Melatonin may improve sleep in those with delayed sleep phase disorder but has no effect on primary sleep disorder ( 1 x 1 Ferguson, S.A., Rajaratnam, S.M., and Dawson, D. Melatonin agonists and insomnia. Expert Rev Neurother. 2010; 10: 305–318 Crossref | PubMed | Scopus (45) | Google Scholar See all References ) (1) . Melatonin may also improve initial sleep quality in older adults with insomnia ( 2 x 2 Olde Rikkert, M.G. and Rigaud, A.S. Melatonin in elderly patients with insomnia. A systematic review. Z Gerontol Geriatr. 2001; 34: 491–497 Crossref | PubMed | Scopus (89) | Google Scholar See all References ) (2) , but its role as a treatment for insomnia in those with Alzheimer disease remains disputed ( 3 x 3 Cardinali, D.P., Brusco, L.I., Liberczuk, C., and Furio, A.M. The use of melatonin in Alzheimer's disease. Neuro Endocrinol Lett. 2002; 23: 20–23 PubMed | Google Scholar See all References , 4 x 4 Singer, C., Tractenberg, R.E., Kaye, J., Schafer, K., Gamst, A., Grundman, M. et al. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003; 26: 893–901 PubMed | Google Scholar See all References ). Melatonin may also affect immune function as well as cancer initiation and growth ( 5 x 5 Fan, L.L., Sun, G.P., Wei, W., Wang, Z.G., Ge, L., Fu, W.Z. et al. Melatonin and doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines. World J Gastroenterol. 2010; 16: 1473–1481 Crossref | PubMed | Scopus (62) | Google Scholar See all References ) (5) . Melatonin is well tolerated with doses of up to 36 mg/d. However, these high doses may produce some adverse reactions: autoimmune hepatitis, confusion, optic neuropathy, fragmented sleep, psychotic episodes, nistagmus, seizures, headache, and skin eruptions ( 6 x 6 Morera, A.L., Henry, M., and de La Varga, M. Safety in melatonin use. Actas Esp Psiquiatr. 2001; 29: 334–337 PubMed | Google Scholar See all References ) (6) .

Apoptosis or programmed death is a biological phenomenon, which is essential for the development and maintenance of a cell population. In this process, senescent or damaged cells are eliminated after activation of a cell death program involving participation of pro-apoptotic molecules (Fas, Fas-L, Bax, caspases 2, 3, 6, 7, 8 and 9). Molecule activation causes typical morphological changes, such as cell shrinkage, loss of adhesion to the extracellular matrix and neighboring cells, chromatin condensation, DNA fragmentation and formation of apoptotic bodies. Anti-apoptotic molecules (Bcl-2, FLIP) block the emergence and evolution of these cell changes and prevent cell death. The balance between molecules pro and anti-apoptotic ensures tissue homeostasis. When apoptosis is out of control, it contributes to the emergence of several neoplastic, autoimmune and neurodegenerative diseases. Several inducing and inhibitors of apoptosis agents are recognized as potential weapons in the fight against diseases related to proliferation and cell death disorders among which stand out hormones. Melatonin has been reported as important anti-apoptotic agent in various tissues by reducing cell calcium uptake, modulating expression of anti-oxidants and decreasing pro-apoptotic protein, such as Bax. The knowledge of new agents capable to act on the course pf apoptosis is important and of great value for developing further therapies against many diseases. Thus, the objective of this review was to elucidate the main aspects of cell death by apoptosis and the role of melatonin in this process.

To analyze steroidogenesis-related gene expression in the rat ovary exposed to melatonin supplementation. Thirty-two virgin adult female rats were randomized to two groups as follows: the control group GI received vehicle and the experimental group GII received melatonin supplementation (10 µg/night per animal) for 60 consecutive days. After the treatment, animals were anesthetized and the collected ovaries were immediately placed in liquid nitrogen for complementary deoxyribonucleic acid microarray analyses. A GeneChip(®) Kit Rat Genome 230 2.0 Affymetrix Array was used for gene analysis and the experiment was repeated three times for each group. The results were normalized with the GeneChip(®) Operating Software program and confirmed through analysis with the secondary deoxyribonucleic acid-Chip Analyzer (dChip) software. The data were confirmed by real-time reverse transcription polymerase chain reaction analysis. Genes related to ovarian function were further confirmed by immunohistochemistry. We found the upregulation of the type 9 adenylate cyclase and inhibin beta B genes and the downregulation of the cyclic adenosine monophosphate response element modulator and cytochrome P450 family 17a1 genes in the ovarian tissue of GII compared to those of the control group. Our data suggest that melatonin supplementation decreases gene expression of cyclic adenosine monophosphate, which changes ovarian steroidogenesis.