Glucocorticoids induce gastroparesis in mice through depletion of l-arginine.

Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action, we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR). Gastroparesis was unrelated to the enhanced gastric acid secretion observed after Dex treatment, although both effects were mediated by the same molecular mechanism of the GR. Using conditional GR-knockout mice, we could further rule out that GC effects on enterocytes or myeloid cells were involved in the induction of gastroparesis. In contrast, we found that Dex upregulated arginase 2 (Arg2) in the stomach both at the mRNA and protein level. This suggests that GC treatment leads to a depletion of l-arginine thereby impeding the production of nitric oxide (NO), which is required for gastric motility. We tested this hypothesis by supplementing the drinking water of the mice with exogenous l-arginine to compensate for the presumed shortage of this major substrate of NO synthases. Importantly, this measure completely prevented both the enlargement of the stomach and the induction of gastroparesis after Dex treatment. Our findings raise considerations of combining orally applied GCs with l-arginine to improve tolerability of GC treatment and provide a possible explanation for the antiemetic effects of GCs widely exploited in chemotherapy.

Traditional concepts and future avenues of glucocorticoid action in experimental autoimmune encephalomyelitis and multiple sclerosis therapy.

Glucocorticoids (GCs) constitute one of the oldest families of anti-inflammatory and immunosuppressive drugs. Since their first clinical use more than half a century ago, they have been employed for therapeutic invention in a variety of conditions, including atopic disorders, autoimmune diseases, and cancer. Nevertheless, their exact mechanism of action is still incompletely understood. In this review, we elaborate especially on the mechanism of GCs in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), and summarize our current knowledge on how therapeutic and endogenous GCs impact the pathogenesis of EAE and MS. This includes findings obtained from genetically modified mice and rats lacking or overexpressing the GC receptor (GR) in specific cell types, and the analysis of new pharmaceutical formulations and chemical GC modifications aimed at improving treatment efficacy and specificity. Stimulated by these recent developments, it can be anticipated that novel therapeutic regimens will find their way into clinical practice for the benefit of affected patients.