The 21-aminosteroid U74006F reduces systemic lipid peroxidation, improves neurologic function, and reduces mortality after cardiopulmonary arrest in dogs.
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Animals↗
Biomedical subjects
E D Hall
Publications and source records attributed to E D Hall.
Inhibition of arachidonic acid-induced vasogenic brain edema by the non-glucocorticoid 21-aminosteroid U74006F.
The effects of the novel non-glucocorticoid 21-aminosteroid U74006F on arachidonic acid (AA)-induced vasogenic brain edema were examined in rats. Vasogenic edema was assessed in terms of the extent of Evan's blue extravasation after subcortical micro-injection of AA indicative of blood-brain barrier disruption. U74006F, given i.v. at 15 min before the AA, produced a dose-related reduction in the area of subsequent Evan's blue staining measured in a coronal brain cross-section through the injection site. The highest dose tested (1.0 mg/kg) resulted in a 65% decrease in the area of blood-brain barrier disruption in comparison to that seen in vehicle-treated animals (P less than 0.0001). The mechanism of the anti-edema effect of U74006F is discussed in relation to the previously demonstrated ability of the compound to inhibit oxygen free radical-mediated lipid peroxidation.
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Attenuation of hemorrhagic shock by the non-glucocorticoid 21-aminosteroid U74006F.
The ability of the novel non-glucocorticoid 21-aminosteroid U74006F to protect against the development of hemorrhagic shock was examined in pentobarbital-anesthetized cats. The animals were hemorrhaged to a mean arterial blood pressure (MAP) of 45-50 mm Hg where they were held for 2 h. At the end of the hemorrhage period, either vehicle, a 30 mg/kg dose of methylprednisolone sodium succinate, or a 10 mg/kg dose of U74006F was administered i.v. followed by reinfusion of the shed blood. In vehicle-treated animals, there was a progressive post-reinfusion decline in the MAP over the subsequent 2 h. In the methylprednisolone-treated cats, the post-reinfusion decrease in the MAP was only slightly and not significantly better. In contrast, U74006F administration resulted in a significant maintenance of the MAP. These results suggest that U74006F may be efficacious for the attenuation of hemorrhagic shock and superior to conventional high dose glucocorticoid therapy in that context.
Animals↗
Effects of the nonglucocorticoid 21-aminosteroid U74006F on acute cerebral hypoperfusion following experimental subarachnoid hemorrhage.
The ability of the nonglucocorticoid 21-aminosteroid U74006F, a potent inhibitor of iron-dependent lipid peroxidation, to antagonize acute progressive cerebral hypoperfusion following experimental subarachnoid hemorrhage (SAH) was examined in chloralose-anesthetized cats. The SAH was produced by injection of 0.5 ml/kg of unheparinized autologous blood into the cisterna magna after prior withdrawal of an equivalent volume of cerebrospinal fluid. In untreated animals the SAH caused a progressive decline in caudate nuclear blood flow (CNBF) (-51.4% by 3 h) and an increase in intracranial pressure (ICP) (+18.5 mm Hg by 3 h). In comparison, in cats that received a 1 mg/kg iv dose of U74006F at 30 min after SAH, there was a complete prevention of the fall in CNBF and a significant attenuation of the rise in ICP. Furthermore, the drug reduced a concomitant fall in the mean arterial blood pressure and cerebral perfusion pressure. While not as effective as the 1 mg/kg dose, a 0.1 mg/kg dose also significantly attenuated the post-SAH fall in CNBF. These results support a role of lipid peroxidation in the acute pathophysiology of SAH and suggest that U74006F may be useful in the early treatment of this disorder.
Animals↗
Attenuation of progressive brain hypoperfusion following experimental subarachnoid hemorrhage by large intravenous doses of methylprednisolone.
Experimental subarachnoid hemorrhage was produced in chloralose-anesthetized cats by slow injection of 0.5 ml/kg autologous arterial blood into the cisterna magna. As a result, there was an initial (within 5 min) 25.1% decrease in caudate nuclear blood flow as measured by hydrogen clearance. Between 5 min and 3 h postinjection, there was a further and progressive 25.9% decline in caudate blood flow. The hemorrhage also caused a slow increase in intracranial pressure, a decrease in cerebral perfusion pressure, and an increase in caudate vascular resistance. In contrast, the administration of a single 30 mg/kg i.v. dose of methylprednisolone sodium succinate 30 min after the acute hemorrhage resulted in stabilization of caudate blood flow and vascular resistance and some restoration of those parameters toward prehemorrhage values. This effect was not correlated with a decrease in intracranial pressure or an increase in cerebral perfusion pressure. A 15 mg/kg i.v. dose of the drug had only a slight effect on caudate blood flow. A 60 mg/kg i.v. dose, while initially supportive, lost its effect during the later stages of the experiment, indicating a sharp biphasic dose-response relationship for the effect of methylprednisolone on caudate blood flow after subarachnoid hemorrhage. However, of the three doses, only 60 mg/kg significantly decreased the slow posthemorrhage rise in intracranial pressure. The beneficial effect of the 30 mg/kg i.v. dose of the drug on caudate blood flow, separate from an effect on the slow rise in intracranial pressure, suggests that the steroid support of caudate perfusion is due to a direct protective effect of the drug on the microvasculature. Based on previous studies showing an identical dose-response pattern for the ability of methylprednisolone to prevent posttraumatic lipid peroxidation of central nervous system tissue and progressive ischemia development, the possibility of the drug's inhibition of hemorrhage-initiated vasoconstrictor prostanoid action and microvascular lipid peroxidation is proposed.
Animals↗
Antioxidant RDA (recommended daily allowance) and supplements.
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Animals↗
New pharmacological treatment of acute spinal cord trauma.
Numerous experimental studies of blunt spinal cord injury have shown that while a variable degree of immediate mechanical damage occurs to spinal blood vessels and axons in proportion to the magnitude of the injury force, a considerable amount of post-traumatic tissue degeneration is due to a secondary pathophysiological process that may be modifiable by appropriate therapeutic intervention. A growing body of biochemical, physiological, and pharmacological evidence has suggested that oxygen free radical-induced lipid peroxidation, working in concert with aberrant calcium fluxes and eicosanoid generation in particular, plays a key role in progressive post-traumatic spinal cord degeneration. Of particular importance, lipid peroxidation has been linked to microvascular damage and hypoperfusion which, if severe enough, can lead to a secondary ischemic insult to the tissue. The ability of intensive dosing with the glucocorticoid steroid methylprednisolone to beneficially affect post-traumatic ischemia and to promote chronic neurologic recovery in spinal cord injured animals has been correlated not with its glucocorticoid activity, but rather with the ability to inhibit post-traumatic spinal lipid peroxidation. In view of this, a novel series of non-glucocorticoid 21-aminosteroids has been developed which lack glucocorticoid activity but are more effective inhibitors of nervous tissue lipid peroxidation than the glucocorticoid steroids. One of these, U74006F, has now been studied in some detail and appears to be a promising new agent for the acute treatment of spinal cord (and brain) trauma. The background and pre-clinical development of this compound to date is reviewed.
Humans↗
Effect of the aminosteroid U74006F after cardiopulmonary arrest in dogs.
The oxygen free radical-induced lipid peroxidative reactions that occur during resuscitation from normothermic cardiac arrest may contribute to the degree of neurologic dysfunction sustained. A blinded, randomized experimental trial was performed to determine whether U74006F, a potent inhibitor of lipid peroxidation, reduces morbidity and 24-hour mortality after 10 minutes of normothermic cardiopulmonary arrest; ventricular fibrillation was induced by electrical stimulation in 24 open-chest, halothane-anesthetized dogs, and circulation was reestablished by direct cardiac compressions, administration of a standardized drug regime, and internal countershocks. When spontaneous circulation was restored, a bolus injection of 1.5 mg/kg U74006F (n = 12) or 25 mM citrate vehicle (n = 12) was infused intravenously in 15 minutes and an infusion was continued at 0.125 mg/kg/hr for the next 12 hours. In the drug-treated group, plasma U74006F concentration averaged 0.13 microgram/ml between 3 and 12 hours after cardiac arrest. By 24 hours after arrest, 10 of 12 (83%) vehicle-treated dogs had died but only four of 12 (33%) U74006F-treated dogs had died (p = 0.017). U74006F-treated dogs survived significantly longer (mean +/- SEM 22 +/- 1 hr) than vehicle-treated dogs (18 +/- 1 hr), with significantly better neurologic function 1, 2, and 24 hours after arrest. Plasma fatty acid hydroperoxide concentrations 12 hours after arrest were 88 +/- 81 pmol/ml in U74006F-treated and 241 +/- 49 pmol/ml in vehicle-treated dogs (p less than 0.05). Vitamin E concentrations were significantly higher in the plasma of U74006F-treated dogs 2, 3, and 6 hours after arrest compared with vehicle-treated dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
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Attenuation of postischemic cerebral hypoperfusion by the 21-aminosteroid U74006F.
The ability of the nonglucocorticoid 21-aminosteroid U74006F, a potent inhibitor of iron-dependent lipid peroxidation, to antagonize progressive brain hypoperfusion after a 5-minute episode of global brain ischemia was examined in alpha-chloralose-anesthetized cats. Immediately after a 5-minute episode of near-total tourniquet-induced brain ischemia, cortical blood flow returned to normal or above normal. Thereafter, cortical blood flow fell progressively to a level 71.7% below normal by 3 hours after ischemia. In contrast, in cats that received 1 mg/kg i.v. U74006F 15 minutes after the ischemic episode, cortical blood flow remained significantly greater than that seen in vehicle-treated cats. At 3 hours, cortical blood flow had declined by only 45.7% (p less than 0.04 compared with vehicle). In addition, U74006F treatment significantly improved postischemic maintenance of blood pressure and recovery of somatosensory evoked potentials and reduced postischemic arterial blood acidosis. U74006F had no effect on cortical blood flow, somatosensory evoked potentials, or blood pressure in nonischemic cats. Our results suggest that U74006F may be useful in the early treatment of global cerebral ischemia.
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Quantitative analysis of effects of kappa-opioid agonists on postischemic hippocampal CA1 neuronal necrosis in gerbils.
The ability of the kappa-opioid receptor agonists U50488H and U62066E (spiradoline mesylate) compared with the non-kappa close structural analogue U54494A to affect postischemic necrosis of the selectively vulnerable hippocampal CA1 neurons was examined in male Mongolian gerbils. The gerbils were treated with either saline vehicle or 10 mg/kg i.p. of one of the test drugs 30 minutes before and again 2 hours after a 10-minute period of bilateral carotid artery occlusion or sham occlusion under light methoxyflurane anesthesia. Seven days after ischemia and reperfusion the brains were perfusion-fixed, and hippocampal CA1 cells were counted in a blind fashion. In ischemic gerbils that received only vehicle, there was a 78.9% loss of CA1 neurons compared with sham-occluded gerbils. In contrast, in U50488H-treated gerbils, mean cell loss was reduced to 33.9% (p less than 0.01 vs. vehicle-treated group). U62066E was even more effective in reducing postischemic CA1 degeneration to only 20.7% (p less than 0.0001 vs. vehicle-treated group). However, treatment with the non-kappa analogue U54494A did not cause any apparent protection; the gerbils in this group showed an 80.7% loss of CA1 neurons. Our results are consistent with the hypothesis that kappa-receptor stimulation is associated with improved postischemic neuronal preservation.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
21-Aminosteroid lipid peroxidation inhibitor U74006F protects against cerebral ischemia in gerbils.
U74006F (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methylpregna-1,4,9(11)-triene-3,20-dione, monomethane sulfonate) is a novel and potent inhibitor of central nervous system tissue lipid peroxidation that is devoid of classical steroid hormonal activities. Its possible efficacy in attenuating postischemic mortality and neuronal necrosis was examined in gerbils following 3-hour unilateral carotid artery occlusion. Male Mongolian gerbils received two intraperitoneal injections of either vehicle or U74006F (3 or 10 mg/kg), the first injection 10 minutes before and the second injection at the end of the 3-hour ischemic episode. In an initial series of experiments, vehicle-treated gerbils displayed 60.9% (14 of 23) survival 24 hours after ischemia, which decreased to 34.8% (8 of 23) at 48 hours. In contrast, the 10 mg/kg U74006F-treated group showed 86.7% (13 of 15) survival at 24 hours (p less than 0.15 vs. vehicle) and 80.0% (12 of 15) survival at 48 hours (p less than 0.02). In a second series, neurons in the hippocampal CA1 subfield and the medial and lateral cerebral cortex were counted in gerbils surviving 24 hours after unilateral carotid artery occlusion. Comparison of neuronal densities in the ischemic hemisphere with those in the contralateral nonischemic hemisphere revealed significant neuronal preservation in all three brain regions of 10 mg/kg i.p. x 2 U74006F-treated gerbils. Our results show that U74006F can improve survival and attenuate neuronal necrosis in a severe brain ischemia model.(ABSTRACT TRUNCATED AT 250 WORDS)
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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.
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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.
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Effects of treatment with U-74006F on neurological outcome following experimental spinal cord injury.
The compound U-74006F is one of a series of 21-aminosteroids that lack glucocorticoid or mineralocorticoid activity. These potent inhibitors of lipid peroxidation have been specifically developed for the acute treatment of central nervous system trauma and ischemia. This study evaluated the dose-response characteristics and capability of U-74006F to promote functional recovery in cats subjected to compression trauma of the upper lumbar (L-2) spinal cord. Thirty minutes following injury, randomized and investigator-blinded treatment was initiated with the intravenous administration of either vehicle (citrate-buffered saline) or one of eight doses of U-74006F. Initial doses of U-74006F ranged from 0.01 to 30 mg/kg. Subsequent doses consisted of intravenous bolus injections followed by a continuous 42-hour intravenous infusion. Over the 48-hour treatment period, cats received total U-74006F doses ranging from 0.048 to 160 mg/kg. The animals were evaluated weekly for neurological recovery based upon an 11-point behavioral scale. With the exception of two cats in one group, the animals receiving accumulated doses of U-74006F (ranging from 1.6 to 160.0 mg/kg/48 hrs) exhibited nearly 75% of normal neurological function by 4 weeks after injury. Lower total doses of 0.16 and 0.48 mg/kg/48 hrs were associated with approximately 50% return of normal function, which was not significantly better than the recovery in the vehicle-treated control group. The lowest total dose tested (0.048 mg/kg/48 hrs) gave results indistinguishable from those in vehicle-treated cats, which had recovered only 20% of their preinjury neurological function by 4 weeks. These findings demonstrate that over a 100-fold range of doses, U-74006F has a remarkable capacity to promote functional recovery in spinal cord-injured cats.
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A new 21-aminosteroid antioxidant lacking glucocorticoid activity stimulates adrenocorticotropin secretion and blocks arachidonic acid release from mouse pituitary tumor (AtT-20) cells.
The compound U74006F (21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha-methyl- pregna-1,4,9(11)-triene-3,20-dione) is one of a novel series of 21-aminosteroids that are potent inhibitors of iron-dependent lipid peroxidation. Chronic (4-6 days) dosing of mice or rats with high doses of U74006F (30-200 mg/kg/day) has indicated that the compound is devoid of both glucocorticoid and mineralocorticoid activity. Although the compound is not a glucocorticoid antagonist, it markedly stimulated secretion of adrenocorticotropin by the murine pituitary tumor (AtT-20) cell. The enhanced secretion of adrenocorticotropin was not associated with an increased incorporation of [3H]thymidine or [14C]leucine into DNA or protein, respectively. Although not a glucocorticoid, U74006F also blocked the release of [14C]arachidonic acid from AtT-20 cells damaged by either Fe++ or the metabolic poison, iodoacetate. U74006F represents a novel class of antioxidant which displays cytoprotective activity and may uniquely affect cell growth or function in culture systems.
Adrenocorticotropic Hormone↗
Cardiovascular depressant effects of the kappa opioid receptor agonists U50488H and spiradoline mesylate.
The cardiovascular effects of the selective kappa opioid receptor agonists U50488H and spiradoline mesylate were examined in pentobarbital-anesthetized mongrel dogs and chloralose-anesthetized cats. In the dog studies, U50488H (0.01-3.0 mg/kg, i.v.) produced a dose-related depression in mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular dp/dt, and heart rate. These effects were completely reversed by a 1 mg/kg i.v. dose of the opioid receptor antagonist naloxone. A second kappa agonist, spiradoline mesylate, also produced a naloxone-reversible cardiovascular depression. Furthermore, the compound did not interfere with the positive inotropic or hypertensive effects of norepinephrine (1 microgram/kg, i.v.), showing that the cardiovascular depressant effects of the kappa agonist are unrelated to interference with alpha- or beta-adrenergic receptor mechanisms. In normal cats anesthetized with chloralose, which produces less depression of sympathetic tone than does pentobarbital, spiradoline mesylate did not decrease the MAP in i.v. doses up to 1.0 mg/kg. However, a dose-related increase in sympathetic nerve discharge (SND) was observed (+290% at 1.0 mg/kg). In contrast, in baroreceptor-denervated cats, spiradoline mesylate caused a dose-related hypotensive effect with no change in SND. These results show that the cardiovascular effects of the kappa agonists are peripherally mediated and that reflex sympathetic activity, if uncompromised, can produce a full compensation.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Beneficial effects of the kappa opioid receptor agonist U-50488H in experimental acute brain and spinal cord injury.
The effects of the selective kappa opioid receptor agonist U-50488H (trans-3,4-dichloro-N-methyl-N[2-(pyrrolidinyl)-cyclohexyl]- benzeneacetamide) were examined in acute head and spinal injury models. First, in a blinded protocol, male CF-1 mice were treated intravenously with either saline or U-50488H (1, 3 or 10 mg/kg) within 3-5 min following a reproducible and quantifiable moderately severe (900 g/cm) concussive head injury. Using a grip test at 1 h postinjury to evaluate the neurological status of the injured mice, U-50488H produced a dose-related improvement in early recovery compared to the saline-treated mice. The effect was significant (P less than 0.05) after the 3 or 10 mg/kg i.v. doses. A similar concussive injury markedly reduced the % of cardiac output perfusing the forebrain (cerebral blood flow). U-50488H (10 and 20 mg/kg) partially reversed this effect to a significant degree 60 min after a 20 mg/kg dose. Secondly, the effects of U-50488H on the development of progressive post-traumatic spinal cord white matter ischemia after a 500 g/cm contusive injury were studied in pentobarbital-anesthetized cats. In 4 untreated cats, there was a progressive fall in spinal cord and blood flow (SCBF) from a 10-min postinjury level of 10.5 +/- 0.7 ml/100 g/min to 6.1 +/- 0.3 (P less than 0.03 by paired t at 4 h).(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
The effects of chronic two-fold dietary vitamin E supplementation on subarachnoid hemorrhage-induced brain hypoperfusion.
The effects of chronic dietary supplementation with D-alpha-tocopherol (vitamin E, 70 I.U./lb dry food for 16 weeks) were examined on the acute pathophysiology of experimental subarachnoid hemorrhage (SAH). The SAH was induced in alpha-chloralose-anesthetized cats by intracisternal injection of 0.5 ml/kg of unheparinized arterial blood after prior withdrawal of an equivalent cerebrospinal fluid (CSF) volume. Caudate nuclear blood flow (CBF) was measured via H2 clearance together with intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP), and caudate vascular resistance (CVR). In 6 non-supplemented cats (30 I.U. vitamin E/lb dry food), the SAH resulted in an initial 21.3 +/- 2.4% decrease in CBF by 5 min, followed by a slower secondary decline of 30.1% over the subsequent 3 h after SAH. Together with the fall in CBF, the ICP rose progressively by 18.5 mm Hg (P less than 0.004) and CPP decreased by 36.6 mm Hg (P less than 0.01) at 3 h post-SAH. Furthermore, the CVR increased by 42.9% over the course of the experiment. In comparison, in 6 vitamin E-pretreated cats, there was a complete inhibition of the acute decline in CBF and increase in CVR. In addition, the magnitude of the SAH-induced increase in ICP was significantly less than in the non-supplemented animals. However, the decrease in CPP was unaffected. The ability of intensive anti-oxidant treatment to antagonize post-hemorrhagic hypoperfusion suggests that cerebral microvascular lipid peroxidation may play a key role in its development.
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