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Diabetes 53:2574-2580, 2004
© 2004 by the American Diabetes Association, Inc.

A Salen-Manganese Catalytic Free Radical Scavenger Inhibits Type 1 Diabetes and Islet Allograft Rejection

Angelica P. Olcott1, Georges Tocco2, Jide Tian1, Dan Zekzer1, Jon Fukuto1, Louis Ignarro1, and Daniel L. Kaufman1

1 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California
2 Harvard Medical School, Boston, Massachusetts

Reactive oxygen species, such as superoxide, and nitrogen oxides, such as peroxynitrite, are thought to contribute to ß-cell destruction during the disease process that leads to type 1 diabetes. EUK-8 is a member of a new class of synthetic salen-manganese compounds with low toxicity that possess catalytic superoxide dismutase, peroxidase, and catalase activity that can inactivate superoxide and nitrogen oxides (e.g., peroxynitrite and nitrogen dioxide). We observed that EUK-8 administration inhibited the adoptive transfer of type 1 diabetes to NOD mice. In addition, administration of EUK-8 to NOD mice with established autoimmunity completely prevented the development of type 1 diabetes for up to 1 year in age, even though the treatment was discontinued after 35 weeks of age. EUK-8 treatment also prolonged the survival of islet allografts in newly diabetic NOD mice. Thus, reactive oxygen and nitrogen species contribute to the pathoetiology of both spontaneous type 1 diabetes and allograft rejection. In cultures of NIT-1 cells, EUK-8 inhibited cytotoxicity caused by superoxide as well as nitric oxide. Collectively, our findings implicate a greater role for nitrogen oxides (other than peroxynitrite) in ß-cell damage. Antioxidants designed to prevent the formation of both cytotoxic reactive oxygen and nitrogen species may effectively protect ß-cells from spontaneous autoimmunity and alloresponses.

Address correspondence and reprint requests to Daniel L. Kaufman, Department of Molecular and Medical Pharmacology, UCLA School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-1735. E-mail: dkaufman{at}mednet.ucla.edu


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