N. M. De Castro

Ovariectomy, a model of menopause in rodents, causes a premature aging of the nervous and immune systems

Ovariectomy in rodents is a good model for mimicking human ovarian hormone loss. This work studies the consequences of ovariectomy on the nervous and immune systems in the context of biological aging. Ovariectomy accelerates the process of aging by impairing the sensorimotor abilities (with loss of muscular vigor and impaired equilibrium and traction capacities) and the exploratory capacities (with reduction of vertical exploratory activity). It also leads to a premature immunosenescence with regard to chemotaxis index, lymphoproliferative response and natural killer activity, parameters investigated in the spleen and axillary nodes. Therefore, ovariectomy deteriorates homeostasis and may be a model of premature aging.

Early Maternal Deprivation in Rats : A Proposed Animal Model for the Study of Developmental Neuroimmunoendocrine Interactions

Adult animals that had been subjected to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal day (PND) 9–10] show long‐term behavioral alterations that resemble specific symptoms of schizophrenia. Moreover, at adolescence MD rats showed depressive‐like behavior and altered motor responses. According to the neurodevelopmental hypothesis, certain behavioral abnormalities observed in MD animals may be related to altered neurodevelopmental processes triggered by MD‐induced elevated glucocorticoids in relevant specific brain regions. We review here these neuroendocrine effects and show new data indicating that the MD procedure induces diverse detrimental effects on the immune system that are already revealed in the short term (PND 13) and persist into adulthood. These long‐lasting effects might be related to altered hypothalamus–pituitary–adrenal axis activity and to social as well as nutrition‐related factors. In fact, MD induces long‐lasting decreases in body weight. In view of our findings we propose the present MD procedure as a potentially useful model to analyze developmental interactions between early psychophysiological stress and immunodeficient states.

Expression of Toll-like receptors on peritoneal macrophages and dendritic cells from old mice treated with soyabean isoflavones and green tea

Cells of the immune system recognize pathogens via Toll-like receptors (TLR), which are the basic signalling receptors of the innate immune system and direct the course of acquired immunity by recognizing specific microbial products that activate immune cells for effector functions. It is well known that ageing correlates with a decline in immunity, an increase in the inflammatory state and an impaired production of several hormones, such as oestrogens. In recent years it has been shown that oestrogens play an essential role in modulating immune function and pro-inflammatory cell signalling. Soyabean isoflavones, since they show a structural similarity to oestradiol, are being investigated in order to determine whether they can mimic oestrogen actions. Furthermore, the possible effects of the green tea plant on human health, because of its content of polyphenolic antioxidants (especially catechins), has been studied with increasing interest in recent years. Since the expression of TLR on cell membranes constitutes the first step in the inflammatory signalling cascade, the aim of the present study was to determine the role of isoflavones and green tea as modulators of such TLR expression on peritoneal macrophages and dendritic cells (those that mediate innate immunity) from old mice. ICR-CD1 female mice aged 16 months were fed a diet supplemented with soyabean or green tea + soyabean (Diviser-Aquilea SL, Barcelona, Spain; 1 mg soyabean per mouse per d; 3.75 mg green tea per mouse per d) for 25 weeks. The control groups were fed standard diet (A04; Panlab LS, Barcelona, Spain). Then, at the age of 22 months peritoneal leucocytes were obtained from the animals and the expression of TLR 2 and 4 was determined by flow cytometry in macrophages and dendritic cells. Previous studies have detected an increased expression of TLR2 and TLR4 with advancing age (L. Arranz, I. Baeza, N. M. De Castro, and M. De la Fuente, unpublished results). In the present experiment the combined diet (soyabean isoflavones + green tea) significantly decreased the presence of TLR2 and TLR4 on cell membranes in the old animals. In conclusion, adequate treatment with isoflavones and green tea could be useful in slowing down the effects of the ageing process through a mechanism of control of the age-related inflammatory state.

Impaired responses to gliadin and gut microbes of immune cells from mice with altered stress-related behavior and premature immune senescence

Stress is associated with impaired communication between the nervous and immune systems leading to immunosenescence and increased disease risk. We investigated whether leukocytes from mice with altered stress-related behavior and premature immunosenescence, as well as from chronologically aged mice differently responded ex vivo to celiac disease (CD) triggers (gliadin) and intestinal bacteria by ELISA and flow cytometry and differed in microbiota composition. We found that altered stress-related behavior and premature immunosenescence led to alterations in T lymphocytes and cytokine release of immune cells basally and in response to peptic fragments of gliadin and commensal and pathogenic bacteria, possibly increasing susceptibility to CD in adulthood.

Premature ageing and inflammatory status of ovariectomized mice. Treatment with soybean isoflavones and green tea

Ageing is characterised by a mild pro-inflammatory status. Ovariectomy in rodents constitutes a model of premature ageing that accelerates immunosenescence and increases oxidative stress in rodents. Previous experiments showed that ovariectomy causes an unbalance in the pro-/anti-inflammatory cytokine levels in old mice (20 months of age). The present study focused on the dysbalance of inflammatory markers after ovariectomy, in late maturity female mice, as well as on the readjustment that takes place after the administration of soybean and green tea enriched diets. Female ICR-CD1 mice were used. They were ovariectomized or sham-operated at a mature age (13 months) in order to mimic human menopause. At 16 months of age, they were administered a diet rich in soy isoflavones (1 mg/mouse/d) or a combined diet rich in soy isoflavones (1 mg/mouse/d) and green tea (3.75 mg/mouse/d) (Diviser-Aquilea, S.L.) for 5 weeks. Control groups received standard diet. At 17 months (late mature mice), peritoneal leucocytes were obtained and set in 72 h cultures in response to the mitogens ConA and LPS. IL-2 and IL-10 levels were measured in ConA supernatants and IL-6 levels were analysed in LPS supernatants. Ovariectomy decreases IL-10 levels and also tends to reduce those of IL-2, while IL-6 levels are not affected. Moreover, treatments with soybean isoflavones and green tea increase IL-2 and IL-10 levels in ovariectomized mice. The combined treatment with isoflavones and green tea is able to decrease IL-6 levels. Sham animals do not show any differences. The inflammatory condition in late maturity mice gets altered by ovariectomy through a decrease of IL-10 cytokine levels. Furthermore, such an inflammatory state is partially reversed by the ingestion of soy isoflavones during a period of 5 weeks.