S-15176 inhibits mitochondrial permeability transition via a mechanism independent of its antioxidant properties.
Mitochondrial Ca(2+) accumulation can induce a sudden increase in the permeability of the inner membrane. This phenomenon is due to the generation of a large nonselective ion channel, termed the permeability transition pore (PTP), which contributes to cellular injury during ischemia and reperfusion. Inhibition of PTP generation constitutes a relevant pharmacological target to protect a cell from death. In this study, we examined the effect of S-15176 ((N-[(3,5-di-tertiobutyl-4-hydroxy-1-thiophenyl)]-3-propyl-N'-(2,3,4-trimethoxybenzyl)piperazine), a novel anti-ischemic agent, on PTP in rat liver mitochondria. S-15176 prevented PTP opening generated by various triggering agents, as attested by the concentration-dependent inhibition of mitochondrial swelling, of mitochondrial membrane potential dissipation and of NADPH oxidation. These effects were associated with an increase in the Ca(2+) loading capacity of mitochondria. S-15176 was a strong inhibitor of lipid peroxidation, but experiments with another trimetazidine derivative devoid of antioxidant activity indicated that this activity was not essential to the inhibitory effect. Binding studies demonstrated that [3H]S-15176 bound to mitochondrial binding sites, especially those localized in the inner membrane. These sites were shared by several well-known inhibitors of PTP opening. These results demonstrate that the mechanism by which S-15176 protects mitochondria against the deleterious effects of ischemia-reperfusion involves inhibition of PTP opening and provide evidence that the drug operates through low structural specificity binding sites located in the inner mitochondrial membrane.
Département de Pharmacologie, Faculté de Médecine de Paris XII, Créteil, France
Aziz
A
Elimadi
Vincent
V
Jullien
Jean Paul
JP
Tillement
Didier
D
Morin
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000975:Antioxidants; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010879:Piperazines; C416838:S 15176; D009249:NADP; D002118:Calcium