A trial of the 21-aminosteroid U74006F in a primate model of chronic cerebral vasospasm

The efficacy of U74006F in the prophylaxis of chronic cerebral vasospasm (VSP) was evaluated in a randomized, double-blind, placebo-controlled trial. Forty cynomolgus monkeys were divided by restricted randomization into 2 treatment groups of 20. Five animals from each treatment group were randomized into subgroups 1 and 2. The animals of subgroup 1 were studied pathologically. Brain biopsies of the animals in subgroup 2 were performed and studied with high-performance liquid chromatography (HPLC). The remaining 20 animals supplemented the number studied angiographically. Significant VSP (P less than 0.05) was detected in the majority of vessels from the clot site (right) of both treatment groups. Electron microscopy results showed positive correlation with the angiographic data. When comparing the effects of U74006F to those of the placebo at day 7, there was a significant difference (P less than 0.05) in the degree of VSP in the right extradural internal carotid and right middle cerebral arteries. This resulted from a greater degree of VSP in placebo animals. Two animals developed delayed ischemic deficits, one from each group. The infarct of the U74006F animal was smaller than the infarct in the placebo animal. Although overall changes in phosphagen levels did not reach statistical significance, HPLC analysis of the cortical biopsies did show a decrease in the ATP/ADP +/- AMP ratio of 54% in placebo animals and only 7% in animals receiving U74006F. The middle cerebral arteries of 2 animals were also studied with HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm

The present work was performed to establish whether the nonglucocorticoid, 21-aminosteroid, U74006F, could prevent the development of delayed cerebral vasospasm after experimental subarachnoid hemorrhage. The subarachnoid hemorrhage was produced by percutaneous injection of 4.5 mL of nonheparinized autologous blood into the cisterna magna of rabbits. U74006F (1 mg/kg) or placebo was injected intraperitoneally every 12 hours starting 12 hours prior to induction of hemorrhage for a total of six doses. The animals were sacrificed by perfusion fixation. The basilar artery was removed on day 2 and processed for morphometric analysis. Control/placebo and subarachnoid hemorrhage/placebo basilar artery diameters were 651.2 +/- 25.4 and 366.3 +/- 34.2 mu, respectively. Control/U74006F basilar artery diameters (669.8 +/- 21.8 mu) were not significantly different from that of the control/placebo group. U74006F treatment greatly minimized subarachnoid hemorrhage-induced reduction in mean luminal diameter (563.7 +/- 48.2 mu) (p less than 0.001). These results demonstrate considerable therapeutic promise for U74006F in the prevention of cerebral vasospasm.     

Effect of the 21-aminosteroid U-74006F on cerebral vasospasm following subarachnoid hemorrhage

The purpose of this study was to use a new 21-aminosteroid (U-74006F) with in vitro antioxidant and antilipolytic properties as a pharmacological probe to assess the role of lipid hydrolysis and peroxidation in a rabbit model of subarachnoid hemorrhage (SAH)-induced vasospasm. Cerebral angiograms were performed on 15 rabbits. Eighteen hours later, 1 cc/kg of autologous blood was infused into the cisterna magna of all 15 animals. Six rabbits received no treatment, six received U-74006F starting 30 minutes after SAH, and three rabbits received the vehicle for U-74006F starting 30 minutes after SAH. At 72 hours post-SAH, a second angiogram was obtained. Digital subtraction angiographic techniques were used to measure the diameter of and contrast material flow through the basilar artery. At 72 hours post-SAH, vasospasm was evident in all untreated and vehicle-treated rabbits. The diameter of and the flow through the basilar artery were significantly reduced 42.3% +/- 6.6% and 46.8% +/- 5.8%, respectively, below pre-SAH levels (means +/- standard error of the means). Treatment with U-74006F eliminated the SAH-induced vasospasm; in treated animals, both the flow through and the diameter of the basilar arteries were at pre-SAH levels. These findings indicate that: 1) membrane lipid changes (that is, hydrolysis with eicosanoid production and/or peroxidation) contribute to the chronic vasospasm resulting from SAH, and 2) U-74006F prevents the SAH-induced chronic vasospasm in this model by limiting these pathological membrane events.     

The effect of the 21-aminosteroid U74006F in a rabbit model of thromboembolic stroke.

U74006F, a novel 21-aminosteroid, is an inhibitor of iron-dependent lipid peroxidation that is devoid of glucocorticoid and mineralocorticoid side effects. The efficacy of U74006F in reducing cerebral infarct size was investigated in a rabbit model of thromboembolic stroke. Each animal received either U74006F (3.0 mg/kg immediately before and 2 hr after embolization, n = 8) or vehicle control (n = 10). Hematocrit, mean arterial pressure, PCO2, PO2, and pH were measured and controlled both before and after the administration of an autologous clot into one internal carotid artery. Regional cerebral blood flow (in ml/100 g/min, mean +/- SEM) measured by hydrogen clearance was similar in both groups, being reduced from 68.2 +/- 9.6 to 5.2 +/- 1.9 in the control group immediately after clot embolization and from 73.3 +/- 14.9 to 7.0 +/- 1.7 in the U74006F group. Four hours after embolization the brain was harvested and cerebral infarct size was determined using the triphenyl-tetrazolium chloride technique (% hemisphere, mean +/- SEM). In the U74006F-treated group, the infarct size was significantly reduced (P < 0.05) to 14.8 +/- 6.4 from a control value of 36.0 +/- 6.4. Additionally, cerebral blood flow values after embolization were consistently higher in the U74006F group, although the differences were not statistically significant. This data suggests that the 21-aminosteroid U74006F may have a protective effect in cerebral ischemia.     

Effects of the 21-aminosteroid U74006F on experimental head injury in mice

The ability of a novel non-glucocorticoid 21-aminosteroid U74006F to inhibit lipid peroxidation of central nervous system tissue in vitro and to enhance the early neurological recovery and survival of mice after a severe concussive head injury is described. In the in vitro studies, U74006F was found to be an extremely potent inhibitor of lipid peroxidation in an assay system where the glucocorticoid steroid methylprednisolone and the non-glucocortoid steroids U72099E and U75718A were almost completely ineffective. In the head-injury studies, unanesthetized male CF-1 mice were subjected to a 900 gm-cm closed head injury produced by a 50-gm weight being dropped 18 cm. This concussive injury resulted in immediate unconsciousness (loss of righting reflex) in all animals and death in approximately 30%. Survivors received a tail vein injection of either vehicle or U74006F (0.001 to 30 mg/kg) within 5 minutes postinjury. Their neurological status was evaluated 1 hour later using a grip test. The grip-test score indicated that intravenous administration of a single dose of U74006F resulted in a significant improvement by as much as 168.6% in the neurological status 1 hour postinjury over a broad dose range (0.003 to 30 mg/kg). A 1-mg/kg dose given intravenously within 5 minutes and again at 1 1/2 hours after a severe injury, in addition to improving early recovery, also increased the 1-week survival rate to 78.6% compared to 27.3% in vehicle-treated mice (p less than 0.02). The compound was also effective in enhancing early recovery after a more moderate injury. This study demonstrates that early treatment after severe concussive head injury with a potent inhibitor of iron-dependent lipid peroxidation can significantly benefit the injured brain in mice and promote both early neurological recovery and long-term survival.     

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

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.     

Blocking weight-induced spinal cord injury in rats: therapeutic effect of the 21-aminosteroid U74006F.

The effect of the 21-aminosteroid U74006F on neurologic recovery after a spinal cord compression trauma was investigated in rats. The compression was induced by a blocking weight technique, in which a 35 g (moderate injury) or a 50 g (severe injury) weight was applied for 5 minutes to an 11 mm2 plate over the midthoracic spinal cord. One hour after trauma, the severely injured animals were treated either with U74006F, 3 mg/kg, methylprednisolone, 30 mg/kg, or vehicle, whereas the moderately injured animals received U74006F, 3 mg/kg or vehicle. Neurologic hind limb function was evaluated by the inclined plane technique. On day 1 after trauma, subtotal paraparesis occurred in the 35 g group treated with vehicle (31 +/- 1 degrees, mean +/- SEM) on the inclined plane vs 64 +/- 1 degrees before trauma) and complete paraplegia in the 50 g group (22 +/- 1 degrees). Treatment with U74006F resulted in less hind limb weakness in the 35 g group (42 +/- 2 degrees) but had no beneficial effect in the 50 g group (25 +/- 2 degrees). Neurologic function gradually improved in the 35 g groups over the 9-day observation period. However, those animals treated with U74006F were significantly better over the entire period. In the 50 g group, no recovery from paraplegia was noted over the 4 day observation period in any of the three groups. These results suggest that after weight-induced spinal cord trauma, U74006F is associated with improved neurologic function in moderately injured, but not severely injured animals.     

The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat.

The present study evaluated the effect of the nonglucocorticoid 21-aminosteroid U74006F, an inhibitor of iron-dependent lipid peroxidation, on the development of regional cerebral edema after lateral fluid-percussion (FP) brain injury. Male Sprague-Dawley rats (n = 40) were anesthetized and subjected to FP brain injury of moderate severity centered over the left parietal cortex (2.5-2.6 atms). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 21) followed by a second bolus (3 mg/kg) at 3 hr or buffered sodium citrate vehicle (equal volume, n = 15). An additional group of 12 surgically prepared but uninjured animals served as preinjury controls. At 48 hr after injury, animals were sacrificed and brain tissue assayed for water content and regional cation concentrations. With the use of specific gravimetric techniques, no significant differences were observed in posttraumatic cerebral edema between drug- and control-treated animals. However, using wet weight/dry weight methodology, we found that administration of U74006F significantly reduced water content in the right hippocampus (contralateral to the site of injury) compared to saline-treated animals (p less than 0.05). U74006F also significantly prevented the postinjury increase in sodium concentrations in the ipsilateral hippocampus (p less than 0.05) and thalamus (p less than 0.03). Regional concentrations of potassium were unaltered after drug treatment. Administration of U74006F significantly reduced postinjury mortality, from 28% in control animals to zero in treated animals (p = 0.01). These results suggest that lipid peroxidation may be involved in the pathophysiological sequelae of brain injury and that 21-aminosteroids may be beneficial in the treatment of brain injury.     

The 21-aminosteroid U74006F does not markedly improve outcome from incomplete ischemia in the rat

The 21-aminosteroid U74006F reportedly decreases neuronal injury following head injury or complete cerebral ischemia. We evaluated the ability of U74006F to improve outcome following incomplete cerebral ischemia in the rat. Ischemia was induced by right carotid occlusion combined with 30 min of hemorrhagic hypotension to 30 or 35 mm Hg. Animals in groups 1 and 2 were maintained on 1.4% isoflurane in room air and rats in groups 3 and 4 were ventilated with 70% nitrous oxide (N2O) and 30% oxygen. Rectal temperature was kept at 37C and PaCO2 and pH were maintained constant during ischemia. Group 1 (n = 10) and group 3 (n = 10) received a vehicle treatment. Group 2 (n = 10) and group 4 (n = 10) received 3 mg/kg of U74006F before ischemia and a 3-h infusion of 3 mg/kg/h of the drug after ischemia. Neurologic outcome was measured for 3 days and histopathology was evaluated at the end of the study. U74006F did not significantly improve neurologic outcome or histopathology during either isoflurane or N2O compared to the vehicle-treated groups. These results suggest that U74006F does not substantially inhibit ischemic damage produced in this model of incomplete cerebral ischemia.     

Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot

The present study was undertaken to investigate the effect of U-74006F on malondialdehyde (a by-product of lipid peroxidation) in subarachnoid clot. Eighteen cynomolgus monkeys were divided into three groups of six each. There were two U-74006F-treated groups, receiving doses of 0.3 or 1.0 mg/kg, and a placebo-treated group. Each monkey underwent baseline cerebral angiography followed by right-sided craniectomy and placement of subarachnoid clot around the middle cerebral artery (MCA). Treatment was administered intravenously every 8 hours for 6 days. Seven days after the experimental subarachnoid hemorrhage (SAH), angiography was repeated and the animals were killed. In the placebo-treated group, significant vasospasm occurred in the MCA on the side of the clot (p less than 0.01). After U-74006F treatment at both dosages, significantly less vasospasm developed in the clot-side MCA (p less than 0.01). The content of malondialdehyde was measured by both the thiobarbituric acid test and high-performance liquid chromatography (HPLC). Comparing the two methods, HPLC proved to be more accurate than the thiobarbituric acid test, especially for measurement of low concentrations of malondialdehyde. In the placebo-treated group, the malondialdehyde content was significantly increased in the Day 7 clot (p less than 0.05). In contrast, malondialdehyde content in freshly prepared clot was very low. In the 0.3-mg/kg U-74006F group, the malondialdehyde content of clot was significantly less at Day 7 compared to clot from the placebo-treated group (p less than 0.05). Although the malondialdehyde content of clot from the 1.0 mg/kg U-74006F-treated group was less than that of placebo, it was not significantly so. Malondialdehyde was not detected in the actual vessel wall of the MCA of any group. These results suggest that lipid peroxidation in subarachnoid clot may play a role in the pathogenesis of vasospasm and that the salutary effects of U-74006F in vasospasm may be mediated by a reduction of lipid peroxidation in SAH.     

Intrathecal nimodipine therapy in a primate model of chronic cerebral vasospasm

The safety, prevention, and treatment of chronic vasospasm by repeated administration of intrathecally applied nimodipine was evaluated in a primate model of chronic cerebral vasospasm. Twenty-four female cynomolgous monkeys were randomized into three groups of 8: sham, clot, and clot + intrathecal nimodipine. All animals underwent a subarachnoid hemorrhage (SAH) induction operative procedure after base line angiography. Nimodipine was administered postoperatively by subcutaneous injection of 1 ml/0.2 mg tid for 6 days through an Ommaya reservoir with the catheter placed in the subarachnoid basal cisterns. Angiography was performed on Day 7 post-SAH induction. Intrathecally applied nimodipine was not effective in the prevention of angiographic vasospasm. It also did not seem to decrease the degree of pathological change when compared to controls. One animal in the nimodipine group died 2 hours after an intrathecal injection secondary to a respiratory arrest. Transient sedation and hypoventilation were common. No adverse pathological effects were noted. Intrathecal nimodipine did not produce a significant dilation of vessels in moderate or severe spasm when assessed by angiography 2 hours after intrathecal injection. Only 1 animal in 8 showed diffuse dilation of vasospastic cerebral vessels after an intrathecal nimodipine injection. Three other animals in this group developed dilation only of the basilar artery, which was in mild spasm.     

Endothelial dysfunction in a primate model of cerebral vasospasm

OBJECT: Although abnormalities in the control of endothelial vasomotility have been reported in both experimental and clinical studies, the mechanism of the endothelial dysfunction that occurs following subarachnoid hemorrhage (SAH) remains unclear. Because of the absence of previous in vivo studies of endothelial function in cerebral vessels in response to SAH or cerebral vasospasm, the authors investigated endothelium-dependent responses in an established primate model of vasospasm after SAH. Endothelial function was assessed by examining vascular responses to intracarotid injections of various drugs known to act via the endothelium. Drugs that have a rapid total body clearance were selected so that their pharmacological effects would be limited to the cerebral circulation after an intracarotid infusion. METHODS: Seventeen adult male cynomolgus monkeys were used. Cerebrovascular endothelium-dependent responses were examined in control animals and in animals with SAH 7, 14, and 21 days after placement of a subarachnoid clot around the right middle cerebral artery. Cortical cerebral blood flow (CBF) and cerebrovascular resistance (CVR) were recorded continuously during 5-minute intracarotid infusions of 5% dextrose vehicle, acetylcholine, histamine, bradykinin, or Calcimycin. In control animals the intracarotid infusion of acetylcholine produced a significant (7.8 +/- 9.5%) increase in CBF and a 9.3 +/- 8.7% reduction in CVR in comparison with a control infusion of dextrose vehicle. The responses to acetylcholine disappeared in animals 7 days post-SAH, specifically in the subset of animals in which arteriography confirmed the presence of vasospasm. Infusion of Calcimycin produced no significant changes in CBF or CVR in control animals, but resulted in a significant reduction in CBF and increase in CVR in animals 7 days after SAH and in animals with vasospasm. An infusion of histamine or bradykinin had no significant effect on CBF or CVR. CONCLUSIONS: An intracarotid infusion of acetylcholine, but not one of histamine, bradykinin, or Calcimycin, produced a measurable physiological response in the normal primate cerebrovasculature. Cerebral vasospasm that occurred after SAH produced a pathophysiological effect similar to the endothelial denudation shown in the in vitro experiments of Furchgott and Zawadzki, in which acetylcholine constricted the vessels via activation of receptors on smooth-muscle cells. Changes in vascular responses to acetylcholine and Calcimycin in animals with vasospasm, compared with control animals, provide evidence that endothelial dysfunction plays a key role in the development and/or sustenance of vasospasm after SAH.     

The effect of timing of clot removal on chronic vasospasm in a primate model

The effect of complete clot removal at times from 48 to 96 hours after subarachnoid hemorrhage (SAH) on the development of chronic cerebral vasospasm was evaluated to determine whether there is a critical point after which clot removal is ineffective in preventing vasospasm. Thirty cynomolgus monkeys were randomized to one of five groups: sham-operated group, clot removal at 48 hours after SAH (48-hour group), clot removal at 72 hours after SAH (72-hour group), clot removal at 96 hours after SAH (96-hour group), and clot placement only (clot group). Standard microsurgical techniques were used to dissect bilaterally the major cerebral arteries free of arachnoid. An autologous blood clot averaging 4.2 gm was placed around the vessels in the subarachnoid space of the monkeys in the 48-hour, 72-hour, 96-hour, and clot groups. Physiological saline was instilled into the subarachnoid space of the sham-operated animals. Animals in the clot-removal groups underwent surgical clot removal at the determined times for each group. Two animals in each of the sham-operated and clot groups were subjected to reoperation at each of 48, 72, and 96 hours after SAH. The incisions were reopened and then simply reclosed. Neurological status, angiographic cerebral vessel caliber, and physiological status were evaluated before and 7 days after SAH induction. There were no significant neurological deficits in the sham-operated, 48-hour, or 72-hour groups. Two animals in each of the 96-hour and clot groups showed deterioration in level of consciousness developing on Day 4 or 5 after SAH induction. All the major cerebral arteries of the animals in the clot and 96-hour groups showed significant vasospasm (p less than 0.01) on Day 7. Animals in the 72-hour group had significant vasospasm (p less than 0.05) of the internal carotid and middle cerebral arteries but not the anterior cerebral arteries. There was no significant vasospasm (p greater than 0.05) in any of the cerebral arteries in the 48-hour group. Severity of vasospasm paralleled the duration of contact between the blood clot and the cerebral vessels. Evacuation of the subarachnoid hematoma later than 48 hours after SAH resulted in no significant reduction in the degree of chronic cerebral vasospasm. It is suggested that clot removal at early operation is likely to be useful only if it is performed within 48 hours of SAH.     

Effect of cyclosporine on the development of cerebral vasospasm in a primate model

The authors studied the effect of the immunosuppressive drug cyclosporine (CS) on the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) using a primate model of vasospasm. Eighteen monkeys were randomly divided into three groups: a sham-operated control group, an SAH group, and a CS-treated group. To induce SAH, the right side of the circle of Willis was dissected free of the arachnoid and an autologous blood clot was placed around the arteries. In the CS group, CS (5 mg/kg/day) was administered intramuscularly for 7 days after the induction of SAH. The vessel caliber was evaluated on angiograms before the induction of SAH (Day 0) and 7 days after SAH (Day 7). Histological changes and the deposition of IgG in the arterial wall were studied in the three groups. The combined values of the average reduction of the right cerebral arteries at Day 7 was significant (P less than 0.05) in the SAH group (-43.3%) and in the CS group (-31.3%) as compared with the Sham group (-0.7%); however, there was no significant difference between the values in the SAH and the CS groups. In the CS group, the average reduction in vessel caliber of the right middle and anterior cerebral arteries was significantly (P less than 0.05) less than in the SAH group; this did not prove true for the internal carotid artery, however. Although the deposition of IgG in the media and an inflammatory reaction were observed in the spastic arterial wall in both the SAH and CS groups, there was no definitive difference in these immune/inflammatory reactions between the two groups. It is suggested that CS may be helpful in reducing the severity of vasospasm, but may not have a major therapeutic effect, considering its systemic toxicity.     

The effect of timing of intrathecal fibrinolytic therapy on cerebral vasospasm in a primate model of subarachnoid hemorrhage

The effect of intrathecal tissue plasminogen activator administered at times from 0 to 72 hours after subarachnoid hemorrhage on the development of cerebral vasospasm in primates was examined. Thirty monkeys were randomly assigned into one of five equal groups: a control group that underwent subarachnoid hemorrhage alone, and 0-, 24-, 48-, and 72-hour treatment groups that received 0.75 mg of tissue plasminogen activator at those times after baseline cerebral angiography and subarachnoid hemorrhage on the right side. Seven days later angiography was repeated and the animals were killed. One animal in the 72-hour group developed a delayed ischemic deficit on Day 7 after subarachnoid hemorrhage. In the control and 72-hour groups significant vasospasm occurred in most of the major, right cerebral arteries (P less than 0.05), but no significant vasospasm developed in the 0-, 24-, and 48-hour groups. Although a large subarachnoid clot remained in the control animals, most clot had been dissolved in all treatment groups. Lysing of subarachnoid hematoma with intrathecal tissue plasminogen activator within 72 hours of subarachnoid hemorrhage is effective in preventing vasospasm in primates.     

A primate model for acute and late cerebral vasospasm: Angiographic findings

Summary A subarachnoid haemorrhage (SAH) in the squirrel monkey was produced by injection of blood via a permanently implanted catheter connected to the cisterna magna and a cannula stereotactically inserted into the interpeduncular cistern. Repeated angiographic examinations of the vertebro-basilar and right internal carotid arteries revealed a biphasic vasospasm with a maximal acute spasm at ten minutes and maximal late spasm at six days after blood injection. The present study has shown that a reproducible biphasic vasospasm can be produced in the squirrel monkey and evaluated by repeated angiographic examinations. The model is suitable in the study of basic mechanisms underlying vasospasm in a primate and, due to the size of the animal, autoradiographic evaluation of the cerebral blood flow and metabolism can be performed at an acceptable cost.     

Correlation between attenuation of posttraumatic spinal cord ischemia and preservation of tissue vitamin E by the 21-aminosteroid U74006F: evidence for an in vivo antioxidant mechanism

In the present study, the ability of U74006F, the 21-aminosteroid inhibitor of lipid peroxidation, to attenuate posttraumatic spinal cord ischemia has been examined in cats following a moderately severe compression injury. Moreover, in an attempt to assess whether U74006F is affecting in vivo posttraumatic lipid peroxidation, the effect of the compound on injury-induced spinal tissue vitamin E depletion was also studied. Following an initial 10 min postinjury hyperperfusion (+45%), spinal cord blood flow (SCBF) returned to the preinjury level at 30 min before entering a phase of progressive hypoperfusion, which reached -42.0 +/- 4.5% by 4 h postinjury in the vehicle-treated animals. In animals that received 30 min postinjury U74006F i.v. doses of 1.0, 3.0, or 10 mg/kg (plus 0.5, 1.5, and 5.0 mg/kg maintenance doses at 2.5 h.), the SCBF decline was reduced to -23.1%, -22.9%, and -26.1%, respectively (p less than 0.05 vs. vehicle at all three doses). A 0.3 mg/kg dose did not reduce the posttraumatic fall in SCBF. In vehicle-treated cats, the vitamin E content of the injured cord segment was reduced by 78.9% at 4 h postinjury in comparison to cord samples from uninjured vehicle-treated cats. In contrast, the same doses of U74006F (1.0, 3.0, and 10 mg/kg) that attenuated posttraumatic ischemia also significantly reduced the depletion of cord vitamin E. The lowest U74006F dosage (0.3 mg/kg), which failed to affect posttraumatic ischemia development, also had no effect on spinal cord vitamin E content.(ABSTRACT TRUNCATED AT 250 WORDS)