Effects of the 21-aminosteroid U74006F on posttraumatic spinal cord ischemia in cats

Abstract

The ability of a single intravenous dose of the 21-aminosteroid U74006F to affect the development of posttraumatic spinal cord ischemia was examined in pentobarbital-anesthetized cats. After surgical preparation, each animal received a 300 gm-cm contusion injury to the exposed L-3 vertebral segment, followed by a single bolus injection of vehicle or U74006F (3 or 10 mg/kg) at 30 minutes postinjury. Spinal cord white matter blood flow (SCBF) was measured by hydrogen clearance in the dorsolateral funiculus in the center of the injured segment before and at various times up to 4 hours after injury. In vehicle-treated cats, there was a progressive decline in SCBF over the course of the experiment. By 4 hours postinjury, SCBF had decreased from a preinjury value of 15.9 +/- 2.4 ml/100 gm/min (mean +/- standard error of the mean) to 5.8 +/- 0.8 ml/100 gm/min, representing a decline of 63.5%. In contrast, the SCBF measured 4 hours postinjury in cats that were treated with a single 10-mg/kg dose of U74006F was 13.6 +/- 1.7 ml/100 gm/min (p less than 0.001 vs. vehicle). Animals that received a 3-mg/kg intravenous dose of U74006F displayed a drop in SCBF equal to that of vehicle-treated cats. However, when a 3-mg/kg dose of U74006F was given to four vehicle-treated cats at the end of the experiment, a partial reversal of ischemia was recorded. Blood flow increased within 30 minutes from a mean of 4.5 +/- 0.8 to 7.4 +/- 1.0 ml/100 gm/min or an increase of 64.4% (p less than 0.05). This rather surprising effect of U74006F in reversing posttraumatic ischemia once it has developed significantly is not shared by a 30-mg/kg intravenous dose of methylprednisolone sodium succinate (MP), although MP has previously been shown to attenuate the posttraumatic drop in SCBF when given before the SCBF drop occurs. The mechanism of action of U74006F in antagonizing posttraumatic ischemia development is believed to involve the ability of the compound to inhibit iron-dependent lipid peroxidation in central nervous system tissue.