Glucocorticoids-potent modulators of astrocytic calcium signaling

Glucocorticoids are the first line of choice in the treatment of cerebral edema associated with brain tumors. High-dose glucocorticoids reduce the extent of edema within hours, often relieving critical increases in intracranial pressure, but the mechanisms by which glucocorticoids modulate brain water content are not well-understood. A possible target of action may be glucocorticoid receptor-expressing astrocytes, which are the primary regulators of interstitial ion homeostasis in brain. In this study, we demonstrate that two glucocorticoids, methylprednisolone and dexamethasone, potentiate astrocytic signaling, via long-range calcium waves. Glucocorticoid treatment increased both resting cytosolic calcium (Ca2+i) level and the extent and amplitude of Ca2+ wave propagation two-fold, compared to matched controls. RU-486, a potent steroid receptor antagonist, inhibited the effects of methylprednisolone. The glucocorticoid-associated potentiation of Ca2+ signaling may result from upregulation of the cellular ability to mobilize Ca2+ and release ATP, because both agonist-induced Ca2+i increments (via ATP and bradykinin) and ATP release were proportionally enhanced by glucocorticoids. In contrast, neither gap junction expression (as manifested connexin 43 immunoreactivity) nor functional coupling was significantly affected by methylprednisolone. Confocal microscopy revealed both the expression of glucocorticoid receptors and nuclear translocation of these receptors when exposed to methylprednisolone. We postulate that the edemolytic effects of glucocorticoids may result from enhanced astrocytic calcium signaling.