Dehydroepiandrosterone Sulfate Decreases the Interleukin-2-Mediated Overactivity of the Natural Killer Cell Compartment in Senile Dementia of the Alzheimer Type

Abstract

Since dehydroepiandrosterone sulfate (DHEAS) has been involved in the regulation of cellular immunity, the aim of the presence study was to evaluate whether the age-dependent reduction of DHEAS was associated with changes of natural killer (NK) immune function in healthy elderly subjects and in patients with senile dementia of the Alzheimer type (SDAT). Circulating DHEAS was determined throughout 24 h (circadian profile). NK cytotoxic activity was measured as spontaneous and induced cytotoxicity during exposure with DHEAS (10^–7 M), interleukin-2 (IL-2; 100 IU) and IL-2 (100 IU) coincubated with DHEAS (10^–7 M). DHEAS was significantly reduced in healthy elderly subjects (mesor M ± SD = 2.3 ± 0.5 µmol/l) and SDAT (1.6 ± 0.4 µmol/l) patients compared to healthy young subjects (6.7 ± 0.9 µmol/l; p < 0.001); significant differences were also found when healthy elderly subjects and SDAT patients were compared (p < 0.01). A significant inverse correlation between age and DHEAS levels was demonstrated in SDAT and healthy elderly subjects (p < 0.05). The decrease in 24-hour DHEAS secretion was associated with a higher NK cytotoxic response to DHEAS in the healthy elderly subject group than in healthy subjects of young age (p < 0.01). Increased NK cell activity during IL-2 incubation was found in patients with SDAT in comparison with the healthy elderly subject (p < 0.001). On the contrary, NK cell cytotoxic response of SDAT patients was less pronounced during DHEAS exposure and when DHEAS was coincubated with IL-2 (p < 0.001). These data suggest an immunomodulatory role of DHEAS on NK functional activity in physiological aging and SDAT. The antagonizing effect of DHEAS on NK overactivity during exposure with cytokines might counteract some neuroimmune components related to the pathogenesis and progression of the disease.

Nitric Oxide Synthase Inhibition Induces Renal Medullary Hypoxia in Conscious Rats

“…Coincidentally, cortical oxygenation increases slightly and MAP increases progressively. These effects are probably blood‐pressure independent because (1) our data (Figure 4E and 4F) show that the direct relation between MAP and pO 2 is depressed in the cortex and lost in the medulla after chronic NOS inhibition, and (2) previous findings show that renal alterations induced by NO deficiency cannot be restored by antihypertensive treatment 57. Welch et al showed that low renal oxygenation and inefficient oxygen consumption were not subject to hypertension in the spontaneously hypertensive rat 58…”

Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner

“…Therefore, DHEA would seem a more desirable choice for therapeutic intervention if it possessed effective antiinflammatory activity against Alzheimer-relevant stimuli. Promising effects of DHEA-S on hypersensitive natural killer cells in Alzheimer have been reported (Solerte et al, 1999). A role for lymphocytes in Alzheimer disease has not been established, however.…”

Salt Sensitivity and Hypertension after Menopause: Role of Nitric Oxide and Angiotensin II

“…AT 1 receptor blockade normalized blood pressure in both strains, suggesting that the AT 1 receptor mediates the impaired renal sodium excretion and blood pressure elevation induced by NO synthesis blockade. However, in experiments conducted in rats treated for 8 weeks with a NOS inhibitor, renin-angiotensin system blockade normalized blood pressure but had no effect on the pressure-natriuresis responses, implying that correction of NOS inhibitor-induced HTN is not enough to overcome the renal alterations associated with the chronic deficiency of NO [61]. These findings highlight the complex interactions between Ang II and NO and indicate that they play an important pathogenetic role in the development of HTN.…”