PURIFICATION OF A MULTIPOTENT ANTIDEATH ACTIVITY FROM BOVINE LIVER AND ITS IDENTIFICATION AS ARGINASE - NITRIC OXIDE-INDEPENDENT INHIBITIONOF NEURONAL APOPTOSIS

Catalase is an antioxidant enzyme that has been shown to inhibit apopt otic or necrotic neuronal death induced by hydrogen peroxide. We repor t the purification of a contaminating antiapoptotic activity from a co mmercial bovine liver catalase preparation by following its ability to inhibit apoptosis when applied extracellularly in multiple death para digms. The antiapoptotic activity was identified by protein microseque ncing as arginase, a urea cycle and nitric oxide synthase-regulating e nzyme, and confirmed by demonstrating the presence of antiapoptotic ac tivity in a >97% pure preparation of recombinant arginase. The pluripo tency of recombinant arginase was demonstrated by its ability to inhib it apoptosis in multiple paradigms including rat cortical neurons indu ced to die by glutathione depletion and oxidative stress, by 100 nM st aurosporine treatment, or by Sindbis virus infection. The protective e ffects of arginase in these apoptotic paradigms, in contrast to previo us studies on excitotoxic neuronal necrosis, are independent of nitric oxide synthase inhibition. Rather, arginase-induced depletion of argi nine leads to inhibition of protein synthesis, resulting in cell survi val. Because inhibitors of nitric oxide synthesis and of protein synth esis have been shown to decrease necrotic and apoptotic death, respect ively, in animal models of stroke and spinal cord injury, arginine-dep leting 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 preparatio ns to catalase.