Block of the permeability transition pore may explain the neuroprotective effect of erythropoietin

Erythropoietin (EPO) was shown to have a neuroprotective action in an in-vitro model of ischemia (Ruscher et al., 2002, J Neurosci 22:10291) and to be beneficial in the therapy of acute stroke (Ehrenreich et al., 2002, Mol Med 8:495). Several neuroprotectants, e.g. the non-ergot dopamine-D2-agonist pramipexole, were found to act by interrupting the signaling chain leading to apoptosis (Sayeed et al., 2006, FASEB J, 20:556). A central step within this cascade is opening of the permeability transition pore (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 show here that EPO causes PTP blockade as well.

We prepared vesicles of inner mitochondrial membrane (mitoplasts) by a hypotonic treatment of the 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. 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 the State of Sachsen-Anhalt and BMFT.