Neuronal protection with superoxide dismutase in repetitive forebrain ischemia in gerbils.
The underlying mechanism for severe damage with repetitive ischemia is not fully understood. Because of prolonged periods of reperfusions between the brief insults, we speculated that the severe damage may be secondary to excessive generation of oxygen free radicals. In this study we tested the efficacy of peg-superoxide dismutase (SOD) in a model of repeated ischemia in gerbils. Superoxide dismutase (SOD) or vehicle (saline) was delivered through osmotic pumps into the lateral ventricles continuously from the onset of the insult until the gerbils were sacrificed 6 days later. Three doses of SOD were used in the experiments (110, 150, and 190 units per microliter). Damage was assessed using a 0-4 point scoring system and statistical comparisons were done using the Mann-Whitney U-test. There was significant protection in the hippocampus (p < 0.05), striatum (p < 0.001), and substantia nigra reticulata (p < 0.05) in the lowest dose SOD-treated group (110 units per microliter). Animals treated with 150 units showed lesser (but significant) protection in the thalamus, medial geniculate nucleus, and striatum. In the animals treated with the higher dose of SOD (190 units per microliter), the extent of damage was no different than vehicle-treated controls in the cortex, striatum, and hippocampus. Compared to controls, neuronal damage was, however, significantly more severe in the medial geniculate nucleus and the thalamus in the high-dose SOD-treated animals (p < 0.05). Our experiments suggest that the SOD may have a small therapeutic window. Higher doses may either have no neuroprotective effects or may be harmful.
Department of Medicine (Neurology), University of Saskatchewan, Saskatoon, Canada.
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Truelove
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Shuaib
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Ijaz
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Ishaqzay
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Kalra
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005609:Free Radicals; D005829:Geniculate Bodies / Q000187:drug effects / Q000473:pathology; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D009928:Organ Specificity; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology; D013482:Superoxide Dismutase / Q000008:administration & dosage / Q000494:pharmacology*; D013788:Thalamus / Q000187:drug effects / Q000473:pathology
D016166:Free Radical Scavengers; D005609:Free Radicals; D011092:Polyethylene Glycols; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase