S-15176 inhibits mitochondrial permeability transition via a mechanism independent of its antioxidant properties.

Abstract

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.

• Authors: Aziz Elimadi, Vincent Jullien, Jean Paul Tillement, Didier Morin
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 468 Issue 2 Pg. 93-101 (May 09 2003) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 12742516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Permeability Transition Pore
• Piperazines
• S 15176
• NADP
• Calcium

Topics

• Animals
• Antioxidants (pharmacology)
• Binding Sites
• Calcium (metabolism)
• Lipid Peroxidation (drug effects)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria, Liver (drug effects, metabolism)
• Mitochondrial Membrane Transport Proteins (drug effects, metabolism)
• Mitochondrial Permeability Transition Pore
• NADP (metabolism)
• Oxidation-Reduction
• Piperazines (pharmacology)
• Rats
• Rats, Wistar