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James B Mitchell - One of the best experts on this subject based on the ideXlab platform.
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Oral administration of the nitroxide radical Tempol exhibits immunomodulatory and therapeutic properties in multiple sclerosis models.
Brain behavior and immunity, 2017Co-Authors: Sarah E. Neil, James B Mitchell, Jaebong Huh, Victoria A. Baronas, Henry F. Mcfarland, Murali K. Cherukuri, Jacqueline A. QuandtAbstract:Therapies with both immunomodulatory and neuroprotective properties are thought to have the greatest promise in reducing the severity and progression of multiple sclerosis (MS). Several reactive oxygen (ROS) and reactive nitrogen species (RNS) are implicated in inflammatory-mediated damage to the central nervous system (CNS) in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a stable nitroxide radical with potent antioxidant activity. The goal of our studies was to investigate the immunomodulatory effects and therapeutic potential of orally-delivered Tempol in the mouse EAE model. Mice receiving Tempol chow ad libitum for 2weeks prior to induction of active EAE showed delayed onset and reduced incidence of disease compared to control-fed animals. Reduced disease severity was associated with limited microglial activation and fewer inflammatory infiltrates. Tempol's effects were immunomodulatory, not immunosuppressive: T cells produced less interferon-γ and tumor necrosis factor-α, and Tempol-fed mice exhibited a shift towards TH2-type antibody responses. Both myeloid and myeloid-dendritic cells of Tempol-fed EAE animals had significantly lower levels of MHC class II expression than controls; CD40 was also significantly reduced. Tempol administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+ regulatory populations. Tempol reduced the severity of clinical disease when administered after the induction of disease, and also after the onset of clinical symptoms. To exclude effects on T cell priming in vivo, Tempol was tested with the passive transfer of encephalitogenic T cells and was found to reduce the incidence and peak severity of disease. Protection was associated with reduced infiltrates and a relative sparing of neurofilaments and axons. The ability of oral Tempol to reduce inflammation and axonal damage and loss demonstrate both anti-inflammatory and protective properties, with significant promise for the treatment of MS and related neurological disorders.
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the nitroxide radical Tempol prevents obesity hyperlipidaemia elevation of inflammatory cytokines and modulates atherosclerotic plaque composition in apoe mice
Atherosclerosis, 2015Co-Authors: James B Mitchell, Anastasia L. Sowers, John A. Cook, Christine H J Kim, Christina A Bursill, Angela Thetford, David Van Reyk, Michael J DaviesAbstract:Abstract Objective The nitroxide compound Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine- N -oxyl radical) has been shown to prevent obesity-induced changes in adipokines in cell and animal systems. In this study we investigated whether supplementation with Tempol inhibits inflammation and atherosclerosis in apoE −/− mice fed a high fat diet (HFD). Methods ApoE −/− mice were fed for 12 weeks on standard chow diet or a high-fat diet. Half the mice were supplemented with 10 mg/g Tempol in their food. Plasma samples were analysed for triglycerides, cholesterol, low- and high-density lipoprotein cholesterol, inflammatory cytokines and markers (interleukin-6, IL-6; monocyte-chemotactic protein, MCP-1; myeloperoxidase, MPO; serum amyloid A, SAA; adiponectin; leptin). Plaques in the aortic sinus were analysed for area, and content of collagen, lipid, macrophages and smooth muscle cells. Results High fat feeding resulted in marked increases in body mass and plasma lipid levels. Dietary Tempol decreased both parameters. In the high-fat-fed mice significant elevations in plasma lipid levels and the inflammatory markers IL-6, MCP-1, MPO, SAA were detected, along with an increase in leptin and a decrease in adiponectin. Tempol supplementation reversed these effects. When compared to HFD-fed mice, Tempol supplementation increased plaque collagen content, decreased lipid content and increased macrophage numbers. Conclusions These data indicate that in a well-established model of obesity-associated hyperlipidaemia and atherosclerosis, Tempol had a significant impact on body mass, atherosclerosis, hyperlipidaemia and inflammation. Tempol may therefore be of value in suppressing obesity, metabolic disorders and increasing atherosclerotic plaque stability.
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Tempol protects cardiomyocytes from nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity.
Toxicological sciences : an official journal of the Society of Toxicology, 2014Co-Authors: Yongmin Liu, James B Mitchell, Eunwoo Shim, Phuonggiang Nguyen, Alexander T. Gibbons, Miriam C. PoirierAbstract:Nucleoside reverse transcriptase inhibitors (NRTIs), essential components of combinational therapies used for treatment of human immunodeficiency virus-1, damage heart mitochondria. Here, we have shown mitochondrial compromise in H9c2 rat cardiomyocytes exposed for 16 passages (P) to the NRTIs zidovudine (AZT, 50μM) and didanosine (ddI, 50μM), and we have demonstrated protection from mitochondrial compromise in cells treated with 200μM 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine (Tempol) or 200μM 1-hydroxy-4-[2-triphenylphosphonio)-acetamido]-2,2,6,6-tetramethylpiperidine (Tempol-H), along with AZT/ddI, for 16P. Exposure to AZT/ddI caused a moderate growth inhibition at P3, P5, P7, and P13, which was not altered by addition of Tempol or Tempol-H. Mitochondrial oxidative phosphorylation capacity was determined as uncoupled oxygen consumption rate (OCR) by Seahorse XF24 Analyzer. At P5, P7, and P13, AZT/ddI-exposed cells showed an OCR reduction of 8.8–57.2% in AZT/ddI-exposed cells, compared with unexposed cells. Addition of Tempol or Tempol-H, along with AZT/ddI, resulted in OCR levels increased by about 300% above the values seen with AZT/ddI alone. The Seahorse data were further supported by electron microscopy (EM) studies in which P16 cells exposed to AZT/ddI/Tempol had less mitochondrial pathology than P16 cells exposed to AZT/ddI. Western blots of P5 cells showed that Tempol and Tempol-H upregulated expression of mitochondrial uncoupling protein-2 (UCP-2). However, Complex I activity that was reduced by AZT/ddI, was not restored in the presence of AZT/ddI/Tempol. Superoxide levels were increased in the presence of AZT/ddI and significantly decreased in cells exposed to AZT/3TC/Tempol at P3, P7, and P10. In conclusion, Tempol protects against NRTI-induced mitochondrial compromise, and UCP-2 plays a role through mild uncoupling.
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Inhibition of adipogenesis by Tempol in 3T3-L1 cells
Free radical biology & medicine, 2010Co-Authors: Yuval Samuni, Murali C. Krishna, Anastasia L. Sowers, John A. Cook, Rajani Choudhuri, William Degraff, James B MitchellAbstract:Obesity is highly associated with an increased risk of serious health conditions including hypertension, cardiovascular disease, diabetes, and cancer. Changes in redox status with increased oxidative stress have been linked with obesity. Previous studies have shown that administration of the antioxidant Tempol in the food of mice prevents obesity, causing significant weight loss without toxicity. To gain a better understanding of the molecular mechanism(s) underlying this effect, the influence of Tempol on the differentiation of mouse 3T3-L1 preadipocytes was studied. Tempol inhibited differentiation of 3T3-L1 cells, resulting in a reduction in cellular lipid storage, down-regulation of protein levels of key adipogenesis transcription factors (PPARγ and PPARα), down-regulation of prolyl hydroxylase, and up-regulation of HIF-1α. Mice on a Tempol diet demonstrated reduced systemic levels of IGF-1, in qualitative agreement with in vitro observations in 3T3-L1 cells, which also showed lower IGF-1 levels as a result of Tempol treatment. These results show that treatment of 3T3-L1 cells with Tempol inhibits the expression of key adipogenesis factors, adipose differentiation, and lipid storage and may underlie, at least in part, some of the in vivo effects of Tempol on body weight.
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Tempol protects against oxidative damage and delays epithelial tumor onset in fanconi anemia mice
Cancer Research, 2008Co-Authors: Qing Shuo Zhang, James B Mitchell, Laura Eaton, Eric Snyder, Scott Houghtaling, Milton J Finegold, Carter Van Waes, Markus GrompeAbstract:Fanconi anemia (FA) is a genetic disorder characterized by congenital abnormalities, bone marrow failure, and marked cancer susceptibility. FA patients have an elevated risk of developing hematologic malignancies and solid tumors. Using Fancd2 −/− knockout mice as a model of FA, we examined the potential of Tempol, a nitroxide antioxidant and a superoxide dismutase mimetic, as a tumor-delaying agent for solid tumors. Dietary Tempol increased the mean tumor-free survival time of Fancd2−/− Trp53+/− mice by 27% ( P < 0.01), from 308 to 390 days, without changing the overall tumor spectrum. More strikingly, Tempol delayed the onset of epithelial tumors and increased the mean epithelial tumor-free survival time by 38% ( P < 0.0001), from 312 to 432 days, in Fancd2−/− Trp53+/− mice. These results show that Tempol can significantly delay tumor formation in Fancd2−/− Trp53+/− mice. Furthermore, Tempol treatment did not adversely affect the repopulating ability of FA hematopoietic stem cells. The reduction in oxidative DNA damage in Tempol-treated FA fibroblasts and mice suggests that its tumor-delaying function may be attributed to its antioxidant activity. [Cancer Res 2008;68(5):1601–8]
Ohara Augusto - One of the best experts on this subject based on the ideXlab platform.
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Tempol reduces inflammation and oxidative damage in cigarette smoke exposed mice by decreasing neutrophil infiltration and activating the nrf2 pathway
Chemico-Biological Interactions, 2020Co-Authors: Danielba Almeida Da Silva, Raphael Ferreira Queiroz, Ohara Augusto, Thiago Macedo Lopes Correia, Rafael Pereira, Robson Amaro Augusto Da SilvaAbstract:Abstract Cigarette smoke is a complex mixture capable of triggering inflammation and oxidative damage in animals at the pulmonary and systemic levels. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) reduces tissue injury associated with inflammation in vivo by mechanisms that are not completely understood. Here we evaluated the effect of Tempol on inflammation and oxidative damage induced by acute exposure to cigarette smoke in vivo. Male C57BL/6 mice (n = 32) were divided into 4 groups (n = 8 each): 1) control group exposed to ambient air (GC), 2) animals exposed to cigarette smoke for 5 days (CSG), mice treated 3) prior or 4) concomitantly with Tempol (50 mg/kg/day) and exposed to cigarette smoke for 5 days. The results showed that the total number of leukocytes and neutrophils increased in the respiratory tract and lung parenchyma of mice exposed to cigarette smoke. Likewise, MPO levels and activity as well as lipid peroxidation and lung protein nitration and carbonylation also increased. Administration of Tempol before or during exposure to cigarette smoke inhibited all the above parameters. Tempol also reduced the pulmonary expression of the inflammatory cytokines Il-6, Il-1β and Il-17 to basal levels and of Tnf-α by approximately 50%. In contrast, Tempol restored Il-10 and Tgf-β levels and enhanced the expression of Nrf2-associated genes, such as Ho-1 and Gpx2. In agreement, total GPx activity increased in lung homogenates of Tempol treated animals. Taken together, the results show that Tempol protects mouse lungs from inflammation and oxidative damage resulting from exposure to cigarette smoke, probably through reduction of leukocyte infiltration and increased transcription of some of the Nrf2-controlled genes.
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the carbonylation and covalent dimerization of human superoxide dismutase 1 caused by its bicarbonate dependent peroxidase activity is inhibited by the radical scavenger Tempol
Biochemical Journal, 2013Co-Authors: Raphael Ferreira Queiroz, Veronica Paviani, Fernando Rodrigues Coelho, Emerson Finco Marques, Paolo Di Mascio, Ohara AugustoAbstract:Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) reduces tissue injury in animal models of various diseases via mechanisms that are not completely understood. Recently, we reported that high doses of Tempol moderately increased survival in a rat model of ALS (amyotrophic lateral sclerosis) while decreasing the levels of oxidized hSOD1 (human Cu,Zn-superoxide dismutase) in spinal cord tissues. To better understand such a protective effect in vivo , we studied the effects of Tempol on hSOD1 oxidation in vitro . The chosen oxidizing system was the bicarbonate-dependent peroxidase activity of hSOD1 that consumes H2O2 to produce carbonate radical, which oxidizes the enzyme. Most of the experiments were performed with 30 μM hSOD1, 25 mM bicarbonate, 1 mM H2O2, 0.1 mM DTPA (diethylenetriaminepenta-acetic acid) and 50 mM phosphate buffer at a final pH of 7.4. The results showed that Tempol (5–75 μM) does not inhibit hSOD1 turnover, but decreases its resulting oxidation to carbonylated and covalently dimerized forms. Tempol acted by scavenging the carbonate radical produced and by recombining with hSOD1-derived radicals. As a result, Tempol was consumed nearly stoichiometrically with hSOD1 monomers. MS analyses of turned-over hSOD1 and of a related peptide oxidized by the carbonate radical indicated the formation of a relatively unstable adduct between Tempol and hSOD1-Trp32•. Tempol consumption by the bicarbonate-dependent peroxidase activity of hSOD1 may be one of the reasons why high doses of Tempol were required to afford protection in an ALS rat model. Overall, the results of the present study confirm that Tempol can protect against protein oxidation and the ensuing consequences. Abbreviations: ALS, amyotrophic lateral sclerosis; bSOD1, bovine cytosolic Cu,Zn-superoxide dismutase 1; DHR, dihydrorhodamine 123; DMPO, 5,5-dimethylpyrroline-N-oxide; DTPA, diethylenetriaminepenta-acetic acid; ESI, electrospray ionization; FTC, fluorescein 5-thiosemicarbazide; hSOD1, cytosolic Cu,Zn-superoxide dismutase; MALDI, matrix-assisted laser-desorption ionization; MS/MS, tandem MS; SOD, Cu,Zn-superoxide dismutase; Tempol, 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl; TOF/TOF, tandem time-of-flight
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Inhibition of the chlorinating activity of myeloperoxidase by Tempol: revisiting the kinetics and mechanisms.
The Biochemical journal, 2011Co-Authors: Raphael Ferreira Queiroz, Sandra Muntz Vaz, Ohara AugustoAbstract:The nitroxide Tempol (4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl) reduces tissue injury in animal models of inflammation by mechanisms that are not completely understood. MPO (myeloperoxidase), which plays a fundamental role in oxidant production by neutrophils, is an important target for anti-inflammatory action. By amplifying the oxidative potential of H2O2, MPO produces hypochlorous acid and radicals through the oxidizing intermediates MPO-I [MPO-porphyrin•+-Fe(IV)=O] and MPO-II [MPO-porphyrin-Fe(IV)=O]. Previously, we reported that Tempol reacts with MPO-I and MPO-II with second-order rate constants similar to those of tyrosine. However, we noticed that Tempol inhibits the chlorinating activity of MPO, in contrast with tyrosine. Thus we studied the inhibition of MPO-mediated taurine chlorination by Tempol at pH 7.4 and re-determined the kinetic constants of the reactions of Tempol with MPO-I (k=3.5×105 M−1·s−1) and MPO-II, the kinetics of which indicated a binding interaction (K=2.0×10−5 M; k=3.6×10−2 s−1). Also, we showed that Tempol reacts extremely slowly with hypochlorous acid (k=0.29 and 0.054 M−1·s−1 at pH 5.4 and 7.4 respectively). The results demonstrated that Tempol acts mostly as a reversible inhibitor of MPO by trapping it as MPO-II and the MPO-II–Tempol complex, which are not within the chlorinating cycle. After turnover, a minor fraction of MPO is irreversibly inactivated, probably due to its reaction with the oxammonium cation resulting from Tempol oxidation. Kinetic modelling indicated that taurine reacts with enzyme-bound hypochlorous acid. Our investigation complements a comprehensive study reported while the present study was underway [Rees, Bottle, Fairfull-Smith, Malle, Whitelock and Davies (2009) Biochem. J. 421, 79–86].
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Inhibition of myeloperoxidase-mediated protein nitration by Tempol: Kinetics, mechanism, and implications.
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Sandra Muntz Vaz, Ohara AugustoAbstract:Despite the therapeutic potential of Tempol (4-hydroxy-2,2,6,6-tetra-methyl-1-piperidinyloxy) and related nitroxides as antioxidants, their effects on peroxidase-mediated protein tyrosine nitration remain unexplored. This posttranslational protein modification is a biomarker of nitric oxide-derived oxidants, and, relevantly, it parallels tissue injury in animal models of inflammation and is attenuated by Tempol treatment. Here, we examine Tempol effects on ribonuclease (RNase) nitration mediated by myeloperoxidase (MPO), a mammalian enzyme that plays a central role in various inflammatory processes. Some experiments were also performed with horseradish peroxidase (HRP). We show that Tempol efficiently inhibits peroxidase-mediated RNase nitration. For instance, 10 μM Tempol was able to inhibit by 90% the yield of 290 μM 3-nitrotyrosine produced from 370 μM RNase. The effect of Tempol was not completely catalytic because part of it was consumed by recombination with RNase-tyrosyl radicals. The second-order rate constant of the reaction of Tempol with MPO compound I and II were determined by stopped-flow kinetics as 3.3 × 106 and 2.6 × 104 M−1 s−1, respectively (pH 7.4, 25°C); the corresponding HRP constants were orders of magnitude smaller. Time-dependent hydrogen peroxide and nitrite consumption and oxygen production in the incubations were quantified experimentally and modeled by kinetic simulations. The results indicate that Tempol inhibits peroxidase-mediated RNase nitration mainly because of its reaction with nitrogen dioxide to produce the oxammonium cation, which, in turn, recycles back to Tempol by reacting with hydrogen peroxide and superoxide radical to produce oxygen and regenerate nitrite. The implications for nitroxide antioxidant mechanisms are discussed.
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the mechanism by which 4 hydroxy 2 2 6 6 tetramethylpiperidene 1 oxyl Tempol diverts peroxynitrite decomposition from nitrating to nitrosating species
Chemical Research in Toxicology, 2002Co-Authors: Marcelo G Bonini, Ronald P Mason, Ohara AugustoAbstract:Tempol is a stable nitroxide radical that has been shown to protect laboratory animals from the injury associated with conditions of oxidative and nitrosoactive stress. Tempol's protective mechanisms against reactive oxygen species have been extensively studied, but its interactions with reactive nitrogen species remain little explored. Recently, it has been shown that Tempol is a potent inhibitor of peroxynitrite-mediated phenol nitration while it increases phenol nitrosation by a complex mechanism [Carrol et al. (2000) Chem. Res. Toxicol. 13, 294]. To obtain further mechanistic insights, we reexamined the interaction of peroxynitrite with Tempol in the absence and presence of carbon dioxide. Stopped-flow kinetic studies confirmed that Tempol does not react directly with peroxynitrite but levels off the amount of oxygen (monitored with an oxygen electrode) and nitrite (monitored by chemiluminescence) produced from peroxynitrite in the presence and absence of carbon dioxide to about 30% and 70% of the initial oxidant concentration at pH 5.4, 6.4, and 7.4. Tempol inhibited phenol nitration while increasing the amounts of 4-nitrosophenol, that attained yields close to 30% of the peroxynitrite in the presence of carbon dioxide at pH 7.4. Fast-flow EPR experiments showed detectable changes in the instantaneous Tempol concentration (maximum of 15%) only in the presence of carbon dioxide. Under these conditions, the instantaneous concentration of the carbonate radical anion was reduced by Tempol in a concentration-dependent manner. The results indicate that Tempol is oxidized by peroxynitrite-derived radicals (*OH and CO(3)(*-), in the absence and presence of carbon dioxide, respectively) to the oxoammonium cation which, in turn, is reduced back to Tempol while oxidizing peroxynitrite to oxygen and nitric oxide. The latter reacts rapidly with peroxynitrite-derived nitrogen dioxide to produce the nitrosating species, dinitrogen trioxide. Overall, the results support a role for peroxynitrite and its derived radicals in the tissue pathology associated with inflammatory conditions.
Stephen M. Hahn - One of the best experts on this subject based on the ideXlab platform.
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A Phase I Study of Topical Tempol for the Prevention of Alopecia Induced by Whole Brain Radiotherapy
Clinical cancer research : an official journal of the American Association for Cancer Research, 2004Co-Authors: James M. Metz, James B Mitchell, Eli Glatstein, Debbie Smith, Rosemarie Mick, Robert H. Lustig, Murali Cherakuri, Stephen M. HahnAbstract:Purpose: Complete alopecia is a universal complication of whole brain radiation therapy which contributes to patient anxiety over treatment. Tempol, a nitroxide radioprotector, has been shown to protect against radiation-induced alopecia in an animal model. This phase Ib study was designed to evaluate the safety and side effect profile of topical Tempol in patients with brain metastases being treated with whole brain radiotherapy. Experimental Design: Twelve patients with metastatic cancer to the brain were enrolled in the study between October 2000 and February 2003. Tempol (70 mg/ml concentration solution) was applied topically to the scalp 15 minutes before and washed off immediately after the completion of each of 10 fractions of whole brain radiation. Pharmacokinetic studies to evaluate the systemic absorption of Tempol were performed. Patients were assessed for toxicity before, during, and after Tempol administration. A secondary end point of the study, hair retention, was also scored. Results: Eleven patients were treated with topical Tempol. Adverse events that were considered possibly, probably, or definitely related to Tempol, included asymptomatic grade 2 (two patients) and grade 1 (one patient) hypoglycemia, grade 1 forehead skin redness (one patient), grade 1 dry scalp (one patient), and grade 1 tingling sensation on the scalp (one patient). Tempol was not detected in blood samples from more than 50% of the patients. Mean maximum Tempol levels for individual patients at any time point varied from 0.4 to 3.1 μmol/L. Hair retention was localized to the base of the scalp where the Tempol solution pooled after application in the first four patients on the study. Subsequently, full scalp hair retention was seen in three of final five evaluable patients after gauze had been wrapped around the head to hold the solution against the scalp. Conclusions: This study demonstrates that topical application of Tempol to the scalp before whole brain radiation is safe and well tolerated. Evidence of protection against radiation-induced alopecia was observed. A phase II study that uses a gel formulation to increase the exposure of scalp to Tempol has been initiated.
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Evaluation of the hydroxylamine Tempol-H as an in vivo radioprotector.
Free radical biology & medicine, 2000Co-Authors: Stephen M. Hahn, Murali C. Krishna, Anne Marie Deluca, Deborah Coffin, James B MitchellAbstract:Nitroxides are stable free radical compounds that protect against the toxicity of reactive oxygen species in vitro and in vivo. Tempol (Aldrich, Milwaukee, WI, USA) is a cell-permeable hydrophilic nitroxide and has been shown to be an in vitro and in vivo radioprotector. The limitations of Tempol as a systemic radioprotector are that it causes substantial reductions in arterial blood pressure when administered intravenously and is associated with seizure activity. Furthermore, Tempol is rapidly reduced to its hydroxylamine form, Tempol-H, which limits the period of time the active form of the nitroxide is available for radioprotection. Based on initial pharmacological and blood pressure experiments performed in mice, we hypothesized that the systemic administration of Tempol-H in vivo would lead to an equilibration between Tempol and Tempol-H that would limit the toxicity of the nitroxide and provide in vivo radioprotection. Tempol-H was administered in increasing doses via an intraperitoneal route to C3H mice. The maximally tolerated dose was found to be 325 mg/kg. The whole-blood pharmacology of Tempol-H was investigated with electron paramagnetic resonance spectroscopy. These studies demonstrated the appearance of Tempol in whole blood immediately after intraperitoneal injection, suggesting that rapid oxidation of Tempol-H to Tempol takes place in vivo. Although the peak concentration of Tempol in whole blood after administration of Tempol-H did not reach the same levels as those observed when Tempol is administered, the whole-blood levels of Tempol were similar by 10 min after injection. Tempol-H provided protection against the lethality of whole-body radiation in C3H mice at 30 d with a dose modification factor of 1.3, which is similar to the results obtained with Tempol. Hemodynamic measurements in C3H mice after intravenous injection showed that Tempol-H produced little effect on blood pressure or pulse compared with Tempol. Tempol-H is a systemic in vivo radioprotector of C3H mice and is associated with less hemodynamic toxicity than Tempol.
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Evaluation of Tempol radioprotection in a murine tumor model
Free radical biology & medicine, 1997Co-Authors: Stephen M. Hahn, Anne Marie Deluca, David Venzon, Francis J. Sullivan, C. Murali Krishna, Nancy Wersto, Angelo Russo, James B MitchellAbstract:Abstract Tempol, a stable nitroxide free radical compound, is an in vitro and in vivo radioprotector. Previous studies have shown that Tempol protects C3H mice against whole-body radiation-induced bone marrow failure. In this study, the radioprotection of tumor tissue was evaluated. RIF-1 tumor cells were implanted in female C3H mice 10 d prior to radiation. Groups of mice were injected intraperitoneally with Tempol (275 mg/kg) or PBS followed 10 min later by a single dose of radiation to the tumor bed. Tumor growth curves generated after 10 and 33.3 Gy doses of radiation showed no difference in growth between the Tempol- and PBS-treated animals. A full radiation dose-response experiment revealed a tumor control dose in 50% of the animals in 30 d (TCD 50/30 ) value of 36.7 Gy for Tempol-treated mice and 41.8 Gy for saline-treated mice suggesting no protection of the RIF-1 tumor by Tempol. Tumor pharmacokinetics were done to determine why Tempol differentially protected bone marrow and not tumor cells. Differential reduction of Tempol in the RIF-1 tumor and bone marrow was evaluated with EPR spectroscopy 10, 20, and 30 min after injection. Bioreduction of Tempol to its corresponding hydroxylamine (which is not a radioprotector) occurred to a greater extent in RIF-1 tumor cells compared to bone marrow. We conclude that the differences in radioprotection may result from enhanced intratumor bioreduction of Tempol to its nonradioprotective hydroxylamine analogue. The nitroxides as a class of compounds may provide a means to exploit the redox differences between normal tissues and tumors. © 1997 Elsevier Science Inc.
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Tempol, a Stable Free Radical, Is a Novel Murine Radiation Protector
Cancer research, 1992Co-Authors: Stephen M. Hahn, Ayelet M. Samuni, Zelig Tochner, C M Krishna, Joseph Glass, L Wilson, M. Sprague, David Venzon, Eli Glatstein, James B MitchellAbstract:Nitroxide compounds are stable free radicals which were previously investigated as hypoxic cell radiosensitizers. The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) has recently been shown to protect aerated cells in culture against superoxide generated from hypoxanthine/xanthine oxidase, hydrogen peroxide, and radiation-induced cytotoxicity and to modestly sensitive hypoxic cultured cells. To extend these observations from the cellular level to the whole animal, the toxicity, pharmacology, and in vivo radioprotective effects of Tempol were studied in C3H mice. The maximum tolerated dose of Tempol administered i.p. was found to be 275 mg/kg, which resulted in maximal Tempol levels in whole blood 5-10 min after injection. Mice were exposed to whole-body radiation in the absence or presence of injected Tempol (275 mg/kg) 5-10 min after administration. Tempol treatment provided significant radioprotection (P less than 0.0001); the dose of radiation at which 50% of Tempol-treated mice die at 30 days was 9.97 Gy, versus 7.84 Gy for control mice. Tempol represents a new class of in vivo, non-sulfur-containing radiation protectors. Given the potential for hypoxic radiosensitization and aerobic cell radioprotection, Temporal or other analogues may have potential therapeutic application.
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Inhibition of oxygen-dependent radiation-induced damage by the nitroxide superoxide dismutase mimic, Tempol
Archives of biochemistry and biophysics, 1991Co-Authors: James B Mitchell, Stephen M. Hahn, Murali C. Krishna, William Degraff, Dwight Kaufman, Amram Samuni, Eli Finkelstein, Min S. Ahn, Janet Gamson, Angelo RussoAbstract:Stable nitroxide radicals have been previously shown to function as superoxide dismutase (SOD)2 mimics and to protect mammalian cells against superoxide and hydrogen peroxide-mediated oxidative stress. These unique characteristics suggested that nitroxides, such as 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), might protect mammalian cells against ionizing radiation. Treating Chinese hamster cells under aerobic conditions with 5, 10, 50, and 100 mM Tempol 10 min prior to X-rays resulted in radiation protection factors of 1.25, 1.30, 2.1, and 2.5, respectively. However, the reduced form of Tempol afforded no protection. Tempol treatment under hypoxic conditions did not provide radioprotection. Aerobic X-ray protection by Tempol could not be attributed to the induction of intracellular hypoxia, increase in intracellular glutathione, or induction of intracellular SOD mRNA. Tempol thus represents a new class of non-thiol-containing radiation protectors, which may be useful in elucidating the mechanism(s) of radiation-induced cellular damage and may have broad applications in protecting against oxidative stress.
Anne M. Dorrance - One of the best experts on this subject based on the ideXlab platform.
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Tempol a superoxide dismutase mimetic prevents cerebral vessel remodeling in hypertensive rats
Microvascular Research, 2010Co-Authors: Paulo W. Pires, Christian Deutsch, Jonathon L. Mcclain, Curt Thomas Rogers, Anne M. DorranceAbstract:Increased reactive oxygen species (ROS) production is involved in the pathogenesis of hypertension and stroke. The effects of ROS on cerebral vessels from hypertensive rats have not been studied. We hypothesized that Tempol, a superoxide dismutase mimetic, would prevent middle cerebral artery (MCA) remodeling in stroke-prone spontaneously hypertensive rats (SHRSP). Six-week-old male SHRSP were treated with Tempol (1mM) for 6weeks. The MCA was then removed and mounted in a pressure myograph to study tone generation, vessel reactivity, and passive vessel structure. Data are shown as mean±SEM, Tempol vs. control. Plasma thiobarbituric acid reactive substances (TBARS) were decreased by Tempol treatment (14.15±1.46 vs. 20.55±1.25nM of malondialdehyde [MDA]/ml, p=0.008). Maximum serotonin-induced constriction was increased by Tempol treatment, without changes in dilation to adenosine diphosphate or tone generation. At an intralumenal pressure of 80mmHg, Tempol caused a dramatic increase in the MCA lumen diameter (246±5 vs. 207±3μm, p<0.001), outer diameter (281±5 vs. 241±3μm, p<0.001), lumen cross-sectional area, and vessel cross-sectional area. Collagen IV mRNA expressions were increased by 2.4-fold after Tempol treatment. These results suggest that ROS are involved in the remodeling of the cerebral vasculature of SHRSP and that ROS scavenging can attenuate this process.
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Tempol, a superoxide dismutase mimetic, prevents cerebral vessel remodeling in hypertensive rats.
Microvascular research, 2010Co-Authors: Paulo W. Pires, Christian Deutsch, Jonathon L. Mcclain, Curt Thomas Rogers, Anne M. DorranceAbstract:Increased reactive oxygen species (ROS) production is involved in the pathogenesis of hypertension and stroke. The effects of ROS on cerebral vessels from hypertensive rats have not been studied. We hypothesized that Tempol, a superoxide dismutase mimetic, would prevent middle cerebral artery (MCA) remodeling in stroke-prone spontaneously hypertensive rats (SHRSP). Six-week-old male SHRSP were treated with Tempol (1mM) for 6weeks. The MCA was then removed and mounted in a pressure myograph to study tone generation, vessel reactivity, and passive vessel structure. Data are shown as mean±SEM, Tempol vs. control. Plasma thiobarbituric acid reactive substances (TBARS) were decreased by Tempol treatment (14.15±1.46 vs. 20.55±1.25nM of malondialdehyde [MDA]/ml, p=0.008). Maximum serotonin-induced constriction was increased by Tempol treatment, without changes in dilation to adenosine diphosphate or tone generation. At an intralumenal pressure of 80mmHg, Tempol caused a dramatic increase in the MCA lumen diameter (246±5 vs. 207±3μm, p
Ulf Simonsen - One of the best experts on this subject based on the ideXlab platform.
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Negative inotropic and hypotensive effects of the superoxide dismutase mimetic Tempol in pigs.
European journal of pharmacology, 2014Co-Authors: Mads Nyboe Kristensen, Ulf Simonsen, Christian Alcaraz Frederiksen, Eleonora Sivén, Janus Adler Hyldebrandt, Peter Juhl-olsen, Erik Sloth, Niels H. BuusAbstract:Abstract Through interference with free radicals, the nitroxide Tempol potentially increases bioavailability of nitric oxide (NO) and along with modulation of potassium channels reduces blood pressure (BP). We studied whether Tempol in pigs lowers BP by mechanisms sensitive to inhibition of NO synthase or large conductance calcium-activated potassium channels (BK Ca ). The cardiovascular effects of intravenous Tempol (25–50 mg/kg) were examined in anesthetized pigs with myocardial function being evaluated by echocardiography. While saline-treated animals remained hemodynamically stable, Tempol induced fast, dose-dependent and transient reductions in BP lasting 5–10 min with a simultaneous impairment of left ventricular contraction. Pretreatment with the NO synthase (NOS) inhibitor N G -nitro- l -arginine methyl ester ( l -NAME, 4 mg/kg) or a blocker of BK Ca (tetraethylammonium (TEA), 100 mg/h) increased baseline BP but also enhanced BP reductions to Tempol. Isolated myocardial trabeculae subjected to an identical protocol also demonstrated dose-related reductions in contractility to Tempol. This effect was not affected by l -NAME, but attenuated by TEA. In isolated mesenteric resistance arteries contracted with noradrenaline, Tempol caused small postjunctional l -NAME sensitive relaxations, while neurogenic contractions were inhibited by Tempol by TEA-sensitive mechanisms and mechanisms insensitive to TEA and l -NAME. In conclusion intravenous Tempol induces fast transient reductions in BP associated with simultaneous reductions in myocardial contraction. Tempol exerts direct negative inotropic effects which are partly sensitive to BK Ca -blockade but independent of NOS inhibition. In addition Tempol has direct vasodilatory effects despite NOS and potassium channel blockade. The negative inotropic and hypotensive effects raise concerns using Tempol, or structurally similar drugs, for intravenous use.
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the superoxide dismutase mimetic Tempol blunts right ventricular hypertrophy in chronic hypoxic rats
British Journal of Pharmacology, 2004Co-Authors: Britt Elmedal, Michael J Mulvany, Mette Yde Dam, Ulf SimonsenAbstract:1. The purpose of this study was to investigate whether a membrane-permeable superoxide dismutase mimetic, Tempol, added either alone or in combination with the nitric oxide (NO) donor molsidomine, prevents the development of pulmonary hypertension (PH) in chronic hypoxic rats. 2. Chronic hypobaric hypoxia (10% oxygen) for 2 weeks increased the right ventricular systolic pressure (RVSP), right ventricle and lung wet weight. Relaxations evoked by acetylcholine (ACh) and the molsidomine metabolite SIN-1 were impaired in isolated proximal, but not distal pulmonary arteries, from chronic hypoxic rats. 3. Treatment with Tempol (86 mg x kg(-1) day(-1) in drinking water) normalized RVSP and reduced right ventricular hypertrophy, while systemic blood pressure, lung and liver weights, and blunted ACh relaxation of pulmonary arteries were unchanged. 4. Treatment with molsidomine (15 mg x kg(-1) day(-1) in drinking water) had the same effects as Tempol, except that liver weight was reduced, and potassium and U46619-evoked vasoconstrictions in pulmonary arteries were increased. Combining Tempol and molsidomine did not have additional effects compared to Tempol alone. ACh relaxation in pulmonary arteries was not normalized by these treatments. 5. The media to lumen diameter ratio of the pulmonary arteries was greater for the hypoxic rats compared to the normoxic rats, and was not reversed by treatment with Tempol, molsidomine, or the combination of Tempol and molsidomine. 6. We conclude that Tempol, like molsidomine, is able to correct RVSP and reduce right ventricular weight in the rat hypoxic model. Functional and structural properties of pulmonary small arteries were little affected. The results support the possibility that superoxide dismutase mimetics may be a useful means for the treatment of PH.
