Effects of melatonin and age on gene expression in mouse CNS using microarray analysis.
ABSTRACT The expression levels of a number of genes associated with inflammation and immune function change with advancing age. Melatonin modulates gene expression levels of several of these genes. Therefore the declining levels of melatonin associated with age may play a role in the physiological effects of aging. We used oligonucleotide microarrays to measure age-related changes in mRNA expression in the murine CNS, and to study the effect of prolonged administration of dietary melatonin upon these changes. CB6F1 male mice were fed 40 ppm melatonin for 2.1 months prior to sacrifice at age 26.5 months, and compared with both age-matched controls and young, 4.5-month-old untreated controls. Total RNA was extracted from whole brain (excluding cerebellum and brain stem) and individual samples were hybridized to Affymetrix Mouse 430-2.0 arrays. The expression of a substantial number of genes was modulated by melatonin treatment and changes in selected genes were validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR). A subset of these genes did not change with age. Conversely, some genes modulated by age were also modulated by melatonin treatment. In general, melatonin treatment drove the expression levels of these genes closer to the expression levels detected in the younger animals. Notably, the abundance of lipocalin 2 (Lcn2) mRNA increased with age and was decreased in old animals treated with melatonin. Lcn2 is a member of the acute phase response family of proteins and its mRNA levels in the brain increase in response to inflammation. Many of the genes with expression reduced by melatonin are involved in inflammation and the immune system. This suggests that melatonin treatment may influence the inflammatory responses of old animals, driving them to resemble more closely those occurring in young animals.
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ABSTRACT: Ageing of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Recent studies suggest that normal brain ageing is associated with subtle morphological and functional alterations in specific neuronal circuits, as opposed to large-scale neuronal loss. In fact, ageing of the central nervous system in diverse mammalian species shares many features, such as atrophy of pyramidal neurons, synaptic atrophy, decrease of striatal dopamine receptors, accumulation of fluorescent pigments, cytoskeletal abnormalities, and reactive astrocytes and microglia. To provide the first global analysis of brain ageing at the molecular level, we used oligonucleotide arrays representing 6,347 genes to determine the gene-expression profile of the ageing neocortex and cerebellum in mice. Ageing resulted in a gene-expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. At the transcriptional level, brain ageing in mice displays parallels with human neurodegenerative disorders. Caloric restriction, which retards the ageing process in mammals, selectively attenuated the age-associated induction of genes encoding inflammatory and stress responses.Nature Genetics 08/2000; 25(3):294-7. · 35.53 Impact Factor
Article: Effect of the preventive-therapeutic administration of melatonin on mammary tumour-bearing animals.[show abstract] [hide abstract]
ABSTRACT: Melatonin has been reported to be involved in the feedback between neuroendocrine and immune functions and to exert oncostatic actions. Likewise, this hormone seems to lengthen life span in healthy animals. As of present, most studies have analysed the therapeutic effect of melatonin on cancer growth, but few have tested the preventive effect of melatonin in reducing the risk of cancer. Thus, the aim of this study was to evaluate the preventive-therapeutic effects of melatonin on rats with DMBA-induced mammary tumours, and to examine the effect of melatonin on the first line of cell defence against cancer (macrophages and NK cells) and on some of the neuroendocrine factors that are involved in the development of tumours (prolactin and catecholamines). Melatonin treatment (5 mg/day/animal) began one month prior to DMBA (9,10-dimethyl-1,2-benzanthracene) administration to females Sprague Dawley rats. It was found that the treatment led to an increase in survival and in latency time in the tumour-bearing rats. Although the melatonin treatment did not influence either the phagocytic capacity of macrophages or the number of peripheral blood NK cells, it did stabilise the levels of prolactin by returning the concentrations of this hormone to those of the healthy animals. We conclude that melatonin can exert an oncostatic action, lengthening the survival time of mammary tumour-bearing animals, and suggest that this effect is due, at least in part, to regulating the neuroendocrine parameters of tumour-bearing animals, bringing them closer to their optimal physiological status.Molecular and Cellular Biochemistry 02/2005; 268(1-2):25-31. · 2.06 Impact Factor
Article: X-Ray diffraction studies of fibrillin-rich microfibrils: effects of tissue extension on axial and lateral packing.[show abstract] [hide abstract]
ABSTRACT: X-ray diffraction of hydrated fibrillin rich microfibrils, in the form of zonular filaments from bovine eyes, demonstrated meridional diffraction peaks indexing on a fundamental periodicity of approximately 56 nm in the relaxed state. The effect of sample extensions of up to 50% in length produced an increase in the axial periodicity of only 4% as judged by alteration of the diffraction peak position of the third meridional order. This effect was shown to be reversible. Further extension to 100% of the tissue rest length caused extensive deterioration in the quality of the diffraction and resulted in a more complex meridional diffraction series, where the fundamental axial periodicity also changed to a length of approximately 80 nm. The fibrillin diffraction image also contains an equatorial diffraction peak that is enhanced upon tissue extension. The measurement of the molecular spacing from the equatorial diffraction profile indicated that the closest approach of molecules gave a broad interference peak of spacing 28 nm, this is nearly twice the molecular diameter as estimated from electron microscopy of dehydrated samples.Journal of Structural Biology 02/1998; 122(1-2):123-7. · 3.41 Impact Factor