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These findings demonstrate that alpha-lipoic acid supplementation prevents development of hypertension and hyperglycemia, presumably through its antioxidative properties, as reflected by prevention of an increase in heart mitochondrial superoxide anion production and in AGE formation in the aorta of chronically glucose treated rats.

Trimetazidine is an anti‐ischaemic drug effective in different experimental models but its mechanism of action is not fully understood. Data indicate that mitochondria could be the main target of this drug. The aim of this work was to investigate the binding of [3H]‐trimetazidine on a purified preparation of rat liver mitochondria. [3H]‐trimetazidine binds to two populations of mitochondrial binding sites with Kd values of 0.96 and 84 μm. The total concentration of binding sites is 113 pmol mg−1 protein. Trimetazidine binding sites are differently distributed. The high‐affinity ones are located on the outer membranes and represent only a small part (4%) of total binding sites, whereas the low‐affinity ones are located on the inner membranes and are more abundant (96%) with a Bmax=108 pmol mg−1 protein. Drug displacement studies with pharmacological markers for different mitochondrial targets showed that [3H]‐trimetazidine binding sites are different from previously described mitochondrial sites. The possible involvement of [3H]‐trimetazidine binding sites in the regulation of the mitochondrial permeability transition pore (MTP), a voltage‐dependent channel sensitive to cyclosporin A, was investigated with mitochondrial swelling experiments. Trimetazidine inhibited the mitochondrial swelling induced by Ca2+ plus tert‐butylhydroperoxide (t‐BH). This effect was concentration‐dependent with an IC50 value of 200 μm. Assuming that trimetazidine effectiveness may be related to its structure as an amphiphilic cation, we compared it with other compounds exhibiting the same chemical characteristic both for their ability to inhibit MTP opening and to displace [3H]‐trimetazidine bound to mitochondria. Selected compounds were drugs known to interact with various biological membranes. A strong correlation between swelling inhibition potency and low‐affinity [3H]‐trimetazidine binding sites was observed: r=0.907 (n=24; P<0.001). These data suggest that mitochondrial sites labelled with [3H]‐trimetazidine may be involved in the MTP inhibiton. British Journal of Pharmacology (1998) 123, 1385–1394; doi:

Trimetazidine, an antiischaemic drug, has been shown to restore impaired mitochondrial functions. Specific binding sites for [3H]‐trimetazidine have been previously detected in liver mitochondria. In the present study we confirm this observation and provide additional evidence for the involvement of these sites in the pharmacological effects of the drug. Inhibition experiments using a series of trimetazidine derivatives revealed the presence of three classes of binding sites. An N‐benzyl substituted analogue of trimetazidine exhibited a very high affinity (Ki=7 nM) for one of these classes of sites. Compounds from different pharmacological classes were evaluated for their ability to inhibit [3H]‐trimetazidine binding. Among the drugs tested pentazocine, ifenprodil, opipramol, perphenazine, haloperidol, and to a lower extent prenylamine, carbetapentane and dextromethorphan competed with high affinity, suggesting a similarity of high affinity [3H]‐trimetazidine sites with sigma receptors. [3H]‐Trimetazidine binding was modulated by pH. Neutral trimetazidine had about 10 fold higher affinity than protonated trimetazidine for its mitochondrial binding sites. Various cations also affected [3H]‐trimetazidine binding. Ca2+ was the most potent inhibitor and totally suppressed the binding of [3H]‐trimetazidine to the sites of medium affinity. An endogenous cytosolic ligand was able to displace [3H]‐trimetazidine from its binding sites. Its activity was not affected by boiling for 15 min, suggesting a non‐protein compound. These data suggest that mitochondrial [3H]‐trimetazidine binding sites could have a physiological relevance and be involved in the antiischaemic effects of the drug. British Journal of Pharmacology (2000) 130, 655–663; doi:

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Cold ischemia--warm reperfusion (CI/WR) injury of liver transplantation involves hepatocyte cell death, the nature and underlying mechanisms of which remain unclear. Isolated hepatocytes and isolated perfused livers were used to determine the prevalence of necrosis and apoptosis as well as mitochondrial dysfunction. In isolated cells, propidium iodide and Hoechst 33342 staining showed a cold-storage, time-dependent increase in necrosis, whereas apoptosis was minimal even after 48 h of hypothermia. Nonetheless, a progressive loss of mitochondrial membrane potential was observed. Translocation of mitochondrial cytochrome c toward microsomes occurred within 24 h of CI/WR, with cytochrome c reaching the cytosol later. Mitochondria isolated from whole livers subjected to CI/WR also display reduced metabolic parameters and increased susceptibility to swelling. These events are associated with increased activity of major initiator (caspase 9) and effector (caspase 3) caspases. The results demonstrate that CI/WR induces mitochondrial dysfunction in isolated cells and in the whole organ; only in the latter is that sufficient to trigger the classical mitochondrial pathway of apoptosis. Our study also provides evidence for the involvement of endoplasmic reticulum stress in CI/WR hepatocyte injury. Combined protection of mitochondria and endoplasmic reticulum may thus represent an innovative therapeutic avenue to enhance liver graft viability and functional integrity.

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