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Biomedical subjects

E D Hall

Publications and source records attributed to E D Hall.

At least 109 records · Page 6Linked to original sources
PubMed1991

Effect of delayed administration of U74006F (tirilazad mesylate) on recovery of locomotor function after experimental spinal cord injury.

Beginning at either 30 minutes, 2 hours, 4 hours, or 8 hours after 180 g compression of the cat L2 spinal cord for 5 minutes, infusion of U74006F was initiated. In this series, the cats received a total U74006F dose of 5 mg/kg/48 hours. An additional group of injured cats was treated at 8 hours postinjury with a three-fold higher dose of U74006F (i.e., a total 48-hour dose of 15 mg/kg). Controls received an equal volume of vehicle (citrate-buffered saline) delivered over 48 hours. The cats were evaluated weekly for 4 weeks for recovery of overground locomotion based on an 11-point scale by an investigator blinded to the time and type (i.e., vehicle or drug) of material administered. By 4 weeks postinjury, there was no significant difference in the locomotor recovery of cats that received U74006F at either 30 minutes, 2 hours, 4 hours, or 8 hours after injury. However, only recovery in the groups treated at 30 minutes, 2 hours, or 4 hours after injury was significantly greater than vehicle-treated controls. Locomotor function in cats receiving either 5 mg/kg/48 hours or 15 mg/kg/48 hours of U74006F at 8 hours postinjury was not significantly different from that of the vehicle-treated animals. Mean (+/- SEM) 4-week recovery scores were 6.8 +/- 0.9, 5.9 +/- 1.0, 7.2 +/- 1.1, and 4.7 +/- 2.9 out of 11 for cats treated at 30 minutes, 2 hours, 4 hours, or 8 hours postinjury, respectively, with the 5 mg/kg/48 hour dose. The mean recovery score for cats treated at 8 hours after injury with the 15 mg/kg/48 hour dose was 3.4 +/- 1.8. The average score for the vehicle-treated controls was 1.8 +/- 0.8. These findings demonstrate that U74006F can significantly protect locomotor function in our model of compression spinal cord injury if administered as late as 4 hours postinjury. Delaying administration of the compound to 8 hours after injury results in considerable loss of its protective capabilities even if the dose is increased threefold.

Animals↗
PubMed1991

Effects of tirilazad mesylate on postischemic brain lipid peroxidation and recovery of extracellular calcium in gerbils.

We describe the effects of the 21-aminosteroid tirilazad mesylate (U-74006F) on postischemic lipid peroxidation (depletion of brain vitamin E) and cortical extracellular calcium recovery in gerbils subjected to 3 hours of unilateral carotid artery occlusion. Male gerbils were treated with either 0.2 ml vehicle (0.05N HCl) or 10 mg/kg i.p. U-74006F 10 minutes before the induction of ischemia and again immediately after the initiation of reperfusion. In the first series of experiments, the brain concentration of vitamin E, which was unaffected by ischemia without reperfusion, was decreased after 2 hours of reperfusion by an average of 60% in vehicle-treated animals compared with sham-operated animals; in the U-74006F-treated gerbils, the 2-hour postischemic vitamin E loss was only 27% (p less than 0.002 different from vehicle-treated animals). In the second series, unilateral carotid artery occlusion produced a decrease in the cortical extracellular calcium concentration from 1.05 mM before ischemia to 0.11 mM by the end of the ischemic episode in both vehicle- and U-74006F-treated gerbils. After 2 hours of reperfusion, the calcium concentration had recovered to only 0.22 mM in the vehicle-treated animals compared with 0.56 mM in the U-74006F-treated group (p less than 0.01). Cortical blood flow, mean arterial blood pressure, and blood gases did not differ significantly between the two treatment groups. Administration of only the immediate postreperfusion dose (i.e., no pretreatment) also significantly improved the recovery of cortical extracellular calcium. The results indicate that U-74006F inhibits postischemic lipid peroxidation as assessed by the preservation of brain vitamin E and that, secondary to this membrane-protective effect, the processes responsible for the reversal of ischemia-triggered intracellular calcium accumulation are preserved.

Animals↗
PubMed1991

Comparison of the efficacy of mechanistically different antioxidants in the rat hemorrhagic shock model.

Four pharmacological mechanisms for antagonizing free radical generation or reactions were compared in terms of their efficacy in attenuating hemorrhagic shock in rats. These included opposing superoxide generation by xanthine oxidase (e.g., oxypurinol), inhibiting arachidonic acid oxidation by cyclooxygenase (e.g., ibuprofen), chelating iron (e.g., desferal), and inhibiting lipid peroxidation (e.g., tirilazad mesylate [U-74006F] and U-78517G). Animals were hemorrhaged to a mean arterial pressure (MAP) of 43-45 mmHg where they were held for 2 hr. Five minutes prior to the end of the hemorrhage period, either vehicle, U-74006F (10 mg/kg), U-78517G (10 mg/kg), oxypurinol (10 or 25 mg/kg), desferal (10 or 25 mg/kg), or ibuprofen (10 mg/kg) was administered i.v., followed by the reinfusion of shed blood. In vehicle-treated animals, MAP declined progressively over the 2 hr post-reinfusion. Ibuprofen, desferal, and oxypurinol treatments each failed to attenuate this decline. In contrast, both U-74006F and U-78517G resulted in a significantly improved maintenance of MAP. Evidence of shock-induced lipid peroxidation was observed in terms of a 73.8% depletion in liver vitamin E content at 2 hr post-reinfusion in vehicle-treated rats. This decrease was prevented by both U-74006F and U-78517G. Inhibition of free radical-induced lipid peroxidation appears more effective for attenuating free radical pathophysiology in hemorrhagic shock that attempting to inhibit specific pathways of oxygen radical generation.

Animals↗
PubMed1991

U-78517F: a potent inhibitor of lipid peroxidation with activity in experimental brain injury and ischemia.

U-78517F (2-[4-[2,6-di-(1-pyrrolidinyl)-4-pyridinyl)-1-piperazinyl] methyl]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, dihydrochloride), which combines the antioxidant ring portion of alpha-tocopherol together with the amine of the previously described 21-aminosteroids (e.g., U-74006F), is a novel inhibitor of iron-catalyzed lipid peroxidation. U-78517F was found to have a 50% inhibitory concentration (IC50) of 0.6 microM against 200 microM ferrous chloride-initiated lipid peroxidation in rat brain homogenates, compared to 8 microM for U-74006F, 28 microM for alpha-tocopherol and 43 microM for the ring portion of alpha-tocopherol (i.e., trolox). Both stereoisomers of the racemic U-78517F proved to be equally active antioxidants. Against lipid peroxidation initiated by xanthine/xanthine oxidase, U-78517F was even more potent, with an IC50 of 0.01 microM. U-78517F was also observed to protect cultured mouse spinal neurons against iron-induced damage, with an IC50 of approximately 0.5 microM. When administered to male CF-1 mice i.v. at 5 min after a severe concussive head injury. U-78517F produced a dose-related improvement in the 1-hr neurological recovery. The minimum effective i.v. dose was 1.0 micrograms/kg. Measurement of U-78517 concentrations in the brains of mice after administration of a 10-mg/kg i.v. dose revealed effective antioxidant levels for as long as 2 hr. Evidence of an in vivo antioxidant action was provided by the attenuation of iron-induced blood-brain barrier disruption (i.e., Evans' blue extravasation) in rats pretreated with U-78517F.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Inhibition of lipid peroxidation in CNS trauma.

It is believed that the key mechanism of protection of the injured spinal cord by methylprednisolone (MP) is the inhibition of posttraumatic lipid peroxidation. Large, i.v. bolus doses are required to achieve this effect, but the biphasic dose-response curve limits the dose size to approximately 30 mg/kg. The mechanism for the reversed effect at higher concentrations is believed currently to be membrane disruption. Early treatment is required because injury mediated by lipid peroxidation is largely irreversible. Furthermore, the time course of the protective effects parallels the tissue pharmacokinetics, defining the need for repeated maintenance dosing by bolus or infusion. The optimum duration of treatment has not been ascertained, but it would appear to extend throughout the period during which biochemical conditions that promote peroxidation exist within the injured cord.

Animals↗
PubMed1990

Preservation of motor nerve function during early degeneration by the 21-aminosteroid anti-oxidant U74006F.

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 only 52 +/- 8%. U74006F pretreatment produced a dose-related improvement with the 13.0 mg/kg dose having the best effect; the ratio was 86 +/- 5% (P less than 0.01 vs 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 only 54.0 +/- 5.2% in untreated animals to 72.2 +/- 5.7 (P less than 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.

Action Potentials↗
PubMed1990

Novel 21-aminosteroids that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma.

A novel class of 21-aminosteroids has been developed. Compounds within this series are potent inhibitors of iron-dependent lipid peroxidation in rat brain homogenates with IC50's as low as 3 microM. Furthermore, selected members enhance early neurological recovery and survival in a mouse head injury model. Significant improvement in the 1 h post-head-injury neurological status (grip test score) by as much as 168.6% of the control has been observed. The most efficacious compound in this assay (30) showed an increase in the 1-week survival of 78.6% as compared to 27.3% for the vehicle-treated mice in the head-injury model. Based on its biological profile, 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piperazinyl]-16 alpha- methylpregna-1,4,9(11)-triene-3,20-dione monomethanesulfonate (30) was selected for further evaluation and is currently entering phase I clinical trials for the treatment of head and spinal trauma.

Amines↗
PubMed1990

Nonsteroidal lazaroid U78517F in models of focal and global ischemia.

U78517F is a novel inhibitor of iron-catalyzed lipid peroxidation that combines the tetramethylchroman antioxidant ring portion of alpha-tocopherol with the amine of the previously described 21-aminosteroids (e.g., U74006F). U78517F inhibited 200 microM FeCl2-initiated lipid peroxidation in rat brain homogenates by 50% at a concentration of 0.6 microM compared with 8 microM for U74006F, 28 microM for alpha-tocopherol, and 43 microM for the ring portion of alpha-tocopherol (i.e., trolox). U78517F is devoid of hypothermic or antiexcitotoxic actions or interactions with known neurotransmitter receptors. When administered intraperitoneally to male gerbils at 10 minutes before and again at the end of a 3-hour period of unilateral carotid artery occlusion, U78517F decreased 24-hour postischemic cortical neuronal necrosis. Neuronal density in the medial portion of the cortex was increased from 34.2% of normal in vehicle-treated animals to 86.3% in the U78517F-treated animals. In the lateral cortical area, the vehicle group showed only 3.3% neuronal survival versus 48.2% in the drug-treated group. In a separate series of experiments with the same focal ischemia model, identical dosing with U78517F enhanced the postischemic recovery of cortical extracellular calcium without any effect on ischemic or postischemic cortical blood flow. The effect on calcium recovery was observed at intraperitoneal doses as low as 0.1 mg/kg. The compound also was effective in partially attenuating 1-week postischemic hippocampal CA1 neuronal loss in a gerbil global ischemia model involving brief (15-minute) bilateral carotid occlusion, but sustained dosing was required. These results document the anti-ischemic efficacy of a novel and potent inhibitor of iron-catalyzed lipid peroxidation and further support a key role of oxygen radicals in postischemic brain damage.

Animals↗
PubMed1990

Steroids and neuronal destruction or stabilization.

Extensive work has indicated that glucocorticoid steroids may play a role in promoting age-related central neuronal degeneration. It has also been shown that glucocorticoid supplementation may intensify acute post-ischaemic neuronal necrosis and that prior adrenalectomy is protective. A glucocorticoid inhibition of injury-induced axonal reactive sprouting has also been reported. The mechanism of this deleterious effect on chronic or acute neuronal degeneration and regenerative responses is thought to involve specific glucocorticoid receptors either on susceptible nerve cells or on adjacent glial cells. However, other studies have shown that intensive short-term glucocorticoid treatment may attenuate post-traumatic and post-ischaemic central neuronal damage. Anterograde degeneration of motor nerve fibres can also be retarded by intensive glucocorticoid pretreatment. The mechanism of these high dose protective effects appears to involve an intrinsic ability of certain glucocorticoids to inhibit oxygen free radical-induced lipid peroxidation, a phenomenon that may be fundamentally involved in neuronal degeneration. Recently, steroid analogues which lack glucocorticoid receptor affinity have been shown to duplicate the antioxidant and cerebroprotective actions of the glucocorticoids in models of neuronal damage. Thus, the deleterious and protective effects of steroids on neuronal viability depend on two different mechanisms, separable by dose, duration of treatment, specific situation and chemical structure.

Animals↗
PubMed1990

Effects of a 21-aminosteroid (U-74006F) on cerebral metabolites and edema after severe experimental head trauma.

U-74006F, a 21-aminosteroid, is a potent inhibitor of CNS tissue LP in vitro. In this study it was tested for effects on brain edema and metabolites after impact injury to the closed skull. Anesthetized cats were blindly treated with U-74006F or vehicle at 30 min (1 mg/kg) and 2.5 hr (0.5 mg/kg) after head or sham injury. They were sacrificed 4 hr after injury by in situ fixation of the brain. Head-injured cats were selected for unilateral (left) cerebral contusion. Metabolites (enzyme fluorometry) and edema (specific gravity) were measured in the cerebral cortex and white matter bilaterally. Cerebral hemisphere, contusion, and vasogenic edema volumes were morphometrically measured. Magnitude of edema and metabolites in tissue with vasogenic edema was similar in vehicle- and drug-treated cats. By contrast, the cortex and nonedematous white matter neighboring contusion in drug-treated cats had lactate, glucose, and glycogen levels that suggested an improved metabolic state over vehicle treatment. Most metabolites were not affected by trauma or treatment in the uncontused hemisphere. These results suggest that postinjury treatment with the nonglucocorticoid steroid U-74006F may benefit the metabolism of nonedematous tissue adjacent to contusion.

Animals↗
PubMed1989

Central nervous system trauma and stroke. I. Biochemical considerations for oxygen radical formation and lipid peroxidation.

The generation of oxygen radicals and the process of lipid peroxidation have become a focus of attention for investigators in the fields of central nervous system (CNS) trauma and stroke (e.g., ischemia). Considering our level of understanding of free radical and lipid peroxidation chemistry, absolute proof for their involvement in the pathophysiology of traumatic and ischemic damage to the CNS has been meager. While direct, unequivocal evidence for the participation of free radicals and lipid peroxidation as primary contributors to the death of neuronal tissue waits to be established, numerous recent studies have provided considerable support for the occurrence of free radical and lipid peroxidation reactions in the injured or ischemic CNS. In addition, the pharmacological use of antioxidants and free radical scavengers in the treatment of experimental CNS trauma and ischemia has provided convincing, although indirect evidence, for the involvement of oxygen radicals and lipid peroxidation in these conditions. The intent of this and its companion paper is to review: 1) the biochemical processes which may give rise to free radical reactions in the CNS, 2) the environment of the ischemic cell as it may affect the generation of oxygen radicals and the catalysis of lipid peroxidation reactions, 3) the evidence for the involvement of free radical mechanisms in CNS trauma and ischemia, and 4) the pathophysiological consequences of these phenomena.

Animals↗
PubMed1989

Central nervous system trauma and stroke. II. Physiological and pharmacological evidence for involvement of oxygen radicals and lipid peroxidation.

The previous article outlined the biochemical basis and evidence for the occurrence of oxygen radical generation and lipid peroxidation during the acute phase of central nervous system (CNS) trauma or stroke (ischemic and hemorrhagic). The identification of oxygen radicals and lipid peroxidation as important pathophysiological mediators of trauma or stroke-induced neural degeneration, rather than simply epiphenomena, depends upon the successful demonstration of their association with actual secondary physiological and structural degenerative events. Moreover, their significance in the pathophysiology of CNS trauma or stroke must be supported by experimental observations that pharmacological antagonism of either oxygen radical generation and/or lipid peroxidation results in a therapeutic effect (i.e., interruption of secondary nervous tissue degeneration). Indeed, recent investigations have provided compelling evidence for the view that oxygen radical-mediated processes play a key pathophysiological role during the acute phase of CNS trauma or stroke. Furthermore, their pharmacological manipulation may serve as an avenue for therapeutic attempts aimed at limiting neural degeneration and improving neurological recovery.

Animals↗
PubMed1989

Comparison of two ester prodrugs of methylprednisolone on early neurologic recovery in a murine closed head injury model.

In prior work, methylprednisolone succinate, sodium salt (MPSS) has been shown to enhance the early neurologic recovery of moderately or severely head-injured mice. In the present study, the relative cerebroprotective potency and efficacy of MPSS was compared to another methylprednisolone ester prodrug, methylprednisolone suleptanate, sodium salt (U67590A). Male CF-1 mice received a 900 g-cm concussive head injury followed within 5 min by an intravenous bolus dose of vehicle, MPSS, or U67590A. At 1 h postinjury, the neurologic status was evaluated blindly using a grip test. Both methylprednisolone esters were found to enhance early neurologic recovery after this severe head injury. However, U67590A was four to eight times more potent than MPSS. Either a 7.5 or 15.0 mg/kg dose of U67590A produced a significant improvement in recovery while a 60.0 mg/kg dose of MPSS was required. The maximal efficacy of the two prodrugs was equal. These results indicate that the ester of methylprednisolone can greatly influence the steroid's cerebroprotective potency and that U67590A may be superior in this regard to MPSS for the acute treatment of CNS injury.

Animals↗
PubMed1989

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)

Animals↗
PubMed1989

Free radicals and CNS injury.

This article has reviewed the current knowledge regarding the occurrence and possible role of oxygen radical generation and lipid peroxidation in acute CNS injury. Although much work remains, three criteria required to establish the pathophysiologic importance of oxygen radical reactions in post-traumatic events have been met, at least in part. First, oxygen radical generation and lipid peroxidative reactions appear to be early biochemical events subsequent to CNS injury. Second, a growing body of direct or circumstantial evidence suggests that these reactions are causally linked to pathophysiologic processes such as hypoperfusion, edema, axonal or synaptic conduction failure, and anterograde (Wallerian) degeneration. Third, compounds that inhibit lipid peroxidation or scavenge oxygen radicals can block post-traumatic pathophysiology and promote nervous tissue function and survival in experimental studies. Nevertheless, the importance of oxygen radicals and lipid peroxidation ultimately depends on whether it can be more clearly demonstrated that early application of effective antifree radical or antiperoxidative agents can promote survival and neurologic recovery after CNS injury in humans.

Antioxidants↗