Proposed toxic oxidant inhibitors fail to reduce brain edema.
Toxic oxidants (oxygen free radicals) have been implicated in the formation of brain edema from ischemia-reperfusion injury or tumor growth. We investigated the ability of an iron chelator, a calcium channel blocker, and a xanthine oxidase inhibitor to reduce formation of brain edema following a cold lesion in cats. The agents were given independently of each other in an attempt to inhibit the Haber-Weiss reaction, prevent Ca++ modulated uncoupling of oxidative phosphorylation, and inhibit the generation of toxic oxidants via xanthine oxidase, respectively. Pentastarch-deferoxamine conjugate at a dose of 50 mg/kg was given 15 minutes before and 60 minutes after the cold lesion. Nimodipine was given at a dose of 1 mg/kg 1 hour before and 2 hours after the cold lesion. Allopurinol was given at a dose of 50 mg/kg 24 hours before, at the time of the lesion and, 24 and 48 hours after the lesion. Gravimetric measurements of multiple brain areas were performed at 24 hours post-lesion in the pentastarch-deferoxamine and nimodipine groups and at 72 hours post-lesion in the allopurinol group. None of these agents led to significant reduction in brain edema formation as measured with a gravimetric column of kerosene and bromobenzene. Pentastarch-deferoxamine conjugate was utilized to avoid the confounding effects of arterial hypotension which is seen with intravenous deferoxamine. There was even a suggestion of increased edema in the periventricular white matter in animals treated with nimodipine. Taken together, independent inhibition of the Haber-Weiss reaction, of calcium channels, or of xanthine oxidase does not reduce formation of brain edema in the cold lesion model.
Judy
K D
KD
Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland.
Bulkley
G B
GB
Hedlund
B E
BE
Long
D M
DM
D000493:Allopurinol / Q000494:pharmacology*; D000818:Animals; D001929:Brain Edema / Q000473:pathology*; D001930:Brain Injuries / Q000473:pathology*; D002118:Calcium / Q000502:physiology*; D002415:Cats; D002540:Cerebral Cortex / Q000187:drug effects / Q000293:injuries / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology*; D003676:Deferoxamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005615:Freezing; D009553:Nimodipine / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014882:Water-Electrolyte Balance / Q000187:drug effects
D017382:Reactive Oxygen Species; D009553:Nimodipine; D000493:Allopurinol; D003676:Deferoxamine; D002118:Calcium