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

Ariella Weinberg, Karen D. Nylander, Chaohua Yan, Li Ma, Carleton J.C. Hsia, Vladimir A. Tyurin, Valerian E. Kagan, Nina F. Schor

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 languageEnglish
Pages (from-to)13-21
Number of pages9
JournalBrain Research
Volume1012
Issue number1-2
DOIs
StatePublished - 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

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