Tomoyuki Yoneta

ROLE OF OXYGEN-DERIVED FREE RADICALS IN GASTRIC MUCOSAL INJURY INDUCED BY ISCHEMIA OR ISCHEMIA-REPERFUSION IN RATS

Oxygen-derived free radicals have been implicated as possible mediators in the development of tissue injury induced by ischemia and reperfusion. Clamping of the celiac artery in rats reduced the gastric mucosal blood flow to 10% of that measured before the clamping. The area of gastric erosions and thiobarbituric acid (TBA) reactants in gastric mucosa were significantly increased 60 and 90 min after clamping. These changes were inhibited by treatment with SOD and catalase. Thirty and 60 min after reoxygenation. produced by removal of the clamps following 30 min of ischemia, gastric mucosal injury and the increase in TBA reactants were markedly aggravated compared with those induced by ischemia alone. SOD and catalase significantly inhibited these changes. The serum alpha-tocopherol/cholesterol ratio, an index of in vivo lipid peroxidation, was significantly decreased after long periods of ischemia (60 and 90 min), or after 30 and 60 min of reperfusion following 30 min of ischemia. These results indicated that active oxygen species and lipid peroxidation may play a role in the pathogenesis of gastric mucosal injury induced by both ischemia alone and ischemia-reperfusion. Although, allopurinol inhibited the formation of gastric mucosal injury and the increase in TBA reactants in gastric mucosa, the depletion of polymorphonuclear leukocytes (PMN) counts induced by an injection of anti-rat PMN antibody did not inhibit these changes. As compared with the hypoxanthine-xanthine oxidase system. PMN seem to play a relatively small part in the formation of gastric mucosal injury induced by ischemia-reperfusion.

The antioxidant properties of a novel zinc-carnosine chelate compound, N-(3-aminopropionyl)-l-histidinato zinc

A zinc-carnosine chelate compound, Z-103, attenuates gastric mucosal injuries and inhibits the increase of lipid peroxide in the gastric mucosa induced by burn shock or ischemia-reperfusion. However, the exact mechanism of the antioxidative effect of Z-103 is not clear. The antioxidant properties of a novel anti-peptic ulcer agent Z-103 in vitro were compared with those of zinc ion and L-carnosine. Z-103 scavenged superoxide anion radicals. Z-103 and ZnSO4, but not L-carnosine, inhibited the superoxide generation from polymorphonuclear leukocytes stimulated by opsonized zymosan, and also inhibited the generation of hydroxyl radicals by the Fenton reaction. The increase of lipid peroxides produced by rat brain homogenates and liver microsomes was also inhibited by Z-103 and ZnSO4. These findings indicate that the strong anti-ulcer and antioxidative actions of Z-103 in vivo are due to a combination of these antioxidant actions in vitro.

Effect of Zinc-Carnosine Chelate Compound (Z-103), A Novel Antioxidant, on Acute Gastric Mucosal Injury Induced by Ischemia-Reperfusion in Rats

The protective effect of a novel synthetic zinc-carnosine chelate compound, zinc N-(3-aminopropionyl)-L-histidine (Z-103), on the gastric mucosal injury induced by ischemia-reperfusion was studied in rats. Ischemia and reperfusion injury was produced on the rat stomach by applying a small clamp to the celiac artery for 30 min and by removal of the clamp for 30 min. The decrease in the gastric mucosal blood flow was not influenced by the treatment with Z-103. The increase in total area of the erosions on the stomach after ischemia-reperfusion and the increase in lipid peroxides in the gastric mucosa were significantly inhibited by the oral administration of Z-103. In addition, Z-103 inhibited lipid peroxidation of rat brain homogenate and liver microsome in vitro. These results suggest that the protective effect of Z-103 against the aggravation of gastric mucosal injury induced by ischemia-reperfusion may be due to its inhibitory effect on lipid peroxidation.

Effects of Polaprezinc on Lipid Peroxidation, Neutrophil Accumulation, and TNF-α Expression in Rats with Aspirin-Induced Gastric Mucosal Injury

We examined the roles of lipid peroxidation, neutrophil accumulation, and inflammatory cytokines in the protective effect of polaprezinc against aspirin-induced gastric mucosal injury in rats. The intragastric administration of acidified aspirin induced hyperemia and hemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited in a dose-dependent manner by treatment with polaprezinc. The increases in thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity 3 hr after aspirin administration were significantly inhibited by pretreatment with polaprezinc. The gastric concentration of TNF-α increased after aspirin administration, and the increase was also inhibited in a dose-dependent manner by treatment with polaprezinc. The peak expression of TNF-α mRNA 1 hr after aspirin administration was inhibited by 30 mg/kg of polaprezinc. Based on these data, the beneficial effects of polaprezinc on aspirin-induced gastric mucosal injury may be attributed to its antioxidative and antiinflammatory properties.

A new gastric ulcer model in rats produced by ferrous iron and ascorbic acid injection.

We developed a new gastric ulcer model in which the ulcers are induced by the local injection of a ferrous iron and ascorbic acid (Fe/ASA) solution into the gastric wall. These ulcers resemble human gastric ulcers that penetrate the muscularis mucosa. The involvement of oxygen radical-mediated lipid peroxidation as the cause of these ulcers was investigated. With ferrous iron or ascorbic acid alone, gastric ulcers did not form, whereas penetrating ulcers were produced by the simultaneous injection of the Fe/ASA solution in a dose-dependent manner. Lipid peroxides significantly accumulated in the gastric mucosa from 1 to 24 h after the injection of the Fe/ASA solution. This increase in lipid peroxides preceded grossly evident gastric ulcer. Treatment with superoxide dismutase (SOD, recombinant human CuZnSOD) significantly reduced the size of the ulcers and inhibited the accumulation in lipid peroxides in the gastric mucosa, while treatment with apo-SOD or heat-inactivated SOD did not. These results suggest that lipid peroxidation mediated by oxygen radicals plays a crucial role in the pathogenesis of the gastric ulceration induced by the Fe/ASA solution.

Antioxidative Action of Zinc-Carnosine Compound Z-103

The objective of the present study was to examine the anti-free radical action of Z-103 in vitro. Z-103 is a novel synthetic compound of zinc and carnosine (β-alanyl-L-histidine) which has strong anti-ulcer action in many types of animal models.1Free radicals have come to considered to be playing a role in the pathogenesis of gastric mucosal injuries2,3. The antifree radical action of Z-103 were expected because zinc and carnosine have antioxidative properties4,5. To know its anti-free radical action in vitro will be significant to understand its mechanism of action as anti-ulcer drug.

Zinc-Carnosine Chelate Compound (Z-103) Attenuates Acute Gastric Mucosal Injury Induced by Ischemia-Reperfusion in Rats

A novel synthesized agent, zinc N-(3-aminopropionyl)-L-histidine (Z-103, Fig. 1), is a chelate compound that consists of zinc iron and L-carnosine. Carnosine was discovered in 1900 by Gulewitsch and Amiradzibi1 from meat extract, and is reportedly present in the range of 1–20 mM in the skeletal muscle and brain of many animals and humans2. Recently, several reports have described the antioxidative activity of carnosine, such as efficient singlet oxygen scavengers3, peroxy radical scavengers4, efficient chelating agent for copper and other transitional metals4, and Superoxide scavenging activity in the presence of copper or zinc5.

Acknowledgment to Referees

Abdelkarim, Ahmad A. Abreu Jr., Murillo J. N. Ahmad, Mansur Akan, Huseyin Aksoy Dogan, Alev Alcaraz, Miguel Aras, Mutan H Ariji, Yoshiko Ariji, Eiichiro Asaumi, Junichi Auluck, Ajit Aydin, Ulkem Baba, Rika Baksi, B Guniz Benn, Douglas Berkhout, Erwin Beyzadeoglu, Murat Bhakdinaronk, Anonknart Bianchi, Silvio D Bollen, Anne-Marie Bousquet, Frederic Brand, John Briner, Andres Brocklebank, Laetitia Brooks, Sharon L Brown, Jacqueline Bryant, Jacqueline A Campos, Paulo S F Carmichael, Fiona Cavalcanti, Marcelo Cederberg, Robert Cevidanes, Lucia Chandak, Rakhi Chaurasia, Akhilanand Chen, Yi-Jane Chen, Curtis Chiandussi, Silvia Cho, Bong Hae Cho, Seok Hyun Choi, Soon-Chul Cizmeci Senel, Figen Coleman, Gary Colosi, Dan C Dalili, Zahra Danforth, Robert Degerliyurt, Mehmet K Delantoni, Antigone Deserno, Thomas Dixon, Debra do Espirito Santo, Alexandre R Drage, Nicholas Drozdzowska, Bogna Edwards, Paul C Edwards, Sean Eggers, Georg Eickholz, Peter Ekram, Mohamed Eleazer, Paul D Enciso, Reyes Eraso, Francisco Farid, Mary M Farman, Taeko Farman, Allan G Faustino, Simone E S Ferretti, Fabio Fidler, Ales Firth, Norman A Flint, Diane J Flygare, Lennart Fontanella, Vania Francis, Ian Friedland, Bernard Friedlander, Arthur Gaviao, Maria B D Geist, James R Gelbrich, Bianca Geraets, Wil Gordy, Frances Gossuin, Yves Gotfredsen, Erik Grondahl, Hans-Goran Guler, Nurhan Hadjidekova, Valeria Haiter-Neto, Francisco Harwood, Anne Hashimoto, Koji Hassfeld, Stefan Hayakawa, Yoshihiko Heaven, Tim Hellen-Halme, Kristina Heo, Min-Suk Hildebolt, Charles Hintze, Hanne Hisatomi, Miki Hishikawa, Toshimitsu Hollender, Lars Honda, Kazuya Horner, Keith Ida, Mizue Ilguy, Dilhan Isberg, Annika Izumi, Masahiro Jacobs, Reinhilde Janhom, Apirum Jayaram, Govindaraj Kabenge, Catherine A Kaffe, Israel Kalathingal, Sajitha Katona, Thomas R Kawai, Taisuke Khan, Emad Kiroglu, Yilmaz Knutsson, Kerstin Koenig, Lisa Kondylidou-Sidira, Athina Kopp, Sigmar Kositbowornchai, Suwadee Kotre, John Kozai, Yusuke Kozakiewicz, Marcin Kurabayashi, Tohru Kurita, Hiroshi Lagravere, Manuel O Lam, Ernest Lamberti, Patricia Lascala, Cesar A L.de Moraes, Mari Eli Ledesma-Montes, Constantino Lee, Peggy P F Li, Gang Li, Thomas Liang, Hui Lindh, Christina Linney, Alf Ludlow, John Ma, Xu-Chen Macan, Darko Macdonald, Ross MacDonald-Jankowski, David Major, Paul Masood, Farah Matsopoulos, George K Mileman, Philip A Miller, Arthur J Minowa, Kazuyuki Mohamed, Maha Mol, Andre Molteni, Roberto Monsour, Paul Morimoto, Yasuhiro Mosier, Kristine Mupparapu, Muralidhar Murakami, Shumei Nair, Madhu Nakayama, Eiji Nalcaci, Ruhi Nambiar, Phrabhakaran Nekooei, Sirous Ng, Suk Y Nixon, Paul P Noffke, Claudia Noujeim, Marcel Odell, Eddie Ohman, Anders Olszewski, Raphael Packota, Garnet Parker, Mohamed E Parks, Ted Peltola, Jaakko Pena, Nilson Perez, Danyel E C Perschbacher, Susanne Petersson, Arne Pharoah, Michael Platin, Enrique Potluri, Anitha Ramos, Flavia M Redpath, Thomas Richards, Philip Rout, John Rudek, Ivan Rushton, Vivian Saba, Luca Sahin, Sermet Dentomaxillofacial Radiology (2009) 38, 556–557 ’ 2009 The British Institute of Radiology