Prevention of catecholaminergic oxidative toxicity by 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl and its recycling complex with polynitroxylated albumin, TEMPOL/PNA.
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-kappaB 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.
Weinberg
Ariella
A
Pediatric Center for Neuroscience, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Nylander
Karen D
KD
Yan
Chaohua
C
Ma
Li
L
Hsia
Carleton J C
CJ
Tyurin
Vladimir A
VA
Kagan
Valerian E
VE
Schor
Nina F
NF
D000418:Albumins / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000037:antagonists & inhibitors* / Q000633:toxicity; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D009589:Nitrogen Oxides / Q000494:pharmacology*; D016877:Oxidants / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology*; D013113:Spin Labels
D000418:Albumins; D002395:Catecholamines; D003497:Cyclic N-Oxides; D009589:Nitrogen Oxides; D016877:Oxidants; D017382:Reactive Oxygen Species; D012709:Serum Albumin; D013113:Spin Labels; C117059:polynitroxyl-albumin; D016627:Oxidopamine; C001803:tempol