It was estimated that the S. nigra of a Parkinson patient at diagnosis has lost about 70% of the neurons by apoptosis. The remnant is slowly declining. As the pathophysiology of the disease is not understood it might be beneficial for the patient to interrupt the apoptotic signaling cascade. A key player within the intrinsic pathway of apoptosis seems to be the permeability transition pore (PTP) of the inner mitochondrial membrane. Its activation is accompanied by the release of cytochrome c from the intermembrane gap which may be the point of no return of the cascade. Thus blockade of the PTP could be a fruitful strategy of neuroprotection. We found that several substances assumed to be neuroprotective, in particular the two dopamine-D2-agonists pramipexole and ropinirole as well as melatonine, are able to inhibit dose-dependently the PTP as measured by patch-clamp on rat liver mitoplasts (IC₅₀ between 26 nM and 3.4 mM). Inhibition is modulated by Pi. We proved these results not only by measuring responses of the mitochondrial membrane potential, respiration, and the Ca²⁺-dependent PTP-induced swelling of intact liver mitochondria but also the swelling of intact brain mitochondria. As it was also proved that down stream parameters of the apoptosis cascade were inhibited we assume that PTP inhibition is useful for neuroprotection.