Antioxidant activity of the monoamine oxidase B inhibitor lazabemide.
Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, the intrinsic antioxidant activity of lazabemide, a potent and reversible inhibitor of monoamine oxidase B (MAO-B), was tested in a membrane-based model of oxidative stress. Under physiologic-like conditions, lazabemide inhibited lipid peroxidation in a highly concentration-dependent manner. At low, pharmacologic levels of lazabemide (100.0 nM), there was a significant (P < 0.001) and catalytic reduction in lipid peroxide formation, as compared with control samples. The antioxidant activity of lazabemide was significantly more effective than that of either vitamin E or the MAO-B inhibitor, selegiline. The ability of lazabemide to inhibit oxidative damage is attributed to physico-chemical interactions with the membrane lipid bilayer, as determined by small angle x-ray diffraction methods. By partitioning into the membrane hydrocarbon core, lazabemide can inhibit the propagation of free radicals by electron-donating and resonance-stabilization mechanisms. These findings indicate that lazabemide is a potent and concentration-dependent inhibitor of membrane oxy-radical damage as a result of inhibiting membrane lipid peroxidation, independent of MAO-B interactions.
Mason
R P
RP
Membrane Biophysics Laboratory, Departments of Biochemistry and Medicine, MCP-Hahnemann University School of Medicine, Allegheny Campus, Pittsburgh, PA, USA. mason@pgh.auhs.edu
Olmstead
E G
EG
Jacob
R F
RF
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010848:Picolinic Acids / Q000494:pharmacology*; D012642:Selegiline / Q000494:pharmacology; D013552:Swine; D014810:Vitamin E / Q000494:pharmacology; D014961:X-Ray Diffraction
D000975:Antioxidants; D008051:Lipid Bilayers; D008996:Monoamine Oxidase Inhibitors; D010848:Picolinic Acids; D014810:Vitamin E; D012642:Selegiline; C059303:lazabemide; D008995:Monoamine Oxidase