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.
Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, Maryland.
K D
KD
Judy
G B
GB
Bulkley
B E
BE
Hedlund
D M
DM
Long
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