Effects of dehydroepiandrosterone, DHEA analogs and food restriction on free radical reactions and autoimmunity in the MRL/1pr mouse

DHEA treatment and food restriction are both methods of dramatically affecting the quality and length of life in laboratory rodents. DHEA is a naturally occurring adrenal steroid which when fed to mice and rats in the diet displays anti-carcinogenic, anti-diabetogenic, anti-obesity, and anti-autoimmune activities. DHEA is a potent inhibitor of the enzyme glucose-6-phosphate dehydrogenase (G6PDH) and may exert some of its beneficial effects through the inhibition of NADPH production. The restriction of caloric intake in mice and rats has been shown to have anti-carcinogenic, anti-obesity, anti-autoimmunity and anti-aging properties.;A hypothesis was formulated that DHEA and food restriction may exert their effects through the modulation of free radical reactions in vivo. There is evidence that this may be the case for food restriction. Food restricted animals have increased hepatic catalase levels and decreased levels of lipoperoxidation in the brain and liver suggesting that free radical-mediated reactions may be curtailed in food restricted animals.;This thesis presents evidence supporting the theory that DHEA can also modulate free radical production. DHEA is shown to inhibit superoxide production from rat liver microsomes and activated neutrophils, both important sources of oxygen radicals in vivo.;To further examine this mechanism we compare and contrast the effects of DHEA and food restriction in an autoimmune mouse model of glomerulonephritis and rheumatoid arthritis, the MRL/1pr mouse. A 35% reduction in food intake is shown to delay the appearance of auto-antibody, prevent the rheumatoid arthritis-like joint destruction, inhibit glomerulonephritis development and increase lifespan by greater than 100%.;DHEA and DHEA-analogs resulted in no protection from auto-antibody production but did result in small but significant increases in lifespan and decreases in glomerulonephritis. Structure/activity analysis of DHEA-analogs show that these beneficial effects are not due to the anti-G6PDH activity of these compounds.;These results neither confirm nor refute a role for free radicals as pathologic agents in the MRL/1pr mouse. However they are interesting because they dissociate between food restriction and DHEA suggesting that these treatments do not act through the same mechanism.