infection.

Non-invasive Redox Imaging of Cisplatin-Induced Nephrotoxicity Using Overhauser-MRI Fuminori Hyodo1, Yohei Honda1, Tatsuya Naganuma2, Kazuhiro Ichikawa1, Ken-ichi Yamada1, and Hideo Utsumi1 1Kyushu University, Japan, 2Japan Redox Inc., Japan Breakdown of redox homoeostasis may lead to oxidative stress and can induce many pathological conditions. Therefore, imaging of tissue redox status could have one of the markers for drug discovery and clinical applications for novel diagnosis. Overhauser-MRI (OMRI) enables visualization of tissue redox status in animals based on dynamic nuclear polarization (DNP). Cisplatin, major anti-cancer agent, is known to often cause nephrotoxicity, suggesting the involvement of reactive oxygen species (ROS). in this presentation, we demonstrated non-invasive redox analysis of cisplatin-induced nephrotoxicity and protective effects of antioxidants using OMRI. The in vivo redox status in kidney was monitored from enhanced OMRI intensity decay rate of intravenously injected nitroxyl probe. the decay rate of cisplatin-treated mice was slower than that of control, suggesting that cisplatin causes a change of redox status even 3hr after injection of cisplatin. in addition, decay rate in cisplatin-treated group was recovered after treatment of antioxidants such as tempol or N-Acetyl Cysteine (NAC). on the other hand, image intensity of T2 weighted MRI in kidney was increased from 24hr after injection of cisplatin. in addition, blood urea nitrogen (BUN) level was increased from 72hr. These results suggested OMRI detected the early change of in vivo tissue redox status before detection of conventional methods.

Molecular Imaging of Nitroxyl Radical Aqueous Solution in Stomach of an Animal Model Using Circular-Transport Overhauser-Enhanced MRI System Shinji Ito1, Fuminori Hyodo1, Keiji Yasukawa1, Tatsuya Naganuma2, Ichikawa Kazuhiro1, and Utsumi Hideo1 1Kyushu University, Japan, 2Japan Redox Co., Ltd., Japan In molecular imaging of a nitroxyl radical aqueous solutions in stomach, it is important to monitor anatomical location of the solution in the body, considering liquidity of the solution to bowels and gastric absorption for its water content. Our home-built 1.5T Circular-Transport Overhauser-enhanced MR Imaging (ctOMRI) system provides high-quality MR and free radical images by repeating a series of electron spin resonance and subsequent MR imaging while circularly transporting a sample. Using this system, we succeeded in obtaining both molecular images of the nitroxyl radicals and its water content simultaneously for some nitroxyl radical aqueous solutions orally administered into stomachs of mice. There are no significant differences in pharmacokinetics of radical decays in stomachs of the animal model among Tempol, Carboxy-PROXYL, and Carbamoyl-PROXYL aqueous solutions.

Role of Nicotine in Oxidative Stress Rakesh Kacham1, Shakila Tobwala1, and Nuran Ercal1 1Missouri University of Science and Technology, United States Nicotine is a major alkaloid that is present in tobacco products and in lower amounts in potatoes, tomatoes, and eggplant. It is the addictive compound in cigarettes and plays a protective role in neurodegenerative disorders such as and Schizophrenia. Researchers have found that short-term administration of nicotine improves the memory process by reducing oxidative stress in the brain. We, therefore, studied the antioxidant properties of nicotine. Our preliminary studies have shown that nicotine can inhibit free radical generation, to a certain extent, by ured reactive oxygen species (ROS) in the cell lines of the alveolar, blood brain barrier, liver, and Chinese hamster ovaries that had been pre-treated with 1mM of nicotine for 2 hours. Results showed that nicotine inhibits the generation of ROS by blockinreaction. This was later confirmed by through metal chelation with nicotine in a concentration dependent fashion. Moreover, we studied the effects of nicotine on glutathione levels in alveolar cells that were treated with 0.4mM t-BHP for 3 hours. Results showed that nicotine increases glutathione levels in t-BHP treated group but not significantly. Overall our preliminary data indicates that nicotine might function as an antioxidant through metal chelation, but further studies are needed.

Synthesis of the Artificial Catalase with Metal Chelate Activity for Pharmaceutics Hiroyoshi Kawakami1, Shohei Yamaguchi1, and Shoichiro Asayama1 1Tokyo Metropolitan University, Japan In a biological system, the antioxidant enzymes such as superoxide dismutase (SOD) and catalase, contribute dominatingly to enhance cellular antioxidative defense against oxidative stress. Manganese (Mn) porphyrin derivatives are well known as a SOD mimic to eliminate O2 to H2O2. However, the resulting H2O2 produced by Mn-porphyrin as SOD mimic is easily converted to the toxic hydroxyl radical ( OH) through the Fenton reaction in the presence of transition metal ions such as Fe2+ and Cu+. Therefore, a new artificial enzyme with the chelate activity of transition metal ions as well as catalase activity is desirable for efficiently responding to oxidative stress in a biological system. We have already reported the antioxidant Mn porphyrin dimer (MnPD) to dismute H2O2 like catalase in water. These backgrounds have led us to synthesize the MnPD catalase mimic with metal chelate activity. In this study, we have synthesized a new Mn-porphyrin dimer, MnPD-N3, which has two cationic Mn-porphyrins linked with the spacer, diethylenetriamine moiety, to chelate the metal ion. in addition, two Mn-porphyrins to take parallel conformation are known to be necessary for synergetic working in catalase-like activity. Therefore, it is expected that MnPD-N3 can exhibit catalase-like activity only in the presence of metal ions.

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