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Biomedical subjects

A R Blight

Publications and source records attributed to A R Blight.

At least 37 records · Page 2Linked to original sources
PubMed1997

Quinolinic acid accumulation in injured spinal cord: time course, distribution, and species differences between rat and guinea pig.

Experimental compression injury of the spinal cord in guinea pigs results in delayed neurologic deficits that continue to increase in severity for several days following trauma, coincident with inflammatory responses, including invasion of the lesion by mononuclear phagocytes and increased levels of the neurotoxin quinolinic acid (QUIN). Inflammatory responses and QUIN elevation also occur following spinal cord contusion in rats, but maximal neurologic deficits develop immediately. In this study, somatosensory evoked potentials (SEP) and tissue, serum, and cerebrospinal fluid levels of QUIN were measured in guinea pigs and rats following similar compression injuries of the thoracic spinal cord. SEP changes differed between the species, consistent with other neurological changes. In guinea pigs, increases in QUIN levels at the lesion site began at 1 day postinjury, achieved maximal elevation (100-fold) by 12 days, then declined, but remained above serum levels at 25 days postinjury. A similar increase occurred in adjacent areas of the spinal cord, with lower peak levels. In rats, tissue QUIN at the center of the lesion remained below serum levels at all times, increasing moderately (<10-fold) up to 7 days, then decreasing between 7 and 25 days. These data demonstrate differences in the time course and magnitude of QUIN accumulation and neurological deficit between guinea pig and rat, which may relate to differences in secondary pathological mechanisms. Such profound differences may affect the use of these species for evaluation of experimental therapy in this and other inflammatory conditions of the central nervous system.

Animals↗
PubMed1996

Histological and functional evaluation of experimental spinal cord injury: evidence of a stepwise response to graded compression.

Most experimental spinal cord injury studies described to date have relied on a limited number of injury gradations, and have tacitly assumed that outcome (functional, histological, and/or neurophysiological) is a monotonically graded function of injury severity. In contrast, the present study provides evidence that functional and morphological outcome after spinal cord compression injury may occur in a discontinuous, non-graded manner in response to linearly graded injury levels. The thoracic spinal cord of adult rats was transiently compressed to thicknesses from 1.8 to 0.8 mm in 0.2 mm steps, or sham injury was administered. Open field motor behavior and segmental reflexes were evaluated up to 21 days post injury and correlated with histological measures and injury level. The highest correlation was between histological outcome and open field motor scores. Among the six injury groups, only three significantly different outcomes were apparent in the open field, reflex, and histological measures, consisting of the injury group pairs 1.8/1.6, 1.4/1.2, and 1.0/0.8 mm. At day 21, the 1.8/1.6 mm injury groups were also indistinguishable from the sham injury group. The implications of these findings in terms of therapeutic studies are discussed. Comparison of the temporal outcome patterns among contusion and compression injuries in rats and other species also revealed a significant species difference: a period of delayed or secondary functional loss reported in the guinea pig was not present in the rat.

Analysis of Variance↗
PubMed1996

Intrathecal infusion of the nitric oxide synthase inhibitor N-methyl L-arginine after experimental spinal cord injury in guinea pigs.

The potential role of nitric oxide (NO) production in secondary pathologic processes that follow spinal cord injury was examined in a guinea pig model that shows secondary loss of function for at least 3 days after trauma. Lateral compression injury of the lower thoracic cord was performed under ketamine/xylazine/acepromazine anesthesia. A fine polyethylene cannula was inserted through an incision in the dura rostral to the injury and run along the dorsal subdural space to the lesion level. The tube was connected to an osmotic pump delivering 1 microL/h of a 10 mM solution of either N-methyl-L-arginine or N-methyl-D-arginine in normal saline (pH 7.2). N-Methyl-L-arginine blocks both constitutive and inducible forms of NO synthase (NOS), present in neurons and inflammatory cells, respectively: N-methyl-D-arginine is the inactive stereoisomer. Two groups of 10 animals were used. Behavioral analysis and somatosensory evoked potential measurements were performed daily for 3 days, then the animals were fixed and survival of white matter at the center of the injury was evaluated, using toluidine-blue stained, 1 microns plastic sections. No significant difference was found between treated and control groups in degree or rate of secondary loss of spinal cord function or in the cross-sectional area of surviving white matter. These data do not support the hypothesis that local NO production by phagocytes, neurons, or other cells plays a significant role in secondary pathology of injury in this model.

Animals↗
PubMed1996

Compression injury of mammalian spinal cord in vitro and the dynamics of action potential conduction failure.

1. White matter strips from the ventral spinal cord of adult guinea pigs were isolated in vitro, and their electrophysiological characteristics and response to controlled focal compression injury were examined. A double sucrose gap technique was used for stimulation and recording at opposite ends of a 12.5 mm-diam central well superfused with oxygenated Krebs solution. 2. The compound action potential recorded with the sucrose gap was similar in form to single fiber potentials recorded with intra-axonal electrodes, including the presence of a prolonged depolarizing afterpotential. 3. Three types of conduction block resulting from compression were identified: an immediate, spontaneously reversible component, which may result from a transient increase in membrane permeability and consequent disturbance of ionic distribution; a second component that was irreversible within 1-2 h of recording, perhaps resulting from complete axolemmal disruption; and a third component, which may have been due to disruption of the myelin sheath, that appeared to be reversible with application of 10-100 microM of the potassium channel blocker 4-aminopyridine. 4. Conduction deficits--decreased amplitude and increased latency of the compound potential--were stable between 5 and 60 min postinjury, and their intensity corellated with the extent of initial compression over a full range of severity. 5. Stimulus-response data indicate that mechanical damage to axons in compression was evenly distributed across the caliber spectrum, suggesting that the susceptibility of large caliber axons seen histopathologically after injury in vivo may be based on delayed, secondary processes. 6. The model provides the ability to monitor changes in the properties of central myelinated axons after compression injury in the absence of pathological variables related to vascular damage. This initial investigation found no evidence of secondary deterioration of axons in the 1st h after injury, although there was evidence of both transient and lasting mechanical damage to axons and their myelin sheaths.

4-Aminopyridine↗
PubMed1995

Quinolinic acid accumulation and functional deficits following experimental spinal cord injury.

Quinolinic acid (QUIN) is an excitotoxic tryptophan metabolite that is produced by activated macrophages. Accumulations of QUIN are implicated in the aetiology of a broad spectrum of human neurological diseases, particularly inflammatory conditions. To determine whether QUIN is an endogenous neurotoxin requires agents that reduce QUIN synthesis, and animal models where QUIN levels increase in association with neurological disease. Compression injury of the spinal cord of guinea pigs results in secondary neurological deficits, related to inflammation and macrophage activation. We evaluated whether 4-chloro-3-hydroxyanthranilate (4Cl-3HAA), an inhibitor of 3-hydroxyanthranilate-3,4-dioxygenase, reduces QUIN accumulations in this model and influences the progression of neurological deficits. Intraperitoneal injections of 4Cl-3HAA (100 mg/kg every 12 h) attenuated QUIN accumulations in spinal cord following injury, and reduced the severity of delayed functional deficits. Intraperitoneal injections of the macrophage toxin, silica, also reduced QUIN levels and attenuated neurological deficits. A direct subdural infusion of Cl-3HAA into the injured spinal cord (50 microM, 1 microliter/h) promptly exacerbated functional impairments, which suggests that the infusate had direct toxic effects. These studies demonstrate that guinea pigs with spinal cord injury constitute a useful model to study the mechanisms that increase central nervous system (CNS) QUIN levels in conditions of CNS inflammation, and to evaluate the neurochemical and neurological effects of agents designed to reduce the accumulations of QUIN and other potential pathogenic mediators within the CNS. The results are consistent with a contributory role for QUIN in the pathogenesis of secondary functional impairments following spinal cord injury, although the possibility that 4Cl-3HAA had additional effects independent of QUIN cannot be excluded. Further studies are required to determine whether the beneficial effects of 4Cl-3HAA are sustained. While it is unknown whether secondary inflammatory processes contribute significantly to neurological deficits in human spinal cord injury, strategies that reduce the accumulation of QUIN are worthy of consideration and evaluation as a therapeutic target.

3-Hydroxyanthranilate 3,4-Dioxygenase↗
PubMed1994

Effects of silica on the outcome from experimental spinal cord injury: implication of macrophages in secondary tissue damage.

A model of spinal cord trauma in guinea-pigs, using lateral compression to a set thickness, produces a delayed functional loss at one to two days, followed by a partial recovery over several weeks, as measured using hindlimb motor behavior, vestibulospinal reflex testing, and mapping the receptive field of the cutaneous trunci muscle reflex. The role of inflammatory events in these secondary changes, was investigated with intraperitoneal injections of the macrophage toxin, silica. In one experiment, 11 matched pairs of animals were injured. One of each pair was selected randomly and injected with a suspension of 1.2 g of silica dust in sterile saline, immediately after injury and surgical closure. In a second experiment, involving 10 pairs of guinea-pigs, a similar dose of silica was administered to one of each pair at either one or two days before the injury. The animals survived up to three months, then were fixed by perfusion with glutaraldehyde. Histopathology of the lesion was quantified by line sampling of myelinated axons, and by measurement of blood vessels, in plastic sections through the center of the lesion. Surgery, injury, analysis of behavior and histology were all performed without knowledge of the experimental status of the animal. The secondary onset of functional loss below the lesion appeared to be delayed by one to two days in silica-treated animals with respect to controls. The number of myelinated axons at the center of the lesion, examined at two weeks to three months after injury was higher in the animals injected with silica immediately after surgery, most significantly in the dorsal quadrant of the cord. Myelin sheath thickness and axon caliber distribution were not different. Hypervascularity of the lesion was significantly reduced in animals injected with silica within one day of injury. These findings support the hypothesis that inflammatory activity plays an important role in secondary tissue damage, and that it may be responsible for some proportion of long-term neurological deficits, but do not suggest a prominent role for early macrophage activity in the mechanisms of demyelination.

Animals↗
PubMed1994

4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury.

4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI.

4-Aminopyridine↗
PubMed1993

Increased levels of the excitotoxin quinolinic acid in spinal cord following contusion injury.

Products of inflammatory phagocytes are potential contributors to secondary pathology following spinal cord trauma. In the present study we quantified the levels of the neurotoxin and product of activated macrophages, quinolinic acid (QUIN), in the lower thoracic spinal cord of adult guinea pigs 5 days after brief compression injury. At the injured site (T13), elevations in tissue QUIN levels (> 10-fold) accompanied proportional increases in the activity of indoleamine-2,3 dioxygenase (> 2-fold) and the concentrations of L-kynurenine (> 2.5-fold). In contrast, no significant changes occurred in two uninjured regions examined compared to controls, namely cervical spinal cord (C2) and the somatosensory cortex. Further studies of QUIN as a potential contributor to spinal cord injury are warranted.

Animals↗
PubMed1993

Effects of induced hypothermia on somatosensory evoked potentials in patients with chronic spinal cord injury.

We have investigated the effects of mild whole body hypothermia on the amplitude and latency of somatosensory evoked potentials (SEPs) in control subjects (n = 12) and patients (n = 15) with chronic compressive or contusive spinal cord injury (SCI). Mild hypothermia (-1 degree C) was induced by controlled circulation of propylene glycol through a 'microclimate' head and vest garment while reductions in oral and limb temperatures were monitored. Cooling induced a delayed onset and reduced amplitude of tibial nerve SEPs in control subjects. All SCI patients with recordable SEPs (n = 11) showed similarly delayed onset of the cortical response. In contrast to the controls, nine of the 11 SCI patients showed an increase in amplitude of cortical SEPs. In three of these patients the increase in amplitude exceeded 100% of the precooling values. The cooling-induced changes in SEP amplitude and latency reversed on rewarming for both groups. The cooling-induced increases in cortical SEP amplitude support the a priori hypothesis that cooling would enhance central conduction in some SCI patients with conduction deficits due to focal demyelination.

Adult↗
PubMed1993

Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury.

4-Aminopyridine (4-AP) is a K+ channel blocking agent that enhances nerve conduction through areas of demyelination by prolonging the duration of the action potential and increasing the safety factor for conduction. We have investigated the effects of 4-AP (24 mg total dose-intravenous) in 6 patients with spinal cord injury (3 complete, 3 incomplete) with the intent of overcoming central conduction block, or slowing, due to demyelination. Vital signs remained stable and only mild side effects were noted. The 3 patients with incomplete injuries all demonstrated enhanced volitional EMG interference patterns and one patient exhibited restored toe movements. The changes were reversed on drug washout. There were no changes in segmental reflex activities. These results are consistent with those obtained from 4-AP trials with animal models of spinal cord injury, showing modest therapeutic benefit attributable to enhanced central conduction.

4-Aminopyridine↗
PubMed1993

4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients.

The potassium channel blocking drug 4-aminopyridine (4-AP) was administered to eight patients with chronic spinal cord injury, in a therapeutic trial based on the ability of the drug to restore conduction of impulses in demyelinated nerve fibers. The study was performed using a randomized, double-blind, crossover design, so that each patient received the drug and a vehicle placebo on different occasions, separated by 2 weeks. Drug and placebo were delivered by infusion over 2 h. An escalating total dose from 18.0 to 33.5 mg was used over the course of the study. Subjects were evaluated neurologically before and after the infusion. Two subjects returned for a second trial after 4 months and were examined daily for 3 to 4 days following drug infusion. Side effects were consistent with previous reports. Administration of the drug was associated with significant temporary neurologic improvement in five of six patients with incomplete spinal cord injury. No effect was detected in two cases of complete paraplegia and one of two severe incomplete cases (Frankel class B). Improvements in neurologic status following drug administration included increased motor control and sensory ability below the injury, and reduction in chronic pain and spasticity. The effects persisted up to 48 h after infusion of the drug, and patients largely returned to preinfusion status by 3 days. Compared with the more rapid elimination of the drug, these prolonged neurologic effects appear to involve a secondary response and are probably not a direct expression of potassium channel blockade.

4-Aminopyridine↗
PubMed1992

Macrophages and inflammatory damage in spinal cord injury.

Disruption of myelinated nerve fibers usually constitutes the most significant damage contributing to chronic neurologic deficits in severe spinal cord injuries. Inflammatory responses form one facet of a wide array of pathologic phenomena that combined to produce this damage. The therapeutic importance of inflammation is amplified by its delayed time-course and the number of different approaches that may be taken to its modulation. The response to trauma involves two significant waves of cellular infiltration: the first, dominated by polymorphonuclear leukocytes, peaks within a few hours; the second, by macrophages, begins after 1-2 days and reaches a peak at 5-7 days. Secondary demyelination of surviving nerve fibers and delayed loss of axons coincide with the macrophage response, and may be an example of "bystander damage" caused by the cytotoxic products of activated phagocytes. We know relatively few details of this delayed pathologic change, even in animal models. In particular, it is difficult to separate potential beneficial effects of macrophages in removing cellular debris, stimulating tissue revascularization and repair of the central nervous system environment, from the potential destructive effects associated with their phagocytic activity and their stimulation of scar formation through the release of factors that induce proliferation of peripheral cellular components within the injured spinal cord.

Animals↗
PubMed1991

Morphometric analysis of a model of spinal cord injury in guinea pigs, with behavioral evidence of delayed secondary pathology.

A model of spinal cord trauma in guinea pigs is described, based on the concept of compression to a set thickness, as an alternative to compression or contusion with a set force or displacement. The model is technically simple and reliable and circumvents some of the biomechanical problems of contusion techniques. It was designed initially to produce moderate injuries, allowing significant recovery of function. A pair of forceps was modified to form an instrument to compress the spinal cord laterally, over a 5-mm length, to a thickness of 1.2 mm. Such compression injuries of the lower thoracic cord were produced in 12 anesthetized, adult guinea pigs, and the outcome monitored, using successive behavioral tests and morphometry of the lesion at 2-3 months. Chronic histopathology was examined quantitatively with line-sampling of axons in 1-micron plastic sections through the lesion center, stained with toluidine blue. The type and distribution of damage to axons was similar to that seen following weight-drop contusion trauma in cats. Spinal cord function was examined by means of hindlimb reflex testing and motor behavior, vestibulospinal reflex testing, and mapping the receptive field of the cutaneus trunci muscle (CTM) reflex. These injuries characteristically resulted in a delayed onset of functional deficits at 1-2 days after injury, followed by partial recovery over the course of several weeks. Overall, functional outcome correlated significantly with the number of surviving axons in the lesion. The phenomenon of "secondary" pathology was striking at the behavioral level, whereas evidence of delayed injury has been indirect in most animal models. The onset of this secondary process occurred with a longer delay than has been assumed or implied by most suggested mechanisms of secondary pathology. The time course of secondary loss and recovery may be related to that of the inflammatory response at the injury site, particularly the phagocytic activity of macrophages.

Animals↗
PubMed1991

Morphometric analysis of blood vessels in chronic experimental spinal cord injury: hypervascularity and recovery of function.

A model of spinal cord trauma in guinea pigs, based on compression to a set thickness, was described previously. Compression injuries of the lower thoracic cord were produced in 11 anesthetized, adult guinea pigs, and the outcome monitored, using successive behavioral tests and morphometry of the lesion at 2-3 months. This report describes changes in the vascularity of the spinal cord, based on light microscopic analysis of 1 micron plastic transverse sections through the center of the lesion. Mean blood vessel density in these lesions was approximately twice that found in equivalent regions of normal, uninjured spinal cords, and hypervascularity of the white matter extended at least four spinal cord segments cranially and caudally from the lesion center. Capillary diameter distribution was significantly shifted to larger values and large perivascular spaces surrounded most capillaries and pre- and post-capillary vessels. Extent of hypervascularity was not correlated with the overall severity of the injury, but there was a significant positive correlation between the density of blood vessels in the outer 400 microns of the white matter and secondary loss of neurological function below the lesion, seen between one day and eight weeks after injury. This suggests that hypervascularization of the lesion is related to secondary pathological mechanisms in spinal cord injury, possibly inflammatory responses, that are relatively independent of the primary mechanical injury but more closely connected with loss and recovery of function.

Animals↗
PubMed1991

The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial.

A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77%) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36%) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis.

4-Aminopyridine↗
PubMed1990

Cutaneus trunci muscle reflex of the guinea pig.

The cutaneus trunci muscle reflex in guinea pigs was studied with a combination of video analysis, electromyography, lesioning, and light microscopy. The muscle forms a bilateral, subdermal sheet over much of the trunk. Local contractions of the dorsal part of the muscle are produced in response to brief tactile or electrical stimulation of the skin and consist of a twitch centered 1-2 cm rostral of the stimulus site. The reflex receptive field covers most of the thoracic and lumbar dorsal surface. The sensory information is carried via segmental dorsal cutaneous nerves. Receptive fields of adjacent nerves overlap and form rectangular areas perpendicular to the midline, at thoracic levels. Motor innervation projects through the lateral thoracic nerves of the brachial plexus. The motoneurons are located near the cervical thoracic junction (C7-T1). Lesions of the lower thoracic cord indicate that ascending sensory information is carried to the motor nuclei via the ventral half of the lateral funiculus. This pathway conveys information primarily from ipsilateral skin. There is a weaker input from contralateral skin, crossing at segmental levels. Electromyographic responses to brief electrical stimulation of lower thoracic skin occur usually as 10-12 msec bursts at latencies of 10-20 msec, and do not readily habituate or fatigue at stimulus frequencies below 10 Hz. The reflex persists under light pentobarbital anesthesia. This combination of characteristics makes the reflex useful for a variety of physiological and pathophysiological studies.

Animals↗