Endocrinology
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Interleukin-1 beta (IL-1 beta) causes rat islet cell dysfunction through mechanisms that involve inducible nitric oxide synthase (iNOS). However, IL-1 beta also activates several lipid pathways, including those generating phosphatidic acid (PA). Lisofylline (LSF), a water-soluble, nontoxic, selective inhibitor of the PA-1 alpha subspecies, which is stimulated by IL-1 beta and tumor necrosis factor-alpha, has been shown to prevent cytokine-induced cytotoxicity in in vivo animal models. ⋯ HPLC quantitation of PA-1 alpha extracted from islets treated with IL-1 beta alone showed an approximately 15-fold increase over the PA-1 alpha content of islets treated with IL-1 beta and LSF. IL-1 beta-induced expression of iNOS was unchanged with the addition of LSF. These results suggest that LSF is effective in reducing IL-1 beta-induced islet dysfunction, thus supporting the role of lipid mediators such as PA in cytokine-induced islet toxicity.
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This study examined the hypothesis that experimentally induced corticosteroid resistance in the brain would lead to adaptations in the activity of the hypothalamic-pituitary-adrenal (HPA) axis similar to the endocrine features of the endogenous resistance accompanying the pathogenesis of depression. For this purpose, the glucocorticoid antagonist RU 38486 (aGC) was infused intracerebroventricularly (i.c.v.) (100 ng/h) via Alzet minipumps for several days. During this chronic receptor blockade, parameters for basal and stress-induced HPA activity were measured in a longitudinal study design. ⋯ The data show that 1) chronic i.c.v. infusion of aGC readily enhances the amplitude of circadian corticosterone changes, presumably by increasing the adrenocortical sensitivity to ACTH; 2) chronic aGC-treated animals show an enhanced ACTH and corticosterone response to stress, which is delayed in termination; 3) corticosteroid receptor expression, basal CRH messenger RNA, and ACTH levels are not altered after prolonged chronic aGC treatment. It is concluded that, over a period of a few days, aGC-induced corticosteroid resistance triggers a sequelae of pituitary-adrenal adaptations ultimately resulting in hypercorticism. Paradoxically, however, this hypercorticism develops because of increased peak levels of corticosteroid hormone rather than through elevated trough levels as is commonly observed during depressive illness.