, tumors sampled from patients over-express MT(1) receptors. In vitro melatonin can almost totally block the proliferation of MCF-7 breast cancer cell lines, an effect that appears to be mediated by the MT(1) receptor, suggesting that agonists of this receptor may be of use in the treatment of breast cancer. Finally, melatonin appears to play a role in the expanding field of neuroimmunology. T-helper cells express melatonin receptors and their activation enhances the release of cytokines that may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Through its pro-inflammatory action, melatonin may also play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of melatonin and their synovial macrophages respond to melatonin with an increased production of IL-12 and nitric oxide. In these patients, inhibition of melatonin synthesis or use of melatonin receptor antagonists might have a therapeutic effect. In summary therefore, melatonin and its receptor ligands have considerable potential in a host of serious and common human conditions and increased pharmaceutical activity in this field may result in the emergence of improved therapeutic options. To date development activity has been limited and is almost entirely restricted to the treatment of sleep or affective disorders and hence further advances are eagerly awaited.

Entry date September, 2002

Adapted from Maestroni et al, Ann N Y Acad Sci 2002 Jun;966:271-5

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