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The Journal of Neuroscience, June 1, 1998, 18(11):4083-4095

Purification of a Multipotent Antideath Activity from Bovine Liver and Its Identification as Arginase: Nitric Oxide-Independent Inhibition of Neuronal Apoptosis

Fred Esch¹, Kuo-I Lin⁴, Anna Hills¹, Khalequz Zaman⁴, Jay M. Baraban³, Sukalyan Chatterjee⁴, Lee Rubin¹, David E. Ash², and Rajiv R. Ratan^{4, 5}

¹ Eisai London Research Laboratories, London, England, ² Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania, ³ Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland, and ⁴ Department of Neurology and ⁵ Program in Neuroscience, Harvard Medical School and The Beth Israel-Deaconess Medical Center, Boston, Massachusetts

Catalase is an antioxidant enzyme that has been shown to inhibit apoptotic or necrotic neuronal death induced by hydrogen peroxide. We report the purification of a contaminating antiapoptotic activity from a commercial bovine liver catalase preparation by following its ability to inhibit apoptosis when applied extracellularly in multiple death paradigms. The antiapoptotic activity was identified by protein microsequencing as arginase, a urea cycle and nitric oxide synthase-regulating enzyme, and confirmed by demonstrating the presence of antiapoptotic activity in a >97% pure preparation of recombinant arginase. The pluripotency of recombinant arginase was demonstrated by its ability to inhibit apoptosis in multiple paradigms including rat cortical neurons induced to die by glutathione depletion and oxidative stress, by 100 nM staurosporine treatment, or by Sindbis virus infection. The protective effects of arginase in these apoptotic paradigms, in contrast to previous studies on excitotoxic neuronal necrosis, are independent of nitric oxide synthase inhibition. Rather, arginase-induced depletion of arginine leads to inhibition of protein synthesis, resulting in cell survival. Because inhibitors of nitric oxide synthesis and of protein synthesis have been shown to decrease necrotic and apoptotic death, respectively, in animal models of stroke and spinal cord injury, arginine-depleting enzymes, capable of simultaneously inhibiting protein synthesis and nitric oxide generation, may be propitious therapeutic agents for acute neurological diseases. Furthermore, our results suggest caution in attributing the cytoprotective effects of some catalase preparations to catalase.

Key words: apoptosis; glutathione; neurons; oxidative stress; arginase; nitric oxide; staurosporine

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18114083-13$05.00/0

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