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Anders Holtz - One of the best experts on this subject based on the ideXlab platform.
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effect of the 21 Aminosteroid u74006f and methylprednisolone on motor function recovery and oedema after spinal cord compression in rats
Acta Neurologica Scandinavica, 2009Co-Authors: Mohammad Farooque, Yngve Olsson, Anders HoltzAbstract:: The effect of the 21-Aminosteroid U74006F and methylprednisolone (MP) on motor function and oedema were investigated after spinal cord compression in rats. Each compound was administered i.v. as a single dose 60 min after injury. The hind limb motor function was assessed using the inclined plane technique and expressed as the capacity angle. The water content was calculated as the percent wet weight of the total weight. Prior to compression the capacity angle was close to 62-64 degrees. One day after compression the motor function was reduced significantly in all rats. However, the capacity angle was significantly higher after treatment with U74006F or MP than with vehicle, i.e. 50 degrees +/- 4, 45 degrees +/- 5, and 32 degrees +/- 3, respectively. This improved functional recovery persisted during the initial nine days. After compression of the spinal cord the water content increased to a maximum on day 4 in all groups. The water content was not significantly different in any of the groups except on day one and nine when it was less in groups treated with U74006F. In conclusion, a single i. v. injection of U74006 or MP given 60 min after compression of the spinal cord improved motor function without effecting oedema expressed as water content.
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Effect of 21-Aminosteroid on extracellular energy-related metabolites and amino acids after compression injury of rat spinal cord
Experimental Brain Research, 1997Co-Authors: Mohammad Farooque, Yngve Olsson, Lars Hillered, Anders HoltzAbstract:We evaluated in a rat model of severe spinal cord compression the effect of the 21-Aminosteroid tirilazad on extracellular levels of energy metabolites and amino acids, until 3 h after injury. The compound was given i.v. 30 min before injury (3 mg/kg) and hourly thereafter (1.5 mg/kg). The findings were compared with previously reported effects of methylprednisolone. Both treated and untreated rats with spinal cord compression showed, at 10 min after injury, a five-to sixfold elevation of extracellular lactate above the preinjury level. There was no significant difference for lactate, pyruvate or lactate/pyruvate ratio between the treated and untreated injured groups at any time point after trauma. Glutamate was significantly elevated both in treated and untreated injured rats for 20 min after trauma. The mean glutamate level was lower in animals treated with 21-Aminosteroid. However, there was no statistically significant difference between the treated and untreated rats at any time after trauma. There was no statistically significant difference between the groups for aspartate, serine, glutamine, histidine, glycine, threonine, taurine, alanine and tyrosine. In conclusion our findings indicate that, in the injured spinal cord, methylprednisolone and the 21-Aminosteroid have differences and similarities, regarding their effects on energy and amino acid metabolism. The lowering of the lactate and arginine levels early after trauma seen with methylprednisolone pretreatment was absent after 21-Aminosteroid pretreatment. However, the mean extracellular level of glutamate was lower with both methyl-prednisolone and 21-Aminosteroid after injury, although the difference was not statistically significant between treated and untreated rats.
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efficacy of the 21 Aminosteroid u74006f in improving neurological recovery after spinal cord injury in rats
Neurological Research, 1992Co-Authors: Anders Holtz, Bengt GerdinAbstract:AbstractThe efficacy of three different regimens of the 21-Aminosteroid U74006F in counteracting the neurological damage after spinal cord compression causing paraparesis in rats was investigated. Three groups of ten animals each were given totally 6 mg I kg of U74006F in different regimens beginning one hour after injury (A: bolus doses of 1.5 mg/kg at 1, 4, 7 and 10 hours; B: bolus of 1.5 mg/kg at 1 hour and 4.5 mg/kg as an infusion over the next 9 hours; and C: infusion alone, 6 mg/kg, given between 1 and 10 hours after trauma). Two groups of ten animals each received vehicle alone in administration modes comparable to those of the U74006F treated animals. The motor function was assessed daily on the inclined plane. On day one, the capacity angle had decreased from about 62 ° preoperatively to 28-30 ° in the two vehicle-treated groups and in group C. In these groups there was a similar improvement in neurological function and on day 9 the capacity angles were 49-55 °. In groups A and B, both of which r...
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blocking weight induced spinal cord injury in rats therapeutic effect of the 21 Aminosteroid u74006f
Journal of Neurotrauma, 1991Co-Authors: Anders Holtz, Bengt GerdinAbstract:ABSTRACT 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...
Michael Banbury - One of the best experts on this subject based on the ideXlab platform.
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The novel 21-Aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat.
Journal of Neurotrauma, 1992Co-Authors: Tracy K Mcintosh, Mark G Thomas, Douglas H Smith, Michael BanburyAbstract: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.
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the novel 21 Aminosteroid u74006f attenuates cerebral edema and improves survival after brain injury in the rat
Journal of Neurotrauma, 1992Co-Authors: Tracy K Mcintosh, Mark G Thomas, Douglas H Smith, Michael BanburyAbstract:The present study evaluated the effect of the non-glucocorticoid 21-Aminosteroid U74006F on the development of regional cerebral oedema after lateral fluid-percussion (FP) brain injury in the rat. Male Sprague-Dawley rats (n = 20) were anaesthetized and subjected to lateral FP brain injury of moderate severity (2.5–2.6 atmospheres). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 11) followed by a second bolus (3 mg/kg) at 3 hours vs buffered saline vehicle (equal volume, n = 9). At 48 hours postinjury, animals were sacrificed and brains tissue assayed for water content using wet weight/dry weight methodology. Administration of U74006F significantly attenuated the increase in water content observed in control animals in the ipsilateral hippocampus (adjacent to the site of maximal injury, p < 0.05). Administration of U74006F also significantly reduced post-injury mortality from 28% in control animals to zero in treated animals (p < 0.001). 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.
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the novel 21 Aminosteroid u 74006f attenuates cerebral oedema and improves survival after brain injury in the rat
Acta Neurochirurgica, 1990Co-Authors: Tracy K Mcintosh, Douglas H Smith, Michael Banbury, Mark G ThomasAbstract:: The present study evaluated the effect of the non-glucocorticoid 21-Aminosteroid U74006F on the development of regional cerebral oedema after lateral fluid-percussion (FP) brain injury in the rat. Male Sprague-Dawley rats (n = 20) were anaesthetized and subjected to lateral FP brain injury of moderate severity (2.5-2.6 atmospheres). Fifteen minutes after brain injury, animals randomly received an i.v. bolus of either U74006F (3 mg/kg, n = 11) followed by a second bolus (3 mg/kg) at 3 hours vs buffered saline vehicle (equal volume, n = 9). At 48 hours postinjury, animals were sacrificed and brains tissue assayed for water content using wet weight/dry weight methodology. Administration of U74006F significantly attenuated the increase in water content observed in control animals in the ipsilateral hippocampus (adjacent to the site of maximal injury, p less than 0.05). Administration of U74006F also significantly reduced post-injury mortality from 28% in control animals to zero in treated animals (p less than 0.001). 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.
Edward D Hall - One of the best experts on this subject based on the ideXlab platform.
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attenuation of motor nerve terminal repetitive discharge by the 21 Aminosteroid tirilazad evidence of a neural calcium antagonist action
Brain Research, 1998Co-Authors: Edward D Hall, Patricia A YonkersAbstract:Abstract Pretreatment with the 21-Aminosteroid antioxidant compound tirilazad mesylate has been previously shown to retard the axotomy-induced anterograde degeneration of soleus motor nerve terminals in the cat. In the present study, we examined tirilazad's effects (7.7, 13.0 or 30.0 mg/kg twice daily P.O. for 6 days) on the excitability of normal cat soleus motor nerve terminals. Low frequency (0.4 Hz) neuromuscular transmission was measured as well as the occurrence of muscle contractile potentiation in response to either a 400 Hz/10 s episode of tetanic conditioning stimulation of the soleus nerve or the administration of a 200 μg/kg i.v. dose of the neuromuscular facilitatory drug edrophonium. The mechanism of the post-tetanic potentiation (PTP) or edrophonium-induced facilitatory response involves the occurrence of a stimulus-dependent repetitive discharge of the soleus motor nerve terminals due to an exaggeration of the nerve terminal Ca2+-mediated after-depolarization. Tirilazad pretreatment caused a dose-related suppression of PTP and the edrophonium response indicative of a suppression of motor nerve terminal repetitive discharge. These effects were not shared by 6 days of oral pretreatment of cats with a high dose combination of the antioxidants vitamin E (200 I.U./day) and selenium (50 μg/day). Thus, it is unlikely that the antioxidant properties of tirilazad are involved in the suppression of motor nerve terminal excitability. Rather, it is proposed that tirilazad suppresses delayed motor nerve terminal Ca2+ conductances secondary to its ability to decrease membrane phospholipid fluidity, and that this action might in some circumstances contribute to its neuroprotective activity.
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therapeutic value of 21 Aminosteroid u74389f in acute spinal cord injury
Neurological Research, 1993Co-Authors: Siavash S. Haghighi, Edward D Hall, Xiao Z Geng, Gayle C JohnsonAbstract:AbstractThe effect of bolus injections of 21-Aminosteroid U74389F after an acute spinal cord compression trauma in rats was studied. Cortical somatosensory evoked potentials (CSEPs) were recorded before and after a weight-induced injury of 120 g and monitored up to five hours post-injury. All U74389F treatments were given as i.v. bolus injections of 15, 7.5, and 3.75 mg kg–1 at 1, 2, 3 h after the trauma, respectively. The CSEPs were abolished immediately after the injury in the control and treated animals. The majority of the treated animals (88.8%) demonstrated a return of the CSEPs within the second hour post-injury. In contrast, the animals in the control group showed only 44.4% recovery at this time period. At three hours post-injury, U74389F-treated animals (n = 18) showed a full recovery (100%) while the recovery rate remained at 44.4% for the control animals. We conclude that the bolus administration of U74389F one hour after injury facilitates the return of the spinal cord function as measured by...
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Therapeutic value of 21-Aminosteroid U74389F in acute spinal cord injury.
Neurological Research, 1993Co-Authors: Siavash S. Haghighi, Edward D Hall, Xiao Z Geng, Gayle C JohnsonAbstract:The effect of bolus injections of 21-Aminosteroid U74389F after an acute spinal cord compression trauma in rats was studied. Cortical somatosensory evoked potentials (CSEPs) were recorded before and after a weight-induced injury of 120 g and monitored up to five hours post-injury. All U74389F treatments were given as i.v. bolus injections of 15, 7.5, and 3.75 mg kg-1 at 1, 2, 3 h after the trauma, respectively. The CSEPs were abolished immediately after the injury in the control and treated animals. The majority of the treated animals (88.8%) demonstrated a return of the CSEPs within the second hour post-injury. In contrast, the animals in the control group showed only 44.4% recovery at this time period. At three hours post-injury, U74389F-treated animals (n = 18) showed a full recovery (100%) while the recovery rate remained at 44.4% for the control animals. We conclude that the bolus administration of U74389F one hour after injury facilitates the return of the spinal cord function as measured by the CSEPs in this compression model of acute spinal cord trauma.
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the 21 Aminosteroid antioxidant tirilazad mesylate u 74006f blocks cortical hypoperfusion following spreading depression
Brain Research, 1991Co-Authors: Edward D Hall, Sarah L SmithAbstract:Abstract Cortical spreading depression (SD) has been implicated in the pathophysiology of classical migraine headache and cerebral ischemia. A reduction in cerebral blood flow (CBF), mimicking that seen during the aura and headache phase of migraine, is typically observed following SD in the rat. This phenomenon may also play a role in potentiating ischemic brain damage. In the present study, brief cortical exposure to 1 M KCl produced a marked suppression of EEG amplitude which persisted 20 min in the rat. Upon normalization of the EEG, cortical blood flow declined 20–30% and remained low for at least 2 h. Treatment with a 1 mg/kg i.v. dose of the 21-Aminosteroid antioxidant trilazad mesylate (U-74006F), 2 min following KCl application, completely blocked the hypoperfusion while leaving the magnitude and duration of the EEG suppression and mean arterial pressure unchanged. Tirilazad mesylate is a potent inhibitor of oxygen radical-mediated lipid peroxidation both in vitro and in vivo. Thus, based on present results, an oxygen radical hypothesis is proposed to account for the SD-induced cerebral hypoperfusion.
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preservation of motor nerve function during early degeneration by the 21 Aminosteroid anti oxidant u74006f
Brain Research, 1990Co-Authors: Edward D Hall, Patricia A YonkersAbstract:The effects of 5 days of pretreatment with the 21-Aminosteroid anti-oxidant U74006F have been examined on the rate of functional degeneration of cat soleus motor nerve terminals after axon section. Female cats were dosed for 5 days with either 7.7, 13.0 or 30.0 mg/kg (average doses) of U74006F p.o. twice daily followed by unilateral sciatic nerve section at the hip level on day 5. On day 7, the bilateral in vivo soleus nerve muscle prep. was set up to assess the neuromuscular functional status of the 48 h degenerating soleus nerve terminals in comparison to the contralateral non-sectioned preparation. In untreated cats, the ratio of the nerve-evoked (0.4 Hz) contractile tension of the 48 h nerve-sectioned to that of the contralateral non-sectioned was only52 ± 8%. U74006F pretreatment produced a dose-related improvement with the 13.0 mg/kg dose having the best effect; the ratio was86 ± 5% (P < 0.01vs untreated). The maintenance of tetanic tension during a 10 s period of 100 Hz nerve stimulation was also improved by the 13.0 mg/kg dose from only54.0 ± 5.2% in untreated animals to72.2 ± 5.7 (P < 0.02). These results show a preservation of motor nerve function during early degeneration by the anti-oxidant U74006F thus providing further evidence for a free radical-mediated process in anterograde degeneration.
Bengt Gerdin - One of the best experts on this subject based on the ideXlab platform.
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effects of a novel 21 Aminosteroid or methylprednisolone in experimental total intestinal ischemia
Archives of Surgery, 1994Co-Authors: Perola Park, Bengt Gerdin, Ulf HaglundAbstract:Objective: To investigate whether tirilazad mesylate, a 21-Aminosteroid, protects the small intestinal mucosa from injury following total warm or cold ischemia and reperfusion. Design: Randomized vehicle-controlled experimental study. Setting: A university department of surgery. Animals: Wistar rats. The warm ischemia series preceded the cold ischemia series. Animals were randomized within each series. Microscopic evaluation was performed on coded tissue slides. Interventions: Warm ischemia was induced by a hydrostatic pressure cuff inflated to 10 mm Hg above the systolic arterial pressure for 60 minutes. Cold ischemia was studied after small intestinal transplantation. The transplant was stored for 5 hours in University of Wisconsin solution at 8°C. Ischemia was followed by 60 minutes of reperfusion. In both series, tirilazad mesylate (3 mg/kg) or methylprednisolone sodium succinate (30 mg/kg) was given. Controls were given tirilazad vehicle or saline solution. Main Outcome Measure: Microscopic grade of small intestinal mucosal injury. Results: Mucosal injury was evident in all groups of animals that were subjected to warm or cold ischemia. Reperfusion following cold ischemia induced a significant reperfusion injury. Neither tirilazad nor methylprednisolone protected the small intestinal mucosa during ischemia or reperfusion. Conclusion: Mucosal injury following warm or cold intestinal ischemia and reperfusion is caused by factors other than or in addition to lipid peroxidation, which is preventable by use of a 21-Aminosteroid. (Arch Surg. 1994;129:857-860)
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efficacy of the 21 Aminosteroid u74006f in improving neurological recovery after spinal cord injury in rats
Neurological Research, 1992Co-Authors: Anders Holtz, Bengt GerdinAbstract:AbstractThe efficacy of three different regimens of the 21-Aminosteroid U74006F in counteracting the neurological damage after spinal cord compression causing paraparesis in rats was investigated. Three groups of ten animals each were given totally 6 mg I kg of U74006F in different regimens beginning one hour after injury (A: bolus doses of 1.5 mg/kg at 1, 4, 7 and 10 hours; B: bolus of 1.5 mg/kg at 1 hour and 4.5 mg/kg as an infusion over the next 9 hours; and C: infusion alone, 6 mg/kg, given between 1 and 10 hours after trauma). Two groups of ten animals each received vehicle alone in administration modes comparable to those of the U74006F treated animals. The motor function was assessed daily on the inclined plane. On day one, the capacity angle had decreased from about 62 ° preoperatively to 28-30 ° in the two vehicle-treated groups and in group C. In these groups there was a similar improvement in neurological function and on day 9 the capacity angles were 49-55 °. In groups A and B, both of which r...
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blocking weight induced spinal cord injury in rats therapeutic effect of the 21 Aminosteroid u74006f
Journal of Neurotrauma, 1991Co-Authors: Anders Holtz, Bengt GerdinAbstract:ABSTRACT 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...
Cordell E Gross - One of the best experts on this subject based on the ideXlab platform.
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delayed adjuvant therapy with the 21 Aminosteroid u74006f and the anion channel blocker l644 711 does not improve outcome following thrombolytic therapy in a rabbit model of thromboembolic stroke
Surgical Neurology, 1997Co-Authors: Cordell E Gross, Harold K Kimelberg, Sheila J Raymondrussell, Christina Booth, Martin M BednarAbstract:BACKGROUND: Both the 21-Aminosteroid U74006F, a potent inhibitor of lipid peroxidation, and L644-711, an anion channel blocker that inhibits both neutrophil and astrocyte function, have been previously shown to reduce brain injury in pretreatment paradigms of cerebral ischemia. It was therefore of interest to examine the effect of these agents in combination, when given on a delayed basis as adjuvants to thrombolytic therapy in a rabbit model of thromboembolic stroke. METHODS: Animals were mechanically ventilated and arterial blood gases controlled. Core and brain temperature, intracranial pressure, and mean arterial pressure were continuously monitored. Regional cerebral blood flow and hematocrit were measured hourly. Blood samples were taken to measure neutrophil (aggregation and chemiluminescence) and platelet (aggregation) activity. Following delivery of an autologous clot via the carotid artery, all experiments were continued for an 8-hour period. U74006F (3 mg/kg I.V.) and L644,711 (12 mg/kg I.V.) or their vehicle control (n = 8, each group) were given 3.5 hours following autologous clot embolization. Both groups received tissue-type plasminogen activator (t-PA) (6.3 mg/kg I.V.), beginning 4 hours following thromboembolic stroke and continuing over a 2-hour infusion period. Infarct size was determined following staining and image analysis. RESULTS: In the L644,711/U74006F group, neutrophil chemiluminescence was reduced following drug therapy; however, there were no significant differences between groups regarding infarct size (50.3 +/- 8.7 vs. 49.9 +/- 10.6, treatment vs. t-PA control, mean +/- SEM), or in regional cerebral blood flow or intracranial pressure over time. CONCLUSIONS: It is concluded that prolonged (3.5 hours) delay of the initiation of therapy with the anion channel blocker L644,711 and the 21-Aminosteroid U74006F fails to further reduce brain injury when given in combination with tissue plasminogen activator in a rabbit model of thromboembolic stroke.
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the effect of the 21 Aminosteroid u74006f in a rabbit model of thromboembolic stroke
Neurosurgery, 1992Co-Authors: James T Wilson, Martin M Bednar, Timothy L Mcauliffe, Sheila J Raymond, Cordell E GrossAbstract:: 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.
