Protective potential of immunosuppressants has been reported in many experimental models of ischemia both in vivo and in vitro suggesting novel therapeutic application of these drugs. On account of fact that high mobility group box 1 (HMGB1) protein has recently been reported to be involved to ischemic brain injury, the purpose of the present study was to determine whether treatment with immunosuppressants could decrease HMGB1 expression and release in astrocytes exposed to ischemia-simulating conditions (combined oxygen glucose deprivation, OGD). We also studied the infl uence of these drugs on expression of NFκB, inducibleNO synthase (iNOS) and cyclooxygenase-2 (COX-2). In addition, we investigated whether the immunosuppressants could attenuate of necrosis in astrocyte cultures exposed to OGD. Cells were treated with cyclosporine A, FK506 and rapamycin (all drugs at concentrations of 0.1, 1 and 10 mM). Our study has provided evidence that immunosuppressants decrease the expression and release of HMGB1 in ischemic astrocytes. The present results provide further information about the cytoprotective mechanisms of immunosuppressants towards ischemic astrocytes, in relation to the pathophysiology of ischemic brain injury. It appears that the immunosuppressants stimulated protective effects could be mediated in part by suppression of HMGB1 expression and release in astrocytes, what leads to attenuation of ischemia-induced necrosis and neuroinfl ammation.