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E D Hall

Publications and source records attributed to E D Hall.

At least 91 records · Page 5Linked to original sources
PubMed1993

Protective efficacy of a hypothermic pharmacological agent in gerbil forebrain ischemia.

BACKGROUND AND PURPOSE: The novel muscarinic cholinergic partial agonist U-80816E was tested in the gerbil brief bilateral carotid occlusion ischemia model based on the rationale that the compound's hypothermic properties might afford effective protection of the selectively vulnerable hippocampal CA1 region. METHODS: Male gerbils were subjected to either 10 or 15 minutes of bilateral carotid occlusion, followed by histopathological assessment of the CA1 neuronal survival 7 days later. RESULTS: In saline-treated animals, 10 minutes of bilateral carotid occlusion resulted in a 30.5% loss of CA1 neurons, whereas a 15-minute insult resulted in a 49.6% loss. Administration of U-80816E (6 mg/kg i.p. 30 minutes before bilateral carotid occlusion and again 2 hours after reperfusion) resulted in a significant protective effect of the CA1 neuronal population with either duration of ischemia; neuronal loss was reduced to 12.6% in the milder model (p < 0.05 versus saline-treated) and 24.9% in the more severe model (p < 0.04 versus saline). However, the 6 mg/kg i.p. dose of U-80816E was found to produce a 1.0 degree C decrease in brain temperature (measured with a tympanic temperature probe) at 10 minutes of ischemia compared with that of saline-treated gerbils. At 10 minutes of reperfusion, after the 10-minute episode of ischemia, the brain temperature of the U-80816E-treated gerbils was 2.2 degrees C lower than that of saline-treated animals. When the U-80816E-treated gerbils were subjected to either 10 or 15 minutes of ischemia but placed in a heated chamber that prevented the hypothermic effects, no cerebroprotection was observed. CONCLUSIONS: These results show that the anti-ischemic efficacy of U-80816E is mediated through its hypothermic properties, thus suggesting the feasibility of pharmacologically induced hypothermia as a cerebroprotective approach.

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PubMed1993

Free radicals in CNS injury.

This chapter has reviewed the current state of knowledge regarding the occurrence and possible role of oxygen radical generation and lipid peroxidation in experimental models of acute CNS injury. Although much work remains, four criteria that are logically required to establish the pathophysiological importance of oxygen radical reactions have been met, at least in part. First of all, oxygen radical generation and lipid peroxidation appear to be early biochemical events subsequent to CNS trauma. Second, a growing body of direct or circumstantial evidence suggests that oxygen radical formation and lipid peroxidation are linked to pathophysiological processes such as hypoperfusion, edema, axonal conduction failure, failure of energy metabolism, and anterograde (wallerian) degeneration. Third, there is a striking similarity between the pathology of blunt mechanical injury to CNS tissue and that produced by chemical induction of peroxidative injury. Fourth, and most convincing, is the repeated observation that compounds that inhibit lipid peroxidation or scavenge oxygen radicals can block posttraumatic pathophysiology and promote functional recovery and survival in experimental studies. Nevertheless, the significance of oxygen radicals and lipid peroxidation ultimately depends on whether it can be demonstrated that early application of effective antifree radical or antiperoxidative agents can promote survival and neurological recovery after CNS injury and stroke in humans. The results of the NASCIS II clinical trial, which have shown that an antioxidant dosing regimen with methylprednisolone begun within 8 hr after spinal cord injury can significantly enhance chronic neurological recovery, strongly supports the significance of lipid peroxidation as a posttraumatic degenerative mechanism. However, ongoing Phase III trials with the more selective and effective antioxidant U74006F (tirilazad mesylate) will give a more clear-cut answer as to the therapeutic importance of inhibition of posttraumatic free radical reactions in the injured CNS.

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PubMed1993

The effects of glucocorticoid and nonglucocorticoid steroids on acute neuronal degeneration.

The glucocorticoid steroid methylprednisolone (MP) has been shown to enhance chronic recovery after human spinal cord injury when administered in a 24-hr high-dose regimen beginning within 8 hr. The doses of MP that effect this improved recovery have been demonstrated to inhibit spinal tissue LP, which has been postulated to be a key event in the secondary posttraumatic degenerative cascade. The molecular mechanism of action of the steroid appears to involve intercalation into the cell membrane and blockade of the propagation of LP reactions. At a physiological level, the inhibition of injury-induced LP has been found to result in an attenuation of progressive posttraumatic ischemia and energy failure together with an augmented reversal of intracellular calcium accumulation. However, MP also acts directly to retard secondary neuronal degeneration, as observed in studies showing the steroid's ability to slow the anterograde degeneration of experimentally injured cat soleus motor nerves. The duplication of this effect by the nonsteroidal lipid antioxidant alpha-tocopherol supports the notion that it is indeed a manifestation of the inhibition of posttraumatic LP. Moreover, the efficacy of MP in limiting lipid peroxidation and secondary spinal cord or motor nerve degeneration has also been duplicated by a nonglucocorticoid 21-aminosteroid, tirilazad mesylate (U-74006F), which suggests the independence of the antioxidant and glucocorticoid effects of MP.

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PubMed1993

The role of oxygen radicals in traumatic injury: clinical implications.

Lipid peroxidation is believed to be a major cause of posttraumatic cell damage and death. In patients with head and spinal injuries, this process is believed to contribute significantly to the development of permanent neurological dysfunction. Lipid peroxidation can be inhibited by pharmacological agents such as the antioxidants methylprednisolone and tirilazad mesylate. Animal models of head and spinal cord injuries have been used to investigate the physiological bases of the effects of antioxidants. These studies have found that antioxidants are capable of inhibiting posttraumatic events such as edema, metabolic dysfunction, and ischemia, indicating that lipid peroxidation participates in all of these processes. Early treatment appears to be essential for antioxidant-mediated neuroprotection. The multiple levels at which lipid peroxidation causes damage suggest that pharmacological modulation of this process may be beneficial in the treatment of a wide range of neural injuries.

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PubMed1993

Protective effect of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U74006F) on hepatic endothelium in experimental hemorrhagic shock.

The effects of the 21-aminosteroid lipid peroxidation inhibitor tirilazad mesylate (U74006F) on ultrastructural damage to the hepatic endothelium in a rat model of hemorrhagic shock were examined. Male Sprague-Dawley rats were anesthetized with urethane and subjected to a 2 hr period of hemorrhagic hypotension (mean arterial pressure clamped at 43-45 mm Hg), followed by reinfusion and follow-up for 2 hr. At the end of the experiment, light microscopic analysis of the livers of animals that received an i.v. injection of vehicle (citrate buffer) just prior to reinfusion showed substantial sinusoidal neutrophil influx. Electron microscopic morphometry revealed significant sinusoidal endothelial degeneration. In contrast, rats that received a 10 mg/kg i.v. bolus of U74006F just prior to posthemorrhage reinfusion displayed a significant preservation of endothelial structural integrity. However, this occurred despite the fact that there was the same degree of hepatic neutrophil influx as in the vehicle-treated rats. These results show that U74006F is capable of protecting endothelial structure, even in the face of significant neutrophil invasion, probably via protection from endothelial cell membrane free radical-induced lipid peroxidation.

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PubMed1992

2-(Aminomethyl)chromans that inhibit iron-dependent lipid peroxidation and protect against central nervous system trauma and ischemia.

A series of 2-(aminomethyl)chromans was developed as potent inhibitors of iron-dependent lipid peroxidation. Compounds within this class are extremely effective at inhibiting lipid peroxidation with IC50's as low as 0.2 microM. Selected members were found to enhance early neurological recovery and survival in a mouse head injury model. In this assay, improvement in the 1-h post-head-injury neurological status (grip test score) by as much as 230% of control was observed. One of the most efficacious compounds (35) was evaluated in two models of cerebral ischemia where significant neuroprotection was observed. These results provide further support for the importance of cerebroprotective antioxidants for the treatment of traumatic and ischemic injury as well as additional evidence for the role of oxygen radicals in postischemic brain damage.

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PubMed1992

Novel inhibitors of iron-dependent lipid peroxidation for neurodegenerative disorders.

A considerable body of information supports the occurrence and pathophysiological importance of oxygen radical-mediated lipid peroxidation in acute cerebral damage secondary to traumatic or ischemic injury. Moreover, peroxidative mechanisms have been implicated in chronic neurodegenerative (e.g., Alzheimer's and Parkinson's diseases) and demyelinating (e.g., multiple sclerosis) disorders. Consequently, there has been interest in identification of pharmacological agents with potent ability to interrupt oxygen radical formation or cell membrane lipid peroxidative mechanisms. Our laboratories have developed a novel series of potent lipid peroxidation inhibitors known as the 21-aminosteroids or "lazaroids." One of these compounds, U-74006F or tirilazad mesylate, has shown efficacy in animal models of brain injury and focal cerebral ischemia. In addition, the compound has been found to attenuate the increased lipid peroxidation observed in Alzheimer's brain tissue, to retard anterograde degeneration of motor nerve fibers, and to be effective in decreasing the clinical disease severity and blood-brain barrier disruption observed in the multiple sclerosis model of experimental allergic encephalomyelitis. Another series of antioxidants, the 2-methylaminochromans typified by the compound U-78517F, have been discovered that are even more potent and effective inhibitors of lipid peroxidation than the 21-aminosteroids.

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PubMed1992

Dextran-coupled deferoxamine improves outcome in a murine model of head injury.

Tissue damage involving oxygen-derived free radicals may be greatly exacerbated by free, reactive iron, which acts as a catalyst in oxidative reactions. The effects of free iron can be attenuated by the administration of deferoxamine (DFO), an iron chelator. However, DFO has limited therapeutic utility because it has a short plasma half-life (approximately 5.5 min in mice) and produces profound hypotension upon intravenous infusion. These negative attributes have been circumvented by the covalent attachment of DFO to large polymers, such as dextran or hydroxyethyl starch. The ability of the dextran-conjugated DFO (DEX-DFO) to inhibit iron-catalyzed reactions with lipids was compared to that of the native molecule in an in vitro model of CNS lipid degradation in the presence of 200 microM ferrous iron. There was no difference between native DFO and the modified form. Modified and unmodified DFO were also compared for therapeutic efficacy in a murine model of head injury. Using a previously described "grip test" as a measure of neurologic impairment following injury, DEX-DFO, native DFO, and dextran were administered intravenously 3-5 min after injury. Dextran-DFO significantly decreased the incidence of severe neurologic impairment at dosage levels of 0.1 (n = 92), 1.0 (n = 76), and 10.0 (n = 80) mg/kg. Administration of native DFO or dextran had no effect at the same dosages and concentrations. These results suggest that the murine model of head injury contains a significant iron-dependent component that should be assessed in other models of neural injury.

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PubMed1992

Tirilazad mesylate protects vitamins C and E in brain ischemia-reperfusion injury.

Brain concentrations of the antioxidant vitamins C and E decreased following unilateral carotid occlusion and reperfusion for 2 or 24 h in gerbils. Administration of the 21-aminosteroid inhibitor of lipid peroxidation, tirilazad mesylate (U74006F), prevented the decrease in level of both of these vitamins following 2 h of reperfusion. After 24 h of reperfusion, however, alpha-tocopherol (vitamin E) continued to be protected, but ascorbic acid (vitamin C) showed a pronounced decrease in content. The changes in concentrations of these vitamins are consistent with U74006F acting to inhibit peroxidation in the CNS by scavenging of lipid peroxyl radicals and suggest that, in the presence of this agent, injury-induced depletion of ascorbic acid may occur without irreversible tissue damage.

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PubMed1992

The neuroprotective pharmacology of methylprednisolone.

A 24-hour intensive intravenous dosing regimen with the glucocorticoid steroid methylprednisolone has recently been shown to be effective in enhancing neurological recovery in spinal cord-injured patients when initiated within 8 hours after injury. The state of knowledge concerning the neuroprotective pharmacology of methylprednisolone, including mechanism(s) of action, dosing requirements, and time-action considerations is reviewed, as are the results of studies with high doses in experimental and clinical head injury, subarachnoid hemorrhage, and cerebral ischemia. A primary neuroprotective mechanism of action in each of these cases is hypothesized to involve the ability of high doses of methylprednisolone to inhibit oxygen free radical-induced lipid peroxidation, although additional mechanisms may contribute. Unresolved issues are also addressed, including the therapeutic window, optimum duration of treatment, and rational combination with other neuroprotective agents. A newer methylprednisolone pro-drug with improved solution stability is discussed, together with a brief consideration of novel nonglucocorticoid steroids that surpass methylprednisolone's lipid antioxidant effects without unwanted glucocorticoid properties.

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PubMed1992

Involvement of lipid peroxidation in CNS injury.

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) injury and stroke (e.g., ischemia). While absolute proof for their involvement in the pathophysiology of traumatic and ischemic damage to the CNS remains 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. Furthermore, the use of antioxidants and free radical scavengers in the treatment of experimental and clinical CNS trauma and ischemia has provided convincing support for the involvement of oxygen radicals and lipid peroxidation in these conditions. In this report we will review some of the history behind the hypothesis for an involvement of oxygen radical-mediated lipid peroxidation in the pathophysiology of CNS injury and look at some of the more recent work conducted in this area.

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PubMed1992

Antioxidant effects in brain and spinal cord injury.

Oxygen radical-mediated lipid peroxidation appears to be a critical factor in posttraumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacologic agents with lipid antioxidant activity in models of spinal cord and brain injury. Intensive pretreatment of animals with the endogenous lipid peroxyl radical scavenger alpha tocopherol (i.e., vitamin E) has been shown to decrease posttraumatic spinal cord ischemia and to enhance chronic neurologic recovery. However, the slow CNS tissue uptake of vitamin E requires chronic dosing, making it an impractical agent for the treatment of acute neural injury. The glucocorticoid steroid methylprednisolone has been shown to possess significant antioxidant efficacy and, when administered to animals or humans in antioxidant dosages, improves chronic neurologic recovery after spinal cord injury. This activity of methylprednisolone is independent of the steroid's glucocorticoid receptor-mediated actions. Novel antioxidant 21-aminosteroids have been developed that are devoid of glucocorticoid activity but have greater antioxidant efficacy than methylprednisolone. One of these, U74006F or tirilazed mesylate, has been shown to be effective in animal models of brain and spinal cord injury and is currently undergoing phase II clinical trials. Compounds that combine the amino functionality of the 21-aminosteroids with the peroxyl radical scavenging chromanol portion of vitamin E (i.e., 2-methylaminochromans) have also recently shown promise as neuroprotective agents. The consistent benefit afforded by antioxidant compounds adds further support to the concept that lipid peroxidation is an important therapeutic target for acute pharmacologic neuroprotection.

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PubMed1992

Biochemistry and pharmacology of lipid antioxidants in acute brain and spinal cord injury.

Oxygen radical-mediated lipid peroxidation (LP) has been suggested increasingly to be an important factor in posttraumatic neuronal degeneration. Thus, numerous studies have evaluated the neuroprotective efficacy of pharmacological agents with lipid antioxidant activity in models of spinal cord and brain injury. Intensive pretreatment of animals with the endogenous lipid peroxyl radical scavenger vitamin E (i.e., alpha-tocopherol) has been shown to decrease posttraumatic spinal cord ischemia and to enhance chronic neurological recovery. However, the slow CNS tissue uptake of vitamin E requires chronic dosing, making it an impractical agent for treatment of acute neural injury. The glucocorticoid steroid, methyl-prednisolone (MP), has been shown to possess significant antioxidant efficacy and, when administered to animals or humans in antioxidant doses, improves chronic neurological recovery after spinal cord injury. This activity of MP is independent of the steroid's glucocorticoid receptor-mediated actions, as evidenced by the efficacy of the novel antioxidant 21-aminosteroids, which are devoid of glucocorticoid activity but have greater antioxidant efficacy than MP. One of these, tirilazad mesylate (U-74006F), has been shown to be effective in animal models of brain and spinal cord injury and is currently the subject of phase II clinical trials. Recently, compounds that combine the amino functionality of the 21-amino-steroids with the peroxyl radical scavenging chromanol portion of vitamin E (i.e., 2-methylaminochromans) also have shown promise as neuroprotective agents. The consistent benefit afforded by antioxidant compounds further supports the concept that LP is an important therapeutic target for acute pharmacological neuroprotection.

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PubMed1991

The 21-aminosteroid antioxidant tirilazad mesylate, U-74006F, blocks cortical hypoperfusion following spreading depression.

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 tirilazad 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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PubMed1991

Sex differences in postischemic neuronal necrosis in gerbils.

Twenty-four hour postischemic neuronal necrosis was compared in male vs. female Mongolian gerbils subjected to a 3-h period of severe incomplete hemispheric ischemia produced by unilateral carotid occlusion. The incidence of stroke-prone males was 42.9% versus 26.7% for the females. Among the stroke-prone animals, the males displayed significantly greater neuronal necrosis at 24 h after ischemia compared to the females in the cerebral cortex and CA1 region of the hippocampus. In the CA1 region of the stroke-prone males, only 2.0% of the normal neuronal population remained by 24 h compared to 36.8% in the stroke-prone females (p less than 0.02). In the cerebral cortex, the males had only 19.9% of normal versus 58.2% in the females (p less than 0.05). In a second series of mechanistic experiments, no differences in cortical blood flow (CBF) were disclosed between preselected male and female stroke-prone animals before, during, or for 2 h after ischemia. As with the CBF, the extent of cortical extracellular hypocalcia during ischemia did not differ significantly. However, the degree of postischemic recovery of cortical extracellular calcium was significantly better in the females from 30 min to 2 h after reperfusion. In the same experiments, hemispheric vitamin E levels were measured at the 2 h time point as an index of postischemic brain lipid peroxidation. No difference in baseline vitamin E levels was observed between male and female sham-operated gerbils. In the males subjected to 3 h of ischemia plus 2 h of reperfusion, the hemispheric vitamin E decreased by 43.5% compared to the sham-operated males.(ABSTRACT TRUNCATED AT 250 WORDS)

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