ABSTRACT
Considerable evidence supports the hypothesis that LDL oxidation has an important role in atherosclerosis. It has been demonstrated that the feeding of hypercholesterolemic mice on an atherogenic diet supplemented with melatonin highly increases the surface of atherosclerotic lesions in aorta and the sensitivity of atherogenic lipoprotein to ex vivo oxidation even though high melatonin doses inhibit lipoprotein oxidation in vitro. A melatonin-related compound (DTBHB: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3,5-di-tert-butyl-4-hydroxybenzamide) has been reported to strongly inhibit lipid peroxidation in vitro. In the present study, DTBHB treatment considerably increased the sensitivity of atherogenic lipoproteins to ex vivo oxidation but did not modify atherosclerotic lesion development in mice. Moreover, DTBHB treatment did not induce detectable lipidic alteration. These data confirm that the capacity of molecules to inhibit atherogenic lipoprotein oxidation in vitro offers no prediction of their capacity to inhibit in vivo atherosclerosis development.
Subject(s)
Antioxidants/pharmacology , Apolipoproteins B/genetics , Atherosclerosis/pathology , Benzamides/pharmacology , Indoles/pharmacology , Lipoproteins, LDL/blood , Melatonin/analogs & derivatives , Melatonin/pharmacology , Animals , Aorta/drug effects , Aorta/metabolism , Cattle , Cell Survival/drug effects , Cells, Cultured , Cholesterol/blood , Cytokines/metabolism , Disease Progression , Endothelial Cells/drug effects , Female , Humans , Lipids/blood , Mice , Mice, Transgenic , Oxidation-ReductionABSTRACT
This study was designed to evaluate the protective effect of two melatonin related compounds towards low density lipoproteins (LDL) oxidation initiated in vitro either by defined free radicals [i.e. superoxide anion (O2*-) and ethanol-derived peroxyl radicals (RO(2)(*))] produced by gamma radiolysis or by copper ions. The compounds studied were N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-3,5-di-tert-butyl-4-hydroxybenzamide (DTBHB) and (R,S)-1-(3-methoxyphenyl)-2-propyl-1,2,3,4-tetrahydro-beta-carboline (GWC20) which is a pinoline derivative. Their effects were compared with those of melatonin at the same concentration (100 micromol/L). None of the three tested compounds protected endogenous LDL alpha-tocopherol from oxidation by RO(2)(*)/O(2)(*)- free radicals. By contrast, they all protected beta-carotene from the attack of these free radicals with GWC20 being the strongest protector. Moreover, melatonin and DTBHB partially inhibited the formation of products derived from lipid peroxidation (conjugated dienes and thiobarbituric acid-reactive substances or TBARS) while GWC20 totally abolished this production. As previously shown, melatonin (at the concentration used) inhibited copper-induced LDL oxidation by increasing 1.60-fold the lag phase duration of conjugated diene formation over the 8 hr of the experimental procedure, however, DTBHB and GWC20 were much more effective, because they totally prevented the initiation of the propagation phase of LDL oxidation. It would be interesting to test in vivo if DTBHB and GWC20 which exhibit a strong capacity to inhibit in vitro LDL oxidation would reduce or not atherosclerosis in animals susceptible to this pathology.
