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

Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Brain Research (Impact Factor: 2.84). 07/2004; 1012(1-2):13-21. DOI: 10.1016/j.brainres.2004.03.048
Source: PubMed


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.

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    • "Tempol protected normal cells from the cytotoxic effect of some chemotherapeutic agents. It prevented the cardiotoxicity of adriamycin (DeGraff et al., 1994; Monti et al., 1996), the hepatotoxicity of antimycin (Niknahad et al., 1995), the cytotoxicity of the semiquinone redox cycling agents, such as streptonigrin (DeGraff et al., 1994), the neurotoxicity of 6- hydroxydopamine (Purpura et al., 1996; Weinberg et al., 2004) and the spinal cord toxicity of etanidazole (Palayoor et al., 1994). "
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    ABSTRACT: Tempol is a redox-cycling nitroxide that promotes the metabolism of many reactive oxygen species (ROS) and improves nitric oxide bioavailability. It has been studied extensively in animal models of oxidative stress. Tempol has been shown to preserve mitochondria against oxidative damage and improve tissue oxygenation. Tempol improved insulin responsiveness in models of diabetes mellitus and improved the dyslipidemia, reduced the weight gain and prevented diastolic dysfunction and heart failure in fat-fed models of the metabolic syndrome. Tempol protected many organs, including the heart and brain, from ischemia/reperfusion damage. Tempol prevented podocyte damage, glomerulosclerosis, proteinuria and progressive loss of renal function in models of salt and mineralocorticosteroid excess. It reduced brain or spinal cord damage after ischemia or trauma and exerted a spinal analgesic action. Tempol improved survival in several models of shock. It protected normal cells from radiation while maintaining radiation sensitivity of tumor cells. Its paradoxical pro-oxidant action in tumor cells accounted for a reduction in spontaneous tumor formation. Tempol was effective in some models of neurodegeneration. Thus, tempol has been effective in preventing several of the adverse consequences of oxidative stress and inflammation that underlie radiation damage and many of the diseases associated with aging. Indeed, tempol given from birth prolonged the life span of normal mice. However, presently tempol has been used only in human subjects as a topical agent to prevent radiation-induced alopecia.
    Pharmacology [?] Therapeutics 02/2010; 126(2):119-45. DOI:10.1016/j.pharmthera.2010.01.003 · 9.72 Impact Factor
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    • "nervous system, and several studies represent attempts to administer 6-hydroxydopamine adjunctively with agents that are selectively protective of normal cells (Schor, 1987; Schor, 1988; Purpura et al., 1996). TEMPOL, a stable nitroxyl radical superoxide dismutase mimic, shows promise in this regard (Purpura et al., 1996; Weinberg et al., 2004). "
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    ABSTRACT: Tumors of the nervous system are among the most common and most chemoresistant neoplasms of childhood and adolescence. Malignant tumors of the brain collectively account for 21% of all cancers and 24% of all cancer-related deaths in this age group. Neuroblastoma, a peripheral nervous system tumor, is the most common extracranial solid tumor of childhood, and 65% of children with this tumor have only a 10 or 15% chance of living 5 years beyond the time of initial diagnosis. Novel pharmacological approaches to nervous system tumors are urgently needed. This review presents the role of and current challenges to pharmacotherapy of malignant tumors of the nervous system during childhood and adolescence and discusses novel approaches aimed at overcoming these challenges.
    Pharmacology [?] Therapeutics 05/2009; 122(1):44-55. DOI:10.1016/j.pharmthera.2009.01.001 · 9.72 Impact Factor
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    • "Similar cytoprotective concentrations of Tempol have been found to be efficient in rescuing PC12 from cell death caused by hypoxia/reoxygenation (Yamada et al., 2003) and 6- hydroxy-dopamine-induced cell death (Weinberg et al., 2004). This neuroprotective effect of Tempol is reminiscent of previous observations of Tempol's neuroprotective effects in animal Parkinson's models (Seaton et al., 1997; Matthews et al., 1999; Weinberg et al., 2004). This neuroprotective effect is also consistent with other therapeutic effects of Tempol, in rodents: amelioration of hypertension (Kimura et al., 2004), prevention of multiple organ injury in a shock model (Leach et al., 1998), reduction of myocardial infarction (McDonald et al., 1999), protection against ischemia-reperfusion injury of the brain, kidney and intestine (Rak et al., 2000; Udassin et al., 1998) and radioprotection (Hahn et al., 2000). "
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    ABSTRACT: Nerve growth factor (NGF) differentiated pheochromocytoma PC12 cells exposed to 1-methyl-4-phenylpyridinium (MPP+) toxin were used as an in vitro pharmacological model of Parkinson's disease to examine the neuroprotective effects of 4-hydroxy-2,2,6,6-tetramethyl piperidine-n-oxyl (Tempol), a free radical scavenger and a superoxide dismutase-mimetic compound. MPP+-induced PC12 cell death was measured 72 h after exposure to 1.5 mM MPP+ by the release of lactate dehydrogenease, caspase-3 activation and stimulation of survival and stress mitogen-activated protein kinases. Exposure of PC12 cells to MPP+ activated ERK1 and ERK2 (forty-fold over control after 72 h), JNK1 and JNK2 (fourfold after 48 h) and p-38alpha (tenfold after 24 h). Pretreatment of PC12 cells with 500 microM Tempol, 1 h before induction of the MPP+ insult, reduced by 70% the release of LDH into the medium, inhibited caspase-3 activity by 30% and improved by 33% mitochondrial function, effects correlated with a 70% reduction in ERK1 and ERK2 phosphorylation activity. These findings support the neuroprotective effect of Tempol in the MPP+-induced PC12 cell death model and its use as a potential drug for treatment of Parkinson's disease.
    European Journal of Pharmacology 12/2006; 549(1-3):50-7. DOI:10.1016/j.ejphar.2006.08.022 · 2.53 Impact Factor
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