Prevention of catecholaminergic oxidative toxicity by 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and its recycling complex with polynitroxylated albumin, TEMPOL/PNA

• Published in: Brain research 2004-06, Vol.1012 (1), p.13-21
• Main Authors: Weinberg, Ariella, Nylander, Karen D, Yan, Chaohua, Ma, Li, Hsia, Carleton J.C, Tyurin, Vladimir A, Kagan, Valerian E, Schor, Nina F
• Format: Article
• Language: English
• Subjects: Albumins - pharmacology; Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Catecholaminergic oxidative toxicity; Catecholamines - antagonists & inhibitors; Catecholamines - toxicity; Cyclic N-Oxides - pharmacology; Dopamine; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Humans; Isolated neuron and nerve. Neuroglia; Mice; Nitrogen Oxides - pharmacology; Oxidants - antagonists & inhibitors; Oxidants - metabolism; Oxidative Stress - drug effects; Oxidative Stress - physiology; Oxidopamine - antagonists & inhibitors; Oxidopamine - toxicity; PC12 Cells; Rats; Reactive oxygen species; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Serum Albumin - pharmacology; Spin Labels; Vertebrates: nervous system and sense organs
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.03.048

Reactive oxygen species (ROS) generated from dopamine and its oxidation products have been implicated in the pathogenesis and toxicity from treatment of Parkinson's disease-associated autonomic neuropathy, and antioxidant therapies have been proposed as treatment and prophylaxis for this disorder. However, many antioxidants are rapidly and, under physiological conditions, irreversibly oxidized, rendering them redox-inactive. We have examined the potential of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and polynitroxylated albumin (TEMPOL/PNA), an antioxidant complex that facilitates recycling of inactivated antioxidant to its redox-active form, as a protective agent against the toxicity of the catecholaminergic ROS generator, 6-hydroxydopamine (6-OHDA). TEMPOL/PNA is more effective against depression of activity level by 6-OHDA than the non-recycling antioxidant, TEMPOL, in a murine model of catecholaminergic oxidative damage. TEMPOL/PNA is also less toxic than TEMPOL in mice, allowing administration of higher doses of antioxidant. Both TEMPOL and TEMPOL/PNA give rise to prevention of apoptosis and to translocation of NF-κB from the cytoplasm to the nucleus of PC12 cells treated with 6-OHDA, but in vivo, TEMPOL/PNA maintains redox-active blood levels of TEMPOL for almost 5 h, whereas administration of TEMPOL alone results in clearance of blood redox activity within 1 h. PNA enhances the therapeutic index of TEMPOL, and the recycling antioxidant that results from their adjunctive administration may prove useful in disorders involving oxidative stress.