Abstract
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.
Original language | English |
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Pages (from-to) | 13-21 |
Number of pages | 9 |
Journal | Brain Research |
Volume | 1012 |
Issue number | 1-2 |
DOIs | |
State | Published - Jun 25 2004 |
Scopus Subject Areas
- General Neuroscience
- Molecular Biology
- Clinical Neurology
- Developmental Biology
Keywords
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl
- 6-OHDA
- Catecholaminergic oxidative toxicity
- Dopamine
- MPTP
- PNA
- polynitroxylated albumin
- Reactive oxygen species
- reactive oxygen species
- ROS
- TEMPOL