Ropinirole: another neuroprotectant blocking the permeability transition pore in the inner mitochondrial membrane

More and more neuroprotectants are found that seem to act by interrupting the signaling chain leading to apoptosis. 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 as was shown with melatonin (Andrabi et al., 2004, FASEB J, 18:869). After demonstrating such an effect for the dopamine agonist pramipexole, we show here that another nonergot dopamine-D2-agonist, ropinirole, causes PTP blockade as well.

We prepared mitoplasts i.e. vesicles of inner mitochondrial membrane by a hypotonic treatment of the mitochondria and studied the PTP by means of the patch-clamp method. Additionally, Ca2+-induced swelling was recorded by a change in light absorbance, and an altered mitochondrial membrane potential was measured by uptake or release of the fluorescent probe safranin.

While the dopamine-D2-agonist pramipexole (Sifrol) inhibited the PTP with an IC50 of 500 nM, and melatonin with an IC50=800 nM, ropinirole (ReQuip) was slightly less effective (IC50=3.2 uM). Ca2+-induced swelling in intact mitochondria was blocked concentration-dependently, as well. Ropinirole also blocks the Ca2+-induced reduction of the mitochondrial membrane potential. At least for melatonin we could show that these effects occur together with a reduced rate of neuronal cell death. Neither L-dopa nor dopamine caused a blockade of the PTP. We thus suggest that the neuroprotective effect of ropinirole may be mediated by blockade of the PTP.

Supported by Deutsche ParkinsonVereinigung, State of Sachsen-Anhalt, and BMFT.