Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N -methyl(R )salsolinol [N M(R )Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. N M(R )Sal reduced mitochondrial membrane potential, DeltaPsim, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in N M(R )Sal-induced loss of DeltaPsim. N M(R )Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in N M(R )Sal-induced apoptosis. In mitochondria isolated from rat liver, N M(R )Sal induced swelling and reduced DeltaPsim, which was inhibited by cyclosporin A and Bcl-2 overexpression. These results indicate that N M(R )Sal induced the PT by direct action on the mitochondria. Rasagiline, N -propargyl-1(R )-aminoindan, which is a now under a clinical trial for Parkinson's disease, suppressed the DeltaPsim reduction, release of cytochrome c, and apoptosis induced by N M(R )Sal in SH-SY5Y cells. Rasagiline also inhibited the N M(R )Sal-induced loss of DeltaPsim and swelling in the isolated mitochondria, proving that rasagiline directly targets the mitochondria also. Altogether, mitochondrial PT plays a key role both in N M(R )Sal-induced cell death and the neuroprotective effect of rasagiline.