Protective effects of human recombinant superoxide dismutase on transient ischemic injury of CA1 neurons in gerbils.

Abstract

It has been postulated that oxygen-derived free radicals are produced in significant quantities upon reperfusion of ischemic brain and that the free radicals play a pivotal role in triggering the ischemic neuronal damage causing delayed neuronal death. This study was undertaken to examine the effects of human recombinant superoxide dismutase on the delayed neuronal death of CA1 neurons and on the change in the expression of messenger ribonucleic acid for endogenous copper-zinc superoxide dismutase after transient ischemia. Human recombinant superoxide dismutase (8 x 10(5) units/kg) or apo-superoxide dismutase was administered intravenously 1 minute before bilateral carotid artery occlusion in gerbils divided among four experimental groups. Endogenous copper-zinc superoxide dismutase messenger ribonucleic acid was analyzed by in situ hybridization histochemistry using a sulfur-35-labeled oligonucleotide probe. Immunohistochemical localizations of administered human recombinant superoxide dismutase were investigated. All gerbils receiving apo-superoxide dismutase exhibited almost complete destruction of CA1 neurons 7 days after 5 minutes of ischemia. The gerbils treated with human recombinant superoxide dismutase showed mild lesions (p less than 0.01). Discrete localizations were observed for endogenous copper-zinc superoxide dismutase messenger ribonucleic acid. Transient ischemia increased labeling throughout the hippocampus after 30 minutes and 24 hours of reperfusion. This increase was abolished by treatment with human recombinant superoxide dismutase. This phenomenon was confirmed by Northern blot analysis. The interneurons in CA3 and cells in the hilus were mainly stained against administered superoxide dismutase at 5 and 30 minutes, and these reactions had disappeared at 20 hours after the administration. Our data demonstrate protective effects of human recombinant superoxide dismutase against ischemic neuronal damage and support the hypothesis that the generated free radicals induce a vicious cycle leading to delayed neuronal death.