We have shown that several neuroprotectants like melatonin, different dopamin-agonists (the non-ergot dopamine-D2-agonists pramipexole and ropinirole), or erythropoietin (EPO) can inhibit the mitochondrial (mt) permeability transition pore (PTP). This could interrupt the intrinsic signaling chain leading to apoptosis (Sayeed et al., 2006, FASEB J, 20:556). A central step within this cascade is opening of the PTP. In contrast, blockade of the PTP is able to suppress apoptotic cell death and to protect neuronal tissue as was shown with melatonin (Andrabi et al., 2004, FASEB J 18:869). We prepared vesicles of inner mt membrane (mitoplasts) by a hypotonic treatment of liver and brain mitochondria and studied the PTP by means of the patch-clamp method. Additionally, Ca2+-induced swelling was recorded from intact mitochondria by a change in light absorbance, mt membrane potential as changes in safranine-O fluorescence, and mt oxygen consumption by high-resolution respirometry. EPO inhibited the single-channel currents through the PTP concentration- dependently (IC50 = 16 mU/mL). Inhibition was complete at the higher and reversible at the lower concentrations. Ca2+-induced swelling of intact mitochondria as an expression of PTP-opening was inhibited by EPO as well. It is thus likely that the neuroprotective effect of EPO is mediated by blockade of the PTP. Supported by State of Sachsen-Anhalt and BMFT.