Nitroxides (lead compound, Tempol), which are potent antioxidants, are proving to have broad utility in a number of disease processes and/or conditions that represent excessive oxidative stress. The fact that nitroxides exert activity over such a range of disease conditions speaks to the importance of free radical reactions in tissue. Likewise, it is becoming apparent that free radicals are important in normal molecular signaling pathways and related gene expression. We have further demonstrated that Tempol application can provide protection of normal tissues exposed to radiation. Using a miniature pig (minipig) model for irradiation-induced oral mucositis, animals were exposed to daily fractionated radiation (5 x 6 Gy), where the nitroxide Tempol was administered i.p. 10 min before each radiation fraction. Tempol provided protection against radiation-induced mucositis and ulceration. These findings are consistent with mouse studies conducted recently showing comparable radioprotective effects. We have also finished studies evaluating Tempol to reduce 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). The goal of these 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-gamma and tumor necrosis factor-alpha. TEMPOL administration was associated with an enrichment of CD8+ T cell populations and CD4+FoxP3+ regulatory populations. Tempol treatment also reduced the severity of clinical disease when administered after the induction of disease, and also after the onset of clinical symptoms. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIASC006387-30
Application #
9556761
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
30
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Hu, L; Wang, Y; Cotrim, A P et al. (2017) Effect of Tempol on the prevention of irradiation-induced mucositis in miniature pigs. Oral Dis 23:801-808
Neil, Sarah; Huh, Jaebong; Baronas, Victoria et al. (2017) Oral administration of the nitroxide radical TEMPOL exhibits immunomodulatory and therapeutic properties in multiple sclerosis models. Brain Behav Immun 62:332-343
Kagiya, Go; Ogawa, Ryohei; Choudhuri, Rajani et al. (2015) Selective enhancement of hypoxic cell killing by tempol-regulated suicide gene expression. Oncol Rep 34:1065-73
Kim, Christine H J; Mitchell, James B; Bursill, Christina A et al. (2015) The nitroxide radical TEMPOL prevents obesity, hyperlipidaemia, elevation of inflammatory cytokines, and modulates atherosclerotic plaque composition in apoE-/- mice. Atherosclerosis 240:234-41
Wu, Haitao; Coble, Vincent; Vasalatiy, Olga et al. (2014) An efficient synthesis of 3-(N-piperidinemethyl)-2, 2, 5, 5-tetramethyl-1-oxy-3-pyrroline, a promising radioprotector for cancer radiotherapy. Tetrahedron Lett 55:5570-5571
Li, Fei; Jiang, Changtao; Krausz, Kristopher W et al. (2013) Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 4:2384
Han, Gangwen; Bian, Li; Li, Fulun et al. (2013) Preventive and therapeutic effects of Smad7 on radiation-induced oral mucositis. Nat Med 19:421-8
Li, Fei; Pang, Xiaoyan; Krausz, Kristopher W et al. (2013) Stable isotope- and mass spectrometry-based metabolomics as tools in drug metabolism: a study expanding tempol pharmacology. J Proteome Res 12:1369-76
Li, Fei; Patterson, Andrew D; Krausz, Kristopher W et al. (2013) Metabolomics reveals that tumor xenografts induce liver dysfunction. Mol Cell Proteomics 12:2126-35
Hyodo, Fuminori; Davis, Ryan M; Hyodo, Emi et al. (2012) The relationship between tissue oxygenation and redox status using magnetic resonance imaging. Int J Oncol 41:2103-8

Showing the most recent 10 out of 23 publications