Effects of the 21-Amino Steroid Tirilazad Mesylate (U-74006F) on Brain Damage and Edema after Perinatal Hypoxia-Ischemia in the Rat

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Abstract
Using 7-d-old rat pups, the neuroprotective efficacy of the lipid peroxidation inhibitor tirilazad mesylate (U-74006F) was tested in a model of perinatal hypoxic-ischemic (HI) brain damage. The experimental protocol was divided into five parts: 1) pre- plus post-HI treatment or 2) only post-HI treatment with tirilazad (7.5 mg/kg intraperitoneally) or vehicle with evaluation of hemispheric weight deficit 14 d after the insult; 3) post-HI treatment with tirilazad or vehicle with histopathologic evaluation 14 d after the insult; 4) pre- plus post-HI treatment; or 5) posthypoxic treatment with tirilazad or vehicle with evaluation of brain edema 20 h after the insult. In the pre- plus post-HI treatment group, the mean left hemispheric weight deficit was 20.7%± 17.8 (mean ± SD) in tirilazad-treated rats and 27.5% ± 20.4 in vehicle-treated rats (p = 0.032). Corresponding values for the post-HI treated animals were 19.6% ± 16.0 and 28.6% ± 15.4(p = 0.043). Histopathologic injury assessed as pathology score on a scale of 0-5 was less extensive in tirilazad-treated animals compared with controls (p = 0.038). There was a significant increase in water content in the HI hemisphere compared with the contralateral (hypoxic) hemispheres in tirilazad- and vehicle-treated animals. This increase of water content in the HI hemispheres did not differ between tirilazad- and vehicle-treated animals. The lipid peroxidation inhibitor tirilazad administered after perinatal HI reduced brain damage by 30%, but no effect was found on early postinsult edema.