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Peptide and Nonpeptide Reactive Oxygen Scavengers Provide Partial Rescue of the Testis After Torsion

TERRY T. TURNER^*,

From the ^* Department of Urology and the Department of Cell Biology, University of Virginia Health Science System, Charlottesville, Virginia.

Correspondence to: Dr Jeffrey J. Lysiak, Department of Urology Box 800422, University of Virginia Health System, Charlottesville, VA 22908 (e-mail: jl6n{at}virginia.edu ).

Ischemia-reperfusion (IR) of the testis results in germ cell-specific apoptosis, followed by a reduction in testis weight and daily sperm production (DSP). This has been associated with an increase in the adhesion of neutrophils to testicular subtunical venules and an increase in reactive oxygen species (ROS). The present study investigated: 1) the effects of a direct, non—IR-related ROS insult to the testis and 2) the effects of catalase, superoxide dismutase (SOD), and a novel nonpeptide mimic of SOD, M40403, on neutrophil recruitment, ROS production, testis weight, and DSP following IR of the rat testis. Results revealed that the infusion of H₂O₂ increased testicular lipid peroxidation 1 hour after administration and increased germ cell apoptosis within 24 hours of administration. Four hours after the repair of torsion plus vehicle infusion, there was a significant increase in myeloperoxidase (MPO) activity, an indicator of neutrophil accumulation, and thiobarbituric acid reactive substances (TBARS), a measure of ROS production, compared to equivalent data in sham-treated testes. Animals sacrificed 30 days after the torsion plus vehicle infusion revealed a significant decrease in testis weight and DSP compared to the same parameters in sham-operated animals. The treatment of animals with catalase plus SOD or M40403 showed a significant decrease in MPO activity and TBARS 4 hours after IR of the testis. Animals treated with SOD, SOD plus catalase, and M40403 provided a partial rescue of DSP 30 days after IR of the testis. These results demonstrate that oxidative stress can directly cause germ cell apoptosis, even outside the IR model, and confirm the importance of oxidative stress in testicular IR injury. Also, following testicular IR, there is a recruitment of neutrophils and an increase in ROS production in the testis. The administration of ROS scavengers significantly reduced the IR-induced responses. Interestingly, the administration of all ROS scavengers also blocked neutrophil recruitment to the testis. The mechanism by which ROS modulates neutrophil adhesion to venules is presently under investigation, as are additional therapeutic regimens to block oxidative stress.

     Key words: Apoptosis, ischemia-reperfusion, oxygen radicals

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