Reactivity of Olanzapine and Tricyclic Antidepressants on the Protective Effects of Trolox on Lipid Peroxidation Evaluated Using Fluorescence Anisotropy, Electron Paramagnetic Resonance Spectrometry, and Thermal Analysis

Abstract

Multiacting receptor-targeting antipsychotics and tricyclic antidepressants stimulate various neurotransmitter receptors despite the different targets of postsynaptic receptors and presynaptic reuptake transporters. Their auxiliary and adverse effects may be caused by multiple targets or the modification of the neuronal membrane. To evaluate the membrane responses to olanzapine, imipramine, desipramine, amitriptyline, lidocaine, and dibucaine, we examined the inhibition of lipid peroxidation in egg yolk phosphatidylcholine liposomes. By contrast, their effects on membrane fluidity were measured as the suppressive contributions of the inhibitory activity of Trolox on lipid oxidation. These drugs inhibit lipid peroxidation and exclude harmful reactive oxygen species and the protective effect of Trolox. The fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene in saturated phospholipid liposome-containing drugs suggested that olanzapine, imipramine, and dibucaine enhanced membrane fluidity. The radical scavenging activity of 2,2-diphenylpicrylhidrazyl and galvinoxyl radicals was determined using electron paramagnetic resonance experiments, and their molecular flexibility was determined using thermograms for differential scanning calorimetry. Multiple regression analyses of the linear free energy relationship approach and comparative investigations revealed that the membranous fluidity of the liposomes, independent of the radical scavenging activity of the drugs, induced the inhibitory activity on lipid peroxidation. We discussed how these drugs act on nervous membranes and aimed to identify the relationship between uncertified functions and membranous fluidity.