Glucocorticoids - Potent modulators of astrocytic calcium signaling

Glucocorticoids are the first line of choice in the treatment of cerebral e dema associated with brain tumors. High-dose glucocorticoids reduce the ext ent of edema within hours, often relieving critical increases in intracrani al pressure, but the mechanisms by which glucocorticoids modulate brain wat er content are not well-understood. A possible target of action may be gluc ocorticoid receptor-expressing astrocytes, which are the primary regulators of interstitial ion homeostasis in brain. In this study, we demonstrate th at two glucocorticoids, methylprednisolone and dexamethasone, potentiate as trocytic signaling, via long-range calcium waves. Glucocorticoid treatment increased both resting cytosolic calcium (Ca-i(2+)) level and the extent an d amplitude of Ca2+ wave propagation two-fold, compared to matched controls . RU-486, a potent steroid receptor antagonist, inhibited the effects of me thylprednisolone. The glucocorticoid-associated potentiation of Ca2+ signal ing may result from upregulation of the cellular ability to mobilize Ca2+ a nd release ATP, because both agonist-induced Ca-i(2+) increments (via ATP a nd bradykinin) and ATP release were proportionally enhanced by glucocortico ids. In contrast, neither gap junction expression (as manifested connexin 4 3 immunoreactivity) nor functional coupling was significantly affected by m ethylprednisolone. Confocal microscopy revealed both the expression of gluc ocorticoid receptors and nuclear translocation of these receptors when expo sed to methylprednisolone. We postulate that the edemolytic effects of gluc ocorticoids may result from enhanced astrocytic calcium signaling. (C) 1999 Wiley-Liss, Inc.