Melatonin, Immune Function and Aging

Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness. Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state

Cadmium-Induced Disruption in 24-h Expression of Clock and Redox Enzyme Genes in Rat Medial Basal Hypothalamus: Prevention by Melatonin

In a previous study we reported that a low daily p.o. dose of cadmium (Cd) disrupted the circadian expression of clock and redox enzyme genes in rat medial basal hypothalamus (MBH). To assess whether melatonin could counteract Cd activity, male Wistar rats (45 days of age) received CdCl2 (5 ppm) and melatonin (3 μg/mL) or vehicle (0.015% ethanol) in drinking water. Groups of animals receiving melatonin or vehicle alone were also included. After 1 month, MBH mRNA levels were measured by real-time PCR analysis at six time intervals in a 24-h cycle. In control MBH Bmal1 expression peaked at early scotophase, Per1 expression at late afternoon, and Per2 and Cry2 expression at mid-scotophase, whereas neither Clock nor Cry1 expression showed significant 24-h variations. This pattern was significantly disrupted (Clock, Bmal1) or changed in phase (Per1, Per2, Cry2) by CdCl2 while melatonin counteracted the changes brought about by Cd on Per1 expression only. In animals receiving melatonin alone the 24-h pattern of MBH Per2 and Cry2 expression was disrupted. CdCl2 disrupted the 24-h rhythmicity of Cu/Zn- and Mn-superoxide dismutase (SOD), nitric oxide synthase (NOS)-1, NOS-2, heme oxygenase (HO)-1, and HO-2 gene expression, most of the effects being counteracted by melatonin. In particular, the co-administration of melatonin and CdCl2 increased Cu/Zn-SOD gene expression and decreased that of glutathione peroxidase (GPx), glutathione reductase (GSR), and HO-2. In animals receiving melatonin alone, significant increases in mean Cu/Zn and Mn-SOD gene expression, and decreases in that of GPx, GSR, NOS-1, NOS-2, HO-1, and HO-2, were found. The results indicate that the interfering effect of melatonin on the activity of a low dose of CdCl2 on MBH clock and redox enzyme genes is mainly exerted at the level of redox enzyme gene expression

Daytime variation in hepatitis C virus replication kinetics following liver transplant

Background: There is a growing interest in the role of circadian regulated pathways in disease pathogenesis. Methods: In a cohort of hepatitis C virus (HCV) infected patients undergoing liver transplantation, we observed differences in early viral infection kinetics of the allograft that associated with the time of liver transplant. Results: A higher frequency of subjects transplanted in the morning showed a rebound in viral RNA levels (n=4/6) during the first week post-surgery. In contrast, no viral rebound was observed in seven subjects transplanted in the afternoon. None of the other parameters previously reported to influence viral replication in the post-transplant setting, such as donor age, cold-ischemia time and length of surgery associated with viral rebound. Conclusions: These observation highlights a role for circadian processes to regulate HCV infection of the liver and warrants further investigation

Prostate response to prolactin in sexually active male rats

BACKGROUND: The prostate is a key gland in the sexual physiology of male mammals. Its sensitivity to steroid hormones is widely known, but its response to prolactin is still poorly known. Previous studies have shown a correlation between sexual behaviour, prolactin release and prostate physiology. Thus, here we used the sexual behaviour of male rats as a model for studying this correlation. Hence, we developed experimental paradigms to determine the influence of prolactin on sexual behaviour and prostate organization of male rats. METHODS: In addition to sexual behaviour recordings, we developed the ELISA procedure to quantify the serum level of prolactin, and the hematoxilin-eosin technique for analysis of the histological organization of the prostate. Also, different experimental manipulations were carried out; they included pituitary grafts, and haloperidol and ovine prolactin treatments. Data were analyzed with a One way ANOVA followed by post hoc Dunnet test if required. RESULTS: Data showed that male prolactin has a basal level with two peaks at the light-dark-light transitions. Consecutive ejaculations increased serum prolactin after the first ejaculation, which reached the highest level after the second, and started to decrease after the third ejaculation. These normal levels of prolactin did not induce any change at the prostate tissue. However, treatments for constant elevations of serum prolactin decreased sexual potency and increased the weight of the gland, the alveoli area and the epithelial cell height. Treatments for transient elevation of serum prolactin did not affect the sexual behaviour of males, but triggered these significant effects mainly at the ventral prostate. CONCLUSION: The prostate is a sexual gland that responds to prolactin. Mating-induced prolactin release is required during sexual encounters to activate the epithelial cells in the gland. Here we saw a precise mechanism controlling the release of prolactin during ejaculations that avoid the detrimental effects produced by constant levels. However, we showed that minor elevations of prolactin which do not affect the sexual behaviour of males, produced significant changes at the prostate epithelium that could account for triggering the development of hyperplasia or cancer. Thus, it is suggested that minute elevations of serum prolactin in healthy subjects are at the etiology of prostate abnormal growth

Sleep and immune function

Sleep and the circadian system exert a strong regulatory influence on immune functions. Investigations of the normal sleep–wake cycle showed that immune parameters like numbers of undifferentiated naïve T cells and the production of pro-inflammatory cytokines exhibit peaks during early nocturnal sleep whereas circulating numbers of immune cells with immediate effector functions, like cytotoxic natural killer cells, as well as anti-inflammatory cytokine activity peak during daytime wakefulness. Although it is difficult to entirely dissect the influence of sleep from that of the circadian rhythm, comparisons of the effects of nocturnal sleep with those of 24-h periods of wakefulness suggest that sleep facilitates the extravasation of T cells and their possible redistribution to lymph nodes. Moreover, such studies revealed a selectively enhancing influence of sleep on cytokines promoting the interaction between antigen presenting cells and T helper cells, like interleukin-12. Sleep on the night after experimental vaccinations against hepatitis A produced a strong and persistent increase in the number of antigen-specific Th cells and antibody titres. Together these findings indicate a specific role of sleep in the formation of immunological memory. This role appears to be associated in particular with the stage of slow wave sleep and the accompanying pro-inflammatory endocrine milieu that is hallmarked by high growth hormone and prolactin levels and low cortisol and catecholamine concentrations

Effect of cadmium on lymphocyte subsets distribution in thymus and spleen

This work was designed to analyze the possible dose dependent effects of cadmium on the distribution of lymphocyte subsets within the thymus and spleen. Cadmium accumulation was also evaluated in these tissues. For this purpose, adult male rats were exposed for one month to 0, 5, 10, 25, 50 or 100 ppm of cadmium chloride (CdCl2) in the drinking water. In both spleen and thymus, the B lymphocytes increased with the doses of 5 and 10 ppm of CdCl2, and decreased with the doses of 25-100 ppm. In spleen, the doses of 25 and 50 ppm decreased CD4+ cells and the doses of 5 and 10 ppm increased CD8+ cells, while the percentage of Thymus T, CD4+, CD8+ and CD4+-CD8+ cells was not modified by cadmium treatment at any dose used in this study. After cadmium exposure, the metal was accumulated in the spleen only from the dose of 50 ppm on, and in the thymus, from the dose of 10 ppm on. In conclusion, although the accumulation of the metal is higher in thymus than in spleen, the metal affected CD4+ and CD8+ lymphocytes at the spleen but not at the thymusEn este trabajo se analizan los posibles efectos inducidos por la exposición al cadmio sobre las subpoblaciones linfocitarias en bazo y timo y se evalúa la acumulación del metal en estos tejidos. Para ello, se tratan ratas macho adultas durante un mes con cloruro de cadmio (CdCl2) en el agua de bebida a dosis de 0, 5, 10, 25, 50 y 100 ppm. En las ratas tratadas con 5 y 10 ppm de CdCl2, el porcentaje de linfocitos B aumenta en bazo y timo, descendiendo a partir de la dosis de 25 ppm, en ambos tejidos. En bazo de ratas expuestas a las dosis de 25 y 50 ppm, el porcentaje de linfocitos CD4+ desciende, mientras que a las dosis de 5 y 10 ppm, aumenta el porcentaje de células CD8+. Tras la exposición al cadmio, el porcentaje de linfocitos T, CD4+, CD8+ y CD4+-CD8+ no varía en el timo con ninguna de las dosis administradas en este estudio. En las ratas tratadas, el cadmio se acumula en el bazo a partir de la dosis de 50 ppm, mientras que en el timo, lo hace a partir de la dosis de 10 ppm. Estos resultados indican, por tanto, que aunque la acumulación de cadmio es mayor en timo que en bazo, este metal afecta a la proporción de linfocitos CD4+ y CD8+ en el bazo pero no en el tim

Effect of melatonin treatment on 24-h variations in responses to mitogens and lymphocyte subset populations in rat submaxillary lymph nodes

Wistar male rats were injected s.c. with melatonin (30 μg) or vehicle, 1 h before lights off, for 11 days. Ten days after beginning melatonin treatment, rats received Freund's complete adjuvant or its vehicle s.c., and after 2 days, they were sacrificed at six different time intervals throughout a 24-h cycle. The mitogenic effect of lipopolysaccharide (LPS) and concanavalin A (Con A), the activity of ornithine decarboxylase (ODC) and the relative size of lymphocyte subset populations were measured in submaxillary lymph nodes. In control rats, the mitogenic effects of LPS and Con A and ODC activity peaked during the afternoon. Injection of Freund's adjuvant induced a 10-h shift in the diurnal rhythm of the mitogenic effect of LPS to attain maximal values at night. Melatonin pretreatment blunted the daily variations in the mitogenic activity of Con A or LPS and, when given to Freund's adjuvant-injected rats, augmented mesor and amplitude of diurnal rhythm in ODC activity. Maxima in B cell number occurred at night whereas those of T and B-T cell number occurred during the afternoon. During the early phase of immunization tested, the number of B cells augmented and the amplitude of its diurnal rhythmicity increased both after immunization and following melatonin pretreatment. Maxima of 24-h rhythms in CD4+ and CD4+/CD8+ cell populations occurred during the afternoon while those of CD8+ cells occurred at late night. Melatonin significantly augmented CD4+ cell number and decreased CD8+ cell number; it therefore augmented the CD4+ :CD8+ ratio. The results suggest that pretreatment with a pharmacological dose of melatonin exerts immunomodulating effects at an early, preclinical, phase of Freund's adjuvant-induced arthritis in rats.Fil: Castrillon, P. O.. Universidad Complutense de Madrid; EspañaFil: Esquifino, A. I.. Universidad Complutense de Madrid; EspañaFil: Varas, A.. Universidad Complutense de Madrid; EspañaFil: Zapata, A.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; ArgentinaFil: Cutrera, Rodolfo Angel. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cardinali, D. P.. Universidad Complutense de Madrid; Españ

Effect of a high-fat diet on 24-hour pattern in expression of prolactin and redox pathway enzymes in the rat adenohypophysis

The effect of a high-fat diet (35% fat) on 24-h changes in expression of prolactin and redox pathway enzyme genes was examined in the anterior pituitary of male rats. When body weight of high-fat fed rats attained values about 20- 25 % higher than controls (after 66 days of treatment) animals were sacrificed at 6 different time intervals throughout a 24-h cycle. Anterior pituitary mRNA levels were measured by real-time PCR analysis. In control rats expression of the prolactin gene peaked in anterior pituitary at early scotophase, 3 h in advance to the peak in plasma prolactin levels. In high-fat fed rats this correlation was lost. A disruption of 24-h rhythmicity of pituitary gene expression of heme oxygenase (HO)-2, Cu/Zn- superoxide dismutases (SOD), Mn-SOD, catalase, glutathione peroxidase (GPx) and glutathione reductase (GR) was apparent in high-fat fed rats. Anterior pituitary mRNA levels for nitric oxide synthase (NOS)-2 and HO-2, Cu/Zn- and Mn- SOD and catalase augmented in high-fat fed rats, whereas those of GPx and GR decreased. The results indicate a disrupted coordination between prolactin gene expression and prolactin release in highfat fed rats that comes along with a disturbed expression of redox enzyme genes in the anterior pituitary