Effect of stobadine on Cu(++)-mediated oxidation of low-density lipoprotein

The pyridoindole derivative stobadine [(-)-cis-2,8-dimethyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido(4,3b) indole] has been described as a drug with antihypoxic and antiarrhythmic cardioprotective properties. The antioxidative properties of this compound were studied during Cu(++)-mediated low-density lipoprotein (LDL) oxidation. Stobadine (concentration 0-5 microM) prolonged the lag phase (in min produced by one molecule antioxidant per LDL particle) as measured by diene formation more effectively than did ascorbate, trolox, or alpha-tocopherol. It also has the ability to decrease the rate of diene formation during the propagation phase very efficiently. Diene formation, Trp destruction, and alpha-tocopherol consumption were measured in the presence and absence of stobadine. Stobadine (10 microM) did not influence tocopherol consumption during oxidation and the Trp fluorescence quenching of Cu++ was not influenced by this compound. From these results, as well as polarographic measurements, we conclude that the antioxidative effect of stobadine is not simply a result of Cu(++)-ion complexation. In contrast to ascorbate, this compound is stable in the presence of Cu++. Stobadine inhibits the oxidation of LDL-Trp residues very efficiently via its radical scavenging properties, and may even have the ability to reduce Trp radicals to tryptophan. The concentration of stobadine used for LDL oxidation was in the range found in plasma (stobadine given p.o. in human and rats results in plasma concentrations between 0.2-3.9 microM.