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Biomedical subjects

E D Hall

Publications and source records attributed to E D Hall.

At least 145 records · Page 8Linked to original sources
PubMed1987

Intensive anti-oxidant pretreatment retards motor nerve degeneration.

Intensive pretreatment of cats with a combination of the antioxidants D-alpha-tocopherol (200 IU) and selenium (50 micrograms) once daily for 5 days (p.o.) was found to significantly preserve the functional capacity of degenerating soleus motor nerve terminals (measured at 48 h after axon section at the hip) in the in vivo soleus nerve-muscle preparation. The preservation of function was apparent in terms of: a greater soleus contractile response to nerve stimulation at low frequencies, a more rapid recovery from D-tubocurarine-induced neuromuscular block, and a better maintenance of tetanic contractile tension during high-frequency nerve stimulation. The ability of antioxidants to retard the anterograde axonal degeneration (i.e. 'Wallerian') process suggests that lipid peroxidation may be a fundamental mechanism of neuronal degeneration.

Animals↗
PubMed1987

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission.

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100 mg/kg (i.p.) simultaneously with HC-3. A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30-300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 micrograms/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 micrograms/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

Animals↗
PubMed1987

Post-traumatic spinal cord ischemia: relationship to injury severity and physiological parameters.

Alterations in lumbar spinal cord white matter blood flow (SCBF) during the initial 4 hours following contusion injury were examined in cats anesthetized with either dial-urethane or sodium pentobarbital and correlated with changes in cardiovascular parameters (MAP, HR), blood gases (pCO2, pO2), and pH. In the dial-urethane anesthetized cats, the effect of a severe 500 g-cm contusion on SCBF was determined at the center of the injury site vs. an adjacent site 3 mm away. At the injury site, SCBF fell progressively from a pre-injury mean of 13.9 +/- 0.8 (S.E.) mg/100 g/min to a 4 hour value of 7.0 +/- 1.3 (-49.6%). In contrast, SCBF in the adjacent white matter tissue was dramatically increased to 22.4 +/- 1.9 ml/100 g/min (+61.2% over pre-injury; p less than 0.025), at 10 min post-injury falling gradually back to only slightly below the pre-injury level at 4 hours. The severe contusion resulted in prolonged hypotension and bradycardia that was significant by 10 min post-injury while arterial blood gases and pH did not change over the experimental course. A very similar post-traumatic hypoperfusion was observed at the injury site in pentobarbital anesthetized animals in regard to the time course and extent of the decline in SCBF (-55.6% at 4 hours). Although the decrease in SCBF over time was gradual, the MAP and HR were maximally depressed by 10 min post-injury. A more moderate contusion (300 g-cm) resulted in an initial hyperemia followed by a return of SCBF to the pre-injury level by 30 min with no significant change thereafter even though the MAP was depressed to nearly the same extent as in the more severely injured cats. These results demonstrate that post-traumatic spinal cord ischemia is a phenomenon localized to the spinal injury site and directly related to the injury force with moderate injury actually causing a temporary hyperemia. In addition, a significant difference in SCBF may exist between the injury site and adjacent spinal tissue only a few mm away. No correlation between the increase or decrease in SCBF and change in cardiovascular parameters or blood gases following injury is demonstrable nor does anesthetic choice seem to make a significant difference. Thus, post-traumatic changes in SCBF appear to be due to the elaboration of local mediators for the most part unrelated to concomitant alterations in spinal cord perfusion pressure.

Animals↗
PubMed1987

Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury.

Beginning 30 minutes after compression trauma of the upper lumbar (L-2) spinal cord, cats were treated with either a high-dose regimen of methylprednisolone (MP) administered as the sodium salt of the 21-succinate ester (Solu-Medrol sterile powder) or the MP vehicle. Animals were randomly assigned to either treatment group (10 cats per group), and all personnel were blind as to which animals received vehicle or drug. The intensive 48-hour dosing regimen was designed to maintain therapeutic tissue levels of MP and consisted of an initial 30 mg/kg intravenous bolus of MP; 2 and 6 hours later additional 15 mg/kg MP doses were administered by intravenous bolus. Immediately following the bolus given at 6 hours, a continuous MP infusion of 2.5 mg/kg/hr was started. The infusion was stopped abruptly at 48 hours with no dose tapering. Animals in the vehicle group received an equivalent volume of MP vehicle. The total MP dose administered over 48 hours was 165 mg/kg. Animals were evaluated weekly for neurological recovery based upon a 12-point functional scale which assessed general mobility, running, and stair-climbing. Mean recovery scores at 1 month after injury (+/- standard error of the mean) were: vehicle group (seven cats) 3.7 +/- 0.9, and MP group (10 cats) 8.7 +/- 0.2; (p less than 0.001). Histological evaluation of the spinal cords revealed a strong negative correlation between neurological recovery and size of the spinal cord cavity at 1 month (r = -0.88). Three of 10 animals in the vehicle group became ill and had to be dropped from the study, whereas all of the 10 MP-treated animals survived in excellent health. The results demonstrate the therapeutic effectiveness and low incidence of side effects associated with an intensive MP dose regimen for treatment of experimental spinal cord injury.

Animals↗
PubMed1987

U-54494A: a unique anticonvulsant related to kappa opioid agonists.

The benzamide U-54494A was compared to U-50488H (a structurally related kappa opioid agonist), phenytoin and phenobarbital in a variety of tests of anticonvulsant and sedative activities. In electroshock convulsion antagonism studies in mice and rats, U-54494A was generally similar to the standards in regard to milligrams of potency, threshold elevation, p.o. activity and duration of action. In contrast to phenytoin and phenobarbital, both U-54494A and U-50488H were effective antagonists of the convulsions induced by the excitatory amino acid agonists (kainic, N-methyl-aspartic and quisqualic acids) and the Ca++ channel agonist (Bay K 8644). They were not, however, effective antagonists of the gamma-aminobutyric acid-related convulsants (bicuculline and pentylenetetrazole), but all four blocked audiogenic convulsions in genetically epileptic mice. U-54494A in contrast to U-50488H lacks the kappa receptor-mediated sedative and analgesic activities but the anticonvulsant properties of both compounds are antagonized by high doses of naltrexone. Further investigations of the mechanism of action of these compounds revealed that both caused a dose-related suppression of post-tetanic repetitive discharge in cats soleus nerve-muscle preparations as measured by an abolition of the obligatory potentiation of soleus muscle contractile tension. On a biochemical level, both U-54494A and U-50488H attenuate the depolarization induced uptake of 45Ca++ into forebrain synaptosomes and block the enhancement of [3H]kainic acid binding induced by CaCl2. Together these results suggest that U-54494A is a unique and selective anticonvulsant agent acting by a Ca++-related mechanism possibly through a subclass of kappa receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

A nonglucocorticoid steroid analog of methylprednisolone duplicates its high-dose pharmacology in models of central nervous system trauma and neuronal membrane damage.

Prior studies have demonstrated that intensive treatment with high doses of methylprednisolone (MP) can beneficially affect the acutely injured central nervous system by a variety of mechanisms and promote neurological recovery in experimentally injured animals. In view of the fact that these actions are associated only with MP doses greatly in excess of those required for classical glucocorticoid receptor-mediated actions of the steroid, the possibility was examined that this high-dose pharmacology of MP could be duplicated by a nonglucocorticoid analog. Accordingly, U-72099E (17,21-dihydroxy-11 alpha-t-butylacetoxy-1,4-pregnadiene-3,20-dione- 21-hemisuccinate, sodium salt) was synthesized and tested for its ability to duplicate the high-dose effects of MP in a concussive head injury model in mice and in an in vitro model of lipid peroxidation-induced membrane damage using rat brain synaptosomes. The absence of glucocorticoid-related activity of U-72099E was confirmed by its inability to either suppress body weight gain or cause thymic involution in mice treated with doses up to 100 mg/kg/day for 4 days. On the other hand, MP at 30 mg/kg/day for 4 days caused a complete inhibition of body weight gain and a 43.5% reduction in thymus weight. Moreover, U-72099E, at concentrations of 10(-5) M or lower, failed to suppress adrenocorticotropin secretion by mouse AtT-20 pituitary cells in culture, whereas dexamethasone or MP at concentrations of 10(-6) M and lower caused a marked suppression in adrenocorticotropin secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1987

Lipid peroxidation and the role of oxygen radicals in CNS injury.

Lipid peroxidation is a radical induced chain reaction which is fundamentally linked to cellular destruction in the secondary injury process which is initiated by head and spinal injury and stroke. Injuries such as these begin a series of molecular events which lead to gradual vascular and neuronal degeneration. This process ultimately precludes neurological recovery. The secondary damage process is a combination of lipid peroxidation, calcium influx, arachidonic acid release and metabolism, transition metal redox reactions and tissue pH. Although CNS cells are particularly susceptible to lipid peroxidation, the process is common to many biological processes (e.g. inflammation, carcinogenesis, aging, radiation damage, transplant rejection, etc.).

Animals↗
PubMed1987

A new class of compounds for stroke and trauma: effects of 21-aminosteroids on lipid peroxidation.

The Lazaroids are the result of a blend of reasonable objectives which sprang from experience and hypothesis with a strong dose of serendipity. We believe that these compounds inhibit lipid peroxidation at a membrane level and, thus, blunt the damage from the secondary wave of injury which follows stroke, trauma and other insults to cell membranes. Certainly, these compounds are superior in animal models in potency and efficacy to older glucocorticoids. One compound, U74006F, has been selected for clinical development. Clinical trials in head injury will begin soon in selected centers in the United States.

Animals↗
PubMed1986

Role of lipid peroxidation in post-traumatic spinal cord degeneration: a review.

A large amount of biochemical, physiological, and pharmacological data has been obtained which supports a mechanistic role of oxygen free radical-induced lipid peroxidation (LP) in post-traumatic spinal cord degeneration. Biochemical evidence of early and progressive lipid peroxidative reactions occurring in the injured spinal cord includes: an increase in polyunsaturated fatty acid peroxidation products (e.g., malonyldialdehyde), a decrease in cholesterol and the appearance of cholesterol oxidation products, an increase in cyclic GMP presumably due to free radical activation of guanylate cyclase, a decrease in tissue anti-oxidant levels (e.g., alpha tocopherol, reduced ascorbate), and inhibition of membrane-bound enzymes such as Na+ + K+-ATPase. In vitro CNS tissue studies have provided support for the possibility that LP may contribute to other early post-traumatic events including intracellular calcium accumulation and arachidonic acid release. Moreover, spinal tissue lactic acidosis, which occurs early after injury, can exacerbate LP reactions. The involvement of LP in the development of progressive post-traumatic spinal white matter ischemia has been strongly inferred from pharmacological studies in cats with known inhibitors of LP. For example, the dose-response curves for the ability of the glucocorticoid methylprednisolone (MP) to inhibit post-traumatic LP and to retard ischemia development are identical. This relationship between LP and post-traumatic ischemia is more directly implied from studies showing that pretreatment of cats with high doses of anti-oxidants (e.g., d-alpha tocopherol plus selenium p.o. or 1-ascorbic acid i.v.) can also significantly antagonize the progressive decrease in spinal cord blood flow that follows severe blunt injury. However, a similar efficacy of certain calcium and prostaglandin antagonists suggests an interrelationship between aberrant calcium fluxes, vasoconstrictor/platelet aggregating prostanoids, and LP in the post-traumatic ischemic phenomenon. In addition to a role of LP in ischemia development, the action of intensive d-alpha tocopherol and selenium pretreatment to retard anterograde cat motor nerve fiber degeneration after nerve section suggests that LP may also be a fundamental mechanism of "Wallerian" axonal degeneration after neural injury. Finally, a critical role of LP in the acute pathophysiology of CNS injury in general has been supported by the finding of an excellent correlation, in terms of efficacy and potency, between the action of glucocorticoid and nonglucocorticoid steroids to inhibit neural tissue LP in vitro and to promote early neurological recovery in severely head-injured mice.

Animals↗
PubMed1986

A pharmacological analysis of the pathophysiological mechanisms of posttraumatic spinal cord ischemia.

A pharmacological analysis was carried out to determine the possible role of aberrant calcium fluxes, vasoactive arachidonic acid metabolites, and microvascular lipid peroxidation in the development of posttraumatic spinal cord white matter ischemia. Pentobarbital-anesthetized cats were treated intravenously 30 minutes before a 500-gm-cm contusion injury to the lumbar spinal cord with one of the following test drugs: the Ca++ channel antagonists verapamil, diltiazem, or nifedipine; the cyclo-oxygenase inhibitors ibuprofen or meclofenamate; the thromboxane A2 (TXA2) synthetase inhibitor furegrelate sodium; or the stable epoprostenol (prostacyclin, or PGI2) analogue ciprostene calcium alone or in combination with furegrelate sodium. Another group of animals was pretreated for 5 days before spinal injury with a combination of the antioxidants vitamin E and selenium in high doses. The hydrogen clearance technique was used to make repeated measurements of spinal cord blood flow (SCBF) in the dorsolateral funiculus of the injured segment before and for 4 hours after injury. In 11 untreated uninjured cats, the mean preinjury SCBF was 12.7 +/- 1.5 ml/100 gm/min. Following contusion, there was a progressive decline in SCBF to 6.8 +/- 0.4 ml/100 gm/min, or 53.5% of the preinjury level at 4 hours. In comparison, the Ca++ antagonists diltiazem and nifedipine (but not verapamil) prevented a significant posttraumatic decrease in SCBF. Similarly, both cyclo-oxygenase inhibitors (ibuprofen and meclofenamate) maintained SCBF within normal limits (10 ml/100 gm/min or greater). However, neither TXA2 synthetase inhibition nor the stable PGI2 analogue alone had a significant effect in preventing ischemia, whereas a combination of the two agents did serve to support SCBF. The most impressive preservation of posttraumatic SCBF, however, was observed in the antioxidant-treated animals. Based upon these results, a hypothesis is presented concerning the pathogenesis of posttraumatic central nervous system ischemia which integrates an injury-induced rise in intracellular Ca++, the increased synthesis of vasoactive prostanoids (such as prostaglandin F2 alpha and TXA2), and progressive microvascular lipid peroxidation.

Animals↗
PubMed1985

Characteristics of lipid peroxidative conduction block induced by an organic hydroperoxide in axons of isolated frog nerve.

The direct effects of lipid peroxidation on axonal conduction were investigated by application of tertiary-butyl hydroperoxide (t-BOOH) to the isolated common peroneal nerve of the frog (Rana catesbeiana). The powerful oxidizing agent t-BOOH caused a concentration-related (0.03-3.0%) block of action potential conduction. This effect, presumably due to axonal lipid peroxidation, was progressive, with the time required for the conduction impairment to occur also being a function of t-BOOH concentration. In contrast, tertiary butyl alcohol had no effect even at a 3.0% concentration. The gamma-fibers in the nerve were the most sensitive to t-BOOH conduction block, followed in order by the larger diameter beta-fibers and the even larger alpha-fibers. The rate of decrease in conduction was faster in nerves that were stimulated continuously (1 Hz) than in those that were activated only at specific measurement times, indicating an association between axonal depolarization and susceptibility to peroxidative conduction block. Recovery of conduction was observed particularly in alpha- and beta-fibers. The rate and extent of recovery were inversely proportional to the concentration of t-BOOH, suggesting that moderate peroxidative damage is potentially reversible. The possible relationship of these results to lipid peroxidative axonal damage in acute central nervous system injury is discussed.

Action Potentials↗
PubMed1985

Lipid hydrolysis and peroxidation in injured spinal cord: partial protection with methylprednisolone or vitamin E and selenium.

Compression trauma of the cat spinal cord induces a very rapid alteration in the lipid metabolism of cellular membranes, including lipid hydrolysis with release of fatty acids including arachidonate, production of biologically active eicosanoids, and loss of cholesterol. This disturbance of cellular membranes can directly damage cells and can lead to the secondary development of tissue ionic imbalance, ischemia, edema, and inflammation with neuronophagia. Pretreatment with either the synthetic glucocorticoid methylprednisolone sodium succinate (MPSS) or the antioxidants vitamin E and selenium (Se) completely prevented the loss of cholesterol and partially inhibited lipolysis and prostanoid production. Treatment with MPSS significantly reduced the postinjury tissue necrosis and paralysis. Preliminary evidence indicates that pretreatment with vitamin E and Se also protected against the effects of spinal cord injury (SCI). We speculate that the ability of these agents to preserve function after SCI may, in part, reside in their capacity to limit the trauma-induced changes in lipid metabolism.

Animals↗
PubMed1985

Beneficial effects of acute intravenous ibuprofen on neurologic recovery of head-injured mice: comparison of cyclooxygenase inhibition with inhibition of thromboxane A2 synthetase or 5-lipoxygenase.

The ability of the cyclooxygenase inhibitor ibuprofen to affect early neurologic recovery following a moderately severe concussive head injury was studied in male CF-1 mice. Each mouse received a 900 g-cm (50 g weight dropped 18 cm) head injury, followed within 5 minutes with a single IV dose of ibuprofen (sodium salt; 1, 3, 10, or 30 mg/kg). At 1 hour postinjury, their neurologic status was assessed using a grip test. Drug administration and neurologic evaluation were carried out blindly. A dose-related improvement in recovery was observed, with a 10 mg/kg IV dose causing a 122% increase in the mean grip test score compared to 0.9% saline treatment (p less than 0.01 by one-way ANOVA). In addition, there was a significant decrease in the number of mice in the 10 mg/kg ibuprofen group that fell off the grip test string in 0-5 seconds (i.e., that were severely impaired). In comparison, neither the selective thromboxane A2 synthetase inhibitor furegrelate sodium, the stable epoprostenol (PGI2) analog ciprostene calcium, nor the selective 5-lipoxygenase inhibitor piriprost potassium caused any therapeutic effect. The highest dose of the TXA2 synthetase inhibitor (30 mg/kg IV) actually had a statistically significant detrimental action that appeared to be due to an increase in posttraumatic cerebral hemorrhage. The possible mechanisms of the beneficial effect of ibuprofen in acute head injury are discussed in relation to an attenuation of the synthesis of vasoactive arachidonic acid metabolites (e.g., prostaglandin F2 alpha, thromboxane A2) and oxygen-free radical-induced lipid peroxidation.

Animals↗
PubMed1985

Current application of "high-dose" steroid therapy for CNS injury. A pharmacological perspective.

Although administration of glucocorticoid steroids is one of the most widely used therapeutic modalities for the clinical management of acute trauma of the central nervous system (CNS), controversy continues regarding their effectiveness. In essence, two viewpoints concerning their use exist. Some believe that despite their poor clinical record, the steroids nevertheless have a place in the treatment of human CNS trauma. In general, this group of clinical investigators uses the steroids primarily out of tradition, feeling that steroid therapy may be of some benefit. Unfortunately, confusion remains as to what constitutes an appropriate dose or regimen. In this regard, it has been suggested that the steroid dose be increased and the regimen intensified. Others believe that steroids should not be used. They contend that in view of their poor clinical record, it is unlikely that increasing the steroid dose or changing the dosing regimen will improve clinical efficacy, since steroids have already failed at what may be considered huge doses by glucocorticoid standards. Furthermore, it is contended that the side effects associated with large steroid doses reduce the margin of safety so as to make the steroids unsafe. Complicating these arguments is a body of experimental evidence that by and large strongly supports the utility of steroids for the acute treatment of CNS trauma. The intent of this article is to evaluate the current use of steroid therapy for CNS trauma from a purely pharmacological perspective, and to compare the steroids' experimental use with their clinical application.

Brain Injuries↗
PubMed1985

High-dose glucocorticoid treatment improves neurological recovery in head-injured mice.

The ability of a single large intravenous dose of the sodium succinate esters of the glucocorticoids methylprednisolone, prednisolone, or hydrocortisone to enhance early neurological recovery after moderate to severe blunt head injury was examined in male CF-1 mice. Unanesthetized mice were restrained and subjected to a 900 gm-cm head injury produced by a 50-gm weight dropped 18 cm. This injury resulted in immediate loss of consciousness (loss of the righting reflex) in all animals, and death in approximately 30%. Survivors received a 0.1-ml tail vein injection of either vehicle or 15, 30, 60, or 120 mg/kg of methylprednisolone, prednisolone, or hydrocortisone within 5 minutes. Their neurological status was evaluated at 1 hour after injury. A 30-mg/kg dose of methylprednisolone was found to improve recovery significantly in comparison to that seen in vehicle-treated mice. A 15-mg/kg dose was less effective, and a 60- or 120-mg/kg dose was essentially ineffective. Prednisolone was also observed to improve neurological scores at 1 hour postinjury. A 60-mg/kg dose of prednisolone was optimal, while lower and higher doses had no effect. Hydrocortisone was unable to improve recovery over the wide dose range tested. The implications of these findings for the clinical management of head injury with glucocorticoid steroids are discussed.

Animals↗