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.
Elimadi
Aziz
A
Département de Pharmacologie, Faculté de Médecine de Paris XII, Créteil, France
Jullien
Vincent
V
Tillement
Jean Paul
JP
Morin
Didier
D
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