Review articleMechanism of action of glucocorticosteroid hormones: possible implications for therapy of neuroimmunological disorders
Introduction
In 1938, natural steroid hormones were first extracted and purified from the suprarenal (adrenal) gland. Soon after the discovery of natural glucocorticosteroids, synthesis of steroid hormones was achieved in 1947 and opened immediate access to steroid therapy of human autoimmune disorders (Hench et al., 1949). Even now, in the realm of molecular medicine, glucocorticosteroids belong to the most potent immunosuppressive drugs. In the 1950s, great progress has been made in the development of new and more potent steroid derivatives. Despite that, treatment with ACTH of hypophyseal origin, which based on the “indirect” release of endogenous glucocorticosteroid and mineralocorticosteroid hormones, has still been widely used until 1970. ACTH has now been abandoned for virtually all neuroimmunological diseases. At present, the standard approach to treat exacerbations of neuroinflammatory disorders is glucocorticosteroid pulse therapy (see metaanalyses in Brusaferri and Candelise, 2000, Kaufman et al., 2000). By using i.v. dosages in the range of 500–1000 mg methylprednisolone (MP) per day, steroid peak levels are 5–10 times higher than those achieved by endogenous steroids released following ACTH.
Most of the mechanisms of glucocorticosteroid actions at the genomic level, i.e. those mediated by the cytosolic receptor, have been described early after the discovery of GS. For engagement with the cytosolic receptor, lower steroid concentrations are sufficient, such as that achieved by endogenous steroid hormones released from the adrenal gland during ACTH therapy or by low-dose GS treatment. We have now started to realize that other (additional) steroid effector pathways are active at very high doses given during pulse therapy, probably mediated by a direct effect on cellular membranes and consequently ion transport (see review in Buttgereit et al., 1998). The consequent reduction of the ATP availability is normally observed in apoptosis before DNA fragmentation ensues, and may explain the experimental findings of induction of apoptosis. Thus, a qualitatively distinct mechanism of GS action may be achieved, which of course may act in concert with the traditional genomic pathways. Here, we briefly review the available evidence supporting the nongenomic action of glucocorticosteroid hormones derived from in vitro data and from findings in disease models for human neuroinflammatory disorders. In the animal models for Guillain–Barré syndrome (GBS) and multiple sclerosis (MS), experimental autoimmune neuritis (EAN) and encephalomyelitis (EAE), high-dose glucocorticosteroid treatment clearly increases apoptosis of invading T cells and accelerates recovery. Recently, these findings have been extended to experimental myositis and may also apply to MP pulse therapy in MS patients.
Section snippets
Nongenomic action of glucocorticosteroids on cellular energy metabolism: therapeutical targeting of lymphocytes by high-dose corticosteroids
The existence of steroid effects mediated by mechanisms distinct from genomic steroid action has been apparent from the very beginning of research into steroid physiology and pharmacology, but was neglected for a long time. These were collectively termed nongenomic actions Buttgereit et al., 1998, Falkenstein et al., 2000a. The evidence came both from the basic sciences and from many areas of clinical medicine showing rapid glucocorticosteroid effects that are incompatible with the more delayed
Apoptosis in neuroinflammation
Apoptosis is a distinct mode of cell death. Although it was primarily defined by morphology (Kerr et al., 1972), it has an array of pathophysiological and functional implications. Typically, chromatin condensation and shrinkage of the cell occur in parallel and the integrity of the cell membrane is preserved for a long time. These morphological events coincide with distinct biochemical events that lead to caspase activation (Nicholson, 1999), changes in mitochondria and cellular membranes
Conclusion
There is growing evidence on GS-action also occurring at the nongenomic level. These mechanisms can easily be delineated in vitro. In vivo, nongenomic steroid effects may interfere with bioenergetic processes including signalling pathways. It is often difficult to distinguish in vivo to which extent genomic action of GS, such as inhibition of cytokine production, act in concert with nongenomic effects. Yet, experimental data are available that support the use of high-dose steroid therapy to
Acknowledgements
We thank our colleagues, Dr. J. Schmidt, Dr. U.K. Zettl, Dr. V.I. Leussink, Dr. C. Schneider and Dr. M.D. Brand for their invaluable contributions to the experimental work cited here. We are indebted to Dr. Marinos C. Dalakas for his critical reading and helpful suggestions.
Our research is supported by grants from the Deutsche Forschungsgemeinschaft, Gemeinnützige Hertie-Stiftung, Deutsche Multiple Sklerose Gesellschaft, Deutscher Akademischer Austauschdienst, Boehringer Ingelheim Fonds and by
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