Central Nervous System Ischemia Research Articles

Normal and Abnormal Calcium Homeostasis in Neurons: A Basis for the Pathophysiology of Traumatic and Ischemic Central Nervous System Injury

Normal and Abnormal Calcium Homeostasis in Neurons: A Basis for the Pathophysiology of Traumatic and Ischemic Central Nervous System Injury

Hemoglobin potentiates excitotoxic injury in cortical cell culture.

Excessive activation of glutamate receptors may contribute to neuronal loss after a traumatic or ischemic central nervous system insult. Such injuries are often associated with hemorrhage and extravasation of hemoglobin, a prooxidant and putative neurotoxin. In this study, we investigated the effect of nontoxic concentrations of hemoglobin on the neurotoxicity of the synthetic glutamate receptor agonists NMDA, AMPA, and kainate in primary murine cortical cultures. Continuous exposure to each excitotoxin alone for 24-28 h produced concentration-dependent neuronal death (EC(50) about 12 mu M for AMP(+)A, 50 mu M for kainate, and 12 mu M for NMDA). Hemoglobin 0.25-1.0 mu M consistently potentiated the neurotoxicity of low concentrations of AMPA and kainate, increasing neuronal loss by about 150% at 6 mu M AMPA and by about 90% at 30 mu M kainate. This effect was attenuated by the iron chelator deferoxamine and the alpha-tocopherol analogue trolox. Hemoglobin coexposure had less impact on slowly triggered NMDA neurotoxicity, significantly increasing neuronal death only at agonist concentrations that alone produced little or no injury. Hemoglobin pretreatment had no effect on the rapidly triggered excitotoxicity induced by brief exposure to high concentrations of NMDA. These results suggest that hemoglobin may contribute to neuronal loss after CNS hemorrhage by exacerbating excitotoxicity. At moderate levels of agonist exposure, this effect may be somewhat selective for the AMPA/kainate component of injury.

Calorie sources and recovery from central nervous system ischemia L CHERIAN, K PEEK, CS ROBERTSON, ET AL Baylor College of Medicine, Houston, TX

Calorie sources and recovery from central nervous system ischemia L CHERIAN, K PEEK, CS ROBERTSON, ET AL Baylor College of Medicine, Houston, TX

Sneddon syndrome

Sneddon syndrome--cerebrovascular lesions and livedo racemosa--is a distinctive and uncommon disorder delineated by Sneddon in 1965. The clinical hallmarks are generalized livedo racemosa and central nervous system ischemia. Cutaneous vascular changes begin with intimal endothelial proliferation and fibromucinous matrix formation, leading to obstruction and obliteration of the vessel. The disorder is slowly progressive. No effective treatment is available, but platelet-inhibiting agents or newer antithrombotic agents may offer some hope in preventing or minimizing serious sequelae of this disease.

The influence of antiadhesion therapies on leukocyte subset accumulation in central nervous system ischemia in rats.

Although treatment with agents that block leukocyte function, including anti-ICAM-1 and doxycycline, reduces experimental central nervous system (CNS) ischemic injury, it is not known how leukocyte subset accumulation is affected by these agents. Using the rat two-vessel occlusion model and immunohistochemistry, we investigated granulocyte (PMN) and monocyte/macrophage (M phi) accumulation at 1 and 4 d postischemia. A total of 24 animals were randomized to sham surgery, or to ischemia with saline, anti-ICAM-1, or doxycycline treatments. No leukocytes were observed in sham animals. At 24 h postischemia, there was a moderate infiltration of PMN and M phi in untreated animals that was significantly decreased with either treatment. At 4 d after ischemia no PMN were identified, with extensive M phi accumulation occurring in untreated animals that was only partially reduced with doxycycline treatment. These results confirm that both anti-ICAM-1 and doxycycline treatments reduce PMN and M phi infiltration at 24 h. Delayed M phi accumulation occurs despite treatment, suggesting that some of these cells represent transformed resident microglia.

Cytokine and superoxide production in clinical stroke

Cytokines appear to play an important role in a variety of central nervous system (CNS) diseases and may be involved in ischemia. Activated leukocytes are a major source of cytokines and other inflammatory mediators that may directly injure ischemic CNS tissue. To investigate the importance of these substances in clinical stroke, we compared spontaneous secretion of IL-lβ, IL-6, IL-8, and superoxide production from neutrophils (PMN) and mononuclear cells (MNC) isolated from either acute stroke patients (n = 10) or matched controls (n = 10). Cytokine production from 5 × 10(6) cells incubated for 24 h was determined by ELISA. MNC from acute stroke patients secreted significantly less IL-1β, IL-6, and IL-8 than MNC from control patients. No significant cytokine production was detected from PMN. Superoxide production from 1.25 × 10(5) cells was determined over 1 h measuring cytochrome C reduction. There was a trend toward higher superoxide production in PMN from acute stroke patients, whereas the superoxide production in MNC from acute stroke patients was significantly higher than that of control MNC. This difference persisted even when various agonists were added preincubation. This study suggests that MNC spontaneous cytokine secretion is reduced in acute stroke patients, whereas superoxide production is increased. This decreased cytokine production may be secondary to the effects of a cytokine inhibitory factor.

Hypoxic and Ischemic Central Nervous System Disorders in Infants and Children

Hypoxic and Ischemic Central Nervous System Disorders in Infants and Children

Calorie sources and recovery from central nervous system ischemia

Glucose is the primary substrate for the energy requirements of the nervous system. Nevertheless, administration of glucose to critically ill patients with central nervous system trauma may have adverse effects on their neurologic recovery. The purpose of this study was to evaluate the effects of other sources of nonprotein calories on spinal cord lactate accumulation and on electrophysiologic recovery after a period of severe spinal cord ischemia. Two randomized, blinded studies were performed: one of glycolytic energy substrates (fructose, xylitol, sorbitol, glycerol) and one of ketogenic energy substrates (beta-hydroxybutyrate, acetate, butyrate). College teaching hospital laboratory. New Zealand albino rabbits (weight 3.5 to 4.5 kg). After infusion of the randomly assigned treatment, temporary ischemia was produced in the lumbosacral spinal cord by occluding the abdominal aorta with a balloon catheter. Blood concentrations of glucose, lactate, pyruvate, and ketone bodies and spinal cord dialysate concentration of lactate were measured before and after infusion of the assigned treatment, and during ischemia and during the first 2 hrs after reperfusion. Spinal somatosensory evoked potentials were recorded during ischemia to assure a similar severity of ischemia in all animals and during the first 2 hrs after reperfusion as a measure of electrophysiologic recovery. Infusion of the glycolytic nutrients xylitol and fructose increased blood glucose and lactate concentrations, and resulted in increased lactate accumulation in the spinal cord during ischemia and resulted in a significantly poorer recovery of the spinal somatosensory evoked potential than infusion of saline. Infusion of sorbitol and glycerol did not have these adverse effects in the doses administered. None of the ketogenic nutrients increased blood glucose concentration or increased lactate accumulation in the spinal cord during ischemia when compared with infusion of saline. Infusion of butyrate and acetate caused arterial hypotension and resulted in a poorer recovery of the spinal somatosensory evoked potential than saline. Infusion of beta-hydroxybutyrate did not have an adverse effect on blood pressure or on evoked potential recovery. Glycerol, sorbitol, and beta-hydroxybutyrate deserve further evaluation as potential nonprotein calorie sources in patients with neurologic injury. Xylitol and fructose are not suitable since these substrates resulted in hyperglycemia and increased lactate accumulation in the central nervous system, and had detrimental effects on electrophysiologic recovery after ischemia. The short-chain fatty acids (acetate and butyrate) also had adverse effects on electrophysiologic recovery after ischemia, probably because of their hypotensive effects when given intravenously, rather than from the effects of their metabolism.

Calorie sources and recovery from central nervous system ischemia

Objectives: Glucose is the primary substrate for the energy requirements of the nervous system. Nevertheless, administration of glucose to critically ill patients with central nervous system trauma may have adverse effects on their neurologic recovery. The purpose of this study was to evaluate the effects of other sources of nonprotein calories on spinal cord lactate accumulation and on electrophysiologic recovery after a period of severe spinal cord ischemia. Design: Two randomized, blinded studies were performed: one of glycolytic energy substrates (fructose, xylitol, sorbitol, glycerol) and one of ketogenic energy substrates (β-hydroxy-butyrate, acetate, butyrate). Setting: College teaching hospital laboratory. Subjects: New Zealand albino rabbits (weight 3.5 to 4.5 kg). Interventions: After infusion of the randomly assigned treatment, temporary ischemia was produced in the lumbosacral spinal cord by occluding the abdominal aorta with a balloon catheter. Measurements and Main Results: Blood concentrations of glucose, lactate, pyruvate, and ketone bodies and spinal cord dialysate concentration of lactate were measured before and after infusion of the assigned treatment, and during ischemia and during the first 2 hrs after reperfusion. Spinal somatosensory evoked potentials were recorded during ischemia to assure a similar severity of ischemia in all animals and during the first 2 hrs after reperfusion as a measure of electrophysiologic recovery. Infusion of the glycolytic nutrients xylitol and fructose increased blood glucose and lactate concentrations, and resulted in increased lactate accumulation in the spinal cord during ischemia and resulted in a significantly poorer recovery of the spinal somatosensory evoked potential than infusion of saline. Infusion of sorbitol and glycerol did not have these adverse effects in the doses administered. None of the ketogenic nutrients increased blood glucose concentration or increased lactate accumulation in the spinal cord during ischemia when compared with infusion of saline. Infusion of butyrate and acetate caused arterial hypotension and resulted in a poorer recovery of the spinal somatosensory evoked potential than saline. Infusion of β-hydroxybu-tyrate did not have an adverse effect on blood pressure or on evoked potential recovery. Conclusions: Glycerol, sorbitol, and β-hydroxybutyrate deserve further evaluation as potential nonprotein calorie sources in patients with neurologic injury. Xylitol and fructose are not suitable since these substrates resulted in hyperglycemia and increased lactate accumulation in the central nervous system, and had detrimental effects on electrophysiologic recovery after ischemia. The short-chain fatty acids (acetate and butyrate) also had adverse effects on electrophysiologic recovery after ischemia, probably because of their hypotensive effects when given intravenously, rather than from the effects of their metabolism. (Crit Care Med 1994; 22:1841–1850)

Diaspirin cross-linked hemoglobin improves neurological outcome following reversible but not irreversible CNS ischemia in rabbits.

Hemodilution using modified hemoglobin solutions may reduce ischemic central nervous system injury. Purified diaspirin cross-linked hemoglobin (DCLHb) is a cell-free hemoglobin that is intramolecularly cross-linked between the two alpha subunits, resulting in enhanced oxygen offloading to tissues and increased half-life. In the present experiments, we evaluated the ability of DCLHb to reduce neurological damage in two rabbit stroke models. In a reversible spinal cord ischemia model, ischemia of the caudal lumbar spinal cord was produced by temporary occlusion of the abdominal aorta. In an irreversible model of cerebral ischemia, plastic microspheres (50 microns) were injected into the internal carotid artery and lodged in the cerebral microvasculature. DCLHb was administered 5 minutes after initiation of ischemia as either a 10-mL/kg infusion, 10-mL/kg exchange transfusion, or a 20-mL/kg infusion. Control animals received human serum albumin that was oncotically matched to the DCLHb. In the spinal cord model, DCLHb significantly increased the duration of ischemia required to produce permanent paralysis from 27.33 +/- 8.71 minutes (mean +/- SD) in controls to 42.59 +/- 10.10 minutes in the 10-mL/kg exchange transfusion group and to 40.82 +/- 18.16 minutes in the 20-mL/kg infusion condition (P < .05). DCLHb did not significantly reduce neurological damage in the microsphere embolization model. These data suggest that cross-linked hemoglobin reduces neurological damage after reversible central nervous system ischemia and that this is not attributable to hemodilution or hypervolemia only.

Effect of gamma-aminobutyric acid modulation on neuronal ischemia in rabbits.

Antagonists of excitatory neurotransmitters are effective in limiting ischemic damage to the brain and spinal cord, but use in clinical stroke may be limited by side effects. Agonists of inhibitory neurotransmitters, such as gamma-aminobutyric acid (GABA), may provide similar neuroprotection with less severe side effects. This study examines the effect of an agonist and antagonist of the GABA-A receptor on neuronal ischemic damage. Either muscimol (a GABA-A agonist) or bicuculline (a GABA-A antagonist) was administered intravenously to groups of rabbits exposed to reversible spinal cord ischemia induced by temporary occlusion of the infrarenal aorta. The duration of occlusion for individual animals was varied, providing a range of ischemia for each experimental group. The group P50 represents the duration (in minutes) associated with 50% probability of resultant permanent paraplegia. Neuroprotection was demonstrated if a drug prolonged the P50 compared with the control group. The P50 of the control group was 26.3 +/- 2.0 minutes. Treatment with intravenous muscimol at 5 mg/kg significantly prolonged the P50 (32.4 +/- 1.3; P = .01). Treatment with intravenous bicuculline at 0.1 mg/kg significantly shortened the P50 (20.6 +/- 1.5; P = .03). The physiological and apparent behavioral effects of the drugs at these doses did not appear substantial. Pharmacological manipulation of the GABA-A receptor may offer another avenue of therapy for central nervous system ischemia, possibly with less severe associated physiological side effects than other effective drugs.

Reduction of Neurological Damage by a Peptide Segment of the Amyloid β/A4 Protein Precursor in a Rabbit Spinal Cord Ischemia Model

Although found as a precursor of Alzheimer amyloid, substantial evidence suggests that β/A4 protein precursor (APP) is involved in regulation of neuronal growth and survival. Recently, we have obtained evidence that the trophic properties of APP are fully preserved in a 17-amino acid sequence. If APP is neurotrophic, then it would be anticipated that administration of the growth-promoting segment of the APP 17-mer peptide might attenuate the neuronal dysfunction or loss or behavioral deficits associated with neuronal injury, such as that accompanying central nervous system ischemia. We evaluated this 17-mer peptide in a rabbit spinal cord ischemia model and found that this peptide alleviates paraplegia resulting from ischemia/reperfusion. Ischemia of the distal lumbar cord was produced by temporary occlusion of the abdominal aorta. Saline, 17-mer APP peptide, or a control peptide (200, 500, or 1000 n M) was administered intrathecally 20 min prior to ischemia and once daily for 3 days thereafter. The neurologic and morphologic outcomes were evaluated after 4 days. Durations of ischemia encompassing all grades of neurologic function were included. The 500 n M dose of 17-mer APP peptide significantly reduced neurologic damage. The average ischemia duration necessary to produce permanent neurologic damage increased from 27.9 ± 1.9 min in saline-injected controls and 27.7 ± 2.0 in scrambled sequence peptide-injected controls to 40.2 ± 4.0 min in the 500 n M 17-mer APP-injected group. The 200 n M dose produced a nonsignificant trend toward reduced neurologic damage. This effect to reduce the neurologic dysfunction was observed 4 days after ischemic insult, but not at 18 h after ischemia, suggesting a restorative rather than protective effect of the APP 17-mer peptide. Consistent with this hypothesis, increased synaptophysin-like immunoreactivity, a presynaptic marker, despite the neuronal loss, was observed in the APP-injected animals subjected to ischemia/reperfusion, suggesting synaptic sprouting. Our results demonstrate that this 17-mer peptide is capable of reducing neurologic damage in vivo in a model of central nervous system ischemia, possibly through its effect on synaptic plasticity.

Dextrorphan inhibits the release of excitatory amino acids during spinal cord ischemia

The release of excitatory amino acids, particularly glutamate, into the extracellular space plays a causal role in irreversible neuronal damage after central nervous system ischemia. Dextrorphan, a noncompetitive N-methyl- d-aspartate receptor antagonist, has been shown to provide significant protection against cerebral damage after focal ischemia. We investigated the changes in extracellular neutotransmitter amino acid concentrations using in vivo microdialysis in a swine model of spinal cord ischemia. After lumbar laminectomies were performed, all animals underwent left thoracotomy and right atrialfemoral cardiopulmonary bypass with additional aortic arch perfusion. Microdialysis probes were then inserted stereotactically into the lumbar spinal cord. The probes were perfused with artificial cerebrospinal fluid and 15-minute samples were assayed using high-performance liquid chromatography. Group 1 animals (n = 9) underwent aortic clamping distal to the left subclavian and proximal to the renal arteries for 60 minutes. Group 2 animals (n = 7) were treated with dextrorphan before application of aortic clamps, and during aortic occlusion and reperfusion. Five amino acids were studied, including two excitatory neurotransmitters (glutamate and aspartate) and three putative inhibitory neurotransmitters (glycine, γ-amino-butyric acid, and serine). Somatosensory-evoked potentials and motor-evoked potentials were monitored. Glutamate exhibited a threefold increase in extracellular concentration during normothermic ischemia compared with baseline values and remained elevated until 60 minutes after reperfusion. In animals treated with dextrorphan, glutamate concentrations decreased to one-third of baseline levels before aortic clamping and remained unchanged during ischemia and reperfusion. There was early loss of somatosensory-evoked potentials and motor-evoked potentials during ischemia in group 1 animals. Group 2 animals demonstrated unchanged somatosensory-evoked potentials and only mild (20%) decrease in the amplitude of motor-evoked potentials. These results suggest that dextrorphan inhibits the release of excitatory amino acids in the spinal cord during ischemia and, therefore, may have a protective effect on spinal cord function during operations on the thoracoabdominal aorta.

Photochemically induced spinal cord ischaemia in rats: assessment of blood flow by laser Doppler flowmetry.

A photochemical technique was used to create central nervous system ischaemia in rats. Changes in blood flow in the spinal cord were assessed by laser Doppler flowmetry. The Th11 spinal cord segment was irradiated by an argon ion laser after intravenous injection of an organic dye, erythrosin B, to rats with or without a laminectomy. In the group of laminectomized rats, laser irradiation for 5 s did not influence cord blood flow, but 10 s irradiation caused a 25% decrease of blood flow, which normalized within 20 min. Decreases of 50 and 80% in spinal cord blood flow were noted after 20 s and after 1 min of laser irradiation, respectively, with no recovery observed after 20 min. In the group of rats without a laminectomy, 1 min of laser irradiation caused approximately a 25% decrease of spinal cord blood flow, which gradually recovered within 12 min, whereas 5 min of laser irradiation caused a more severe reduction of spinal cord blood flow (45%) with some recovery was observed 30 min later. We could thus confirm that the interaction between a photosensitizing dye and laser irradiation reduced the regional spinal cord blood flow and the extent of this effect could be modified by varying the duration of laser irradiation. The present results therefore provide further support for using this photochemical technique to create animal models of central nervous system ischaemia.

Painless aortic dissection presenting as a progressive myelopathy

We report a patient with a painless aortic dissection whose neurologic symptoms progressed over 5 days to a complete transverse myelopathy. She did not experience pain as her neurologic deficits evolved. Magnetic resonance imaging revealed a thoracic aortic dissection extending from the arch to the level of the 12th thoracic vertebra and demonstrated ischemic changes in the spinal cord and one thoracic vertebral body. Aortic dissection must be included in the differential diagnosis of spinal cord syndromes even in the absence of pain. Early recognition of aortic dissection as a cause of progressive myelopathy may become increasingly important as new therapies for central nervous system ischemia are developed.

Genetic factors influence the development of mechanical hypersensitivity, motor deficits and morphological damage after transient spinal cord ischemia in the rat

Genetic influence on the sensory, motor and histopathological outcome of transient spinal cord ischemia was studied in Sprague-Dawley (SD), spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats. Ischemia caused minor motor deficits and no identifiable morphological damage in the spinal cord of the majority of SD rats after 1 min laser irradiation. However, severe mechanical hypersensitivity, characterized by an allodynia-like reaction to non-noxious tactile and pressure stimuli, was observed for several days in SD rats after spinal cord ischemia. SH rats exhibited less allodynia than SD rats, but developed profound motor deficits. WKY rats, the normotensive progenitor of SH rats, developed both severe mechanical allodynia and motor impairment after spinal cord ischemia. Histological examination revealed that there was significantly more extensive morphological damage in the epicenter of the irradiated segments of the spinal cord in SH and WKY rats than in SD rats after transient spinal cord ischemia. The results indicated that SH rats are more resistant to the development of central pain after central nervous system ischemia, but SH and WKY rats are more susceptible to neuronal damage than SD rats. Thus, genetic variability can lead to variable predisposition for the development of pain and spinal cord damage after ischemia. Such factors may underlie the wide variability in the occurrence of pain after central nervous system injury in humans.

A tissue culture ischemic device to study eicosanoid release by pheochromocytoma PC12 cultures

In an attempt to search for neuronal models to investigate the molecular pharmacology of central nervous system ischemia, we have focused on PC12 pheochromocytoma cultures which are now popular in neuroscience research. These chromaffinergic transformed cells, originary from the adrenal medulla, synthesize and release catecholamines and, upon treatment with nerve growth factor (NGF), differentiate to a sympathetic phenotype expressing neurites and excitability. To measure eicosanoid production, undifferentiated or NGF-treated PC12 cultures have been exposed for 1 h to a mixture of N 2/CO 2 (95:5%) resulting in hypoxia (5 ± 1% O 2), followed by 1 h reoxygenation (21% O 2) using a special ischemic device. Hypoxia, up to 2 h, was not followed by significant cytotoxicity or significant production of prostaglandin PGE 2. However, upon reoxygenation, a specific release of PGE 2 (2–3 fold over control) was measured. A similar PGE 2-enhanced release could be induced by ‘chemical hypoxia’ using 2-deoxyglucose and oligomycin to reduce cellular adenosine triphosphate (ATP). Anoxia (0.1–1% O 2, 1 h) achieved by a reduction of culture incubation volume and the reduction in ATP level have been found as critical parameters leading to PC12 cells cytotoxicity. These results emphasize the simplicity and applicability of the tissue culture ischemic device proposed to investigate hypoxia and ischemia at a cellular level.

Delayed therapy of experimental ischemia with competitive N-methyl-D-aspartate antagonists in rabbits.

N-methyl-D-aspartate antagonists are effective in limiting ischemic damage to the brain and spinal cord if treatment is begun at time of ischemic injury. More clinically relevant delayed therapy has not been adequately investigated. We report the temporal profile of efficacy for two competitive N-methyl-D-aspartate antagonists in therapy of central nervous system ischemia. CGS-19755 (30 mg/kg) or LY233053 (100 mg/kg) was administered 5, 30, or 60 minutes after reversible spinal cord ischemia in rabbits, induced by temporary occlusion of the infrarenal aorta. Duration of occlusion for individual animals was varied to provide a range of ischemia for each experimental group. The P50 represents the duration (in minutes) associated with a 50% probability of resultant permanent paraplegia. Neuroprotection is demonstrated if a drug prolongs the P50. CGS-19755 significantly prolonged the P50 (t test, P = .003) when given 5 minutes after ischemia, but not if delayed by 30 or 60 minutes (P50: control, 24.1; 5 minutes, 31.4; 30 minutes, 30.1; 60 minutes, 26.6). LY233053 was efficacious at 5 (P = .0008) and 30 (P = .002) minutes, but not at 60 minutes (P50: control, 26.8; 5 minutes, 39.4; 30 minutes, 36.0; 60 minutes, 25.6). These competitive N-methyl-D-aspartate antagonists are effective in limiting ischemic damage, but protection is lost if therapy is not initiated within 60 minutes of injury.

Neutrophil Adhesion in Central Nervous System Ischemia in Rabbits

Activated neutrophils appear to be directly involved in potentiating central nervous system ischemic injury. After initial endothelial adherence, neutrophils can potentiate ischemia by causing capillary plugging and infiltrating ischemic tissue to release toxic metabolites. We used an endothelial component adherence assay to characterize neutrophil adhesion following reversible central nervous system ischemia. Rabbit spinal cord ischemia was produced by 40 min of reversible arterial occlusion. Neutrophils were isolated using density gradient centrifugation and adherence to laminin or fibronectin was determined using a myeloperoxidase assay. The baseline (N = 26) percentage of adherent neutrophils was 3.8 ± 0.3/5.6 ± 0.6 (laminin/fibronectin), sham-operated controls (2 h post) (N = 6) 3.3 ± 0.5/3.9 ± 0.4. 30 min post ischemia (N = 6) 2.5 ± 1.1/4.1 ± 1.9, 2 h (N = 6) 7.6 ± 1.4/9.9 ± 2.6 (p < .05 to baseline and sham), 18 h (N = 8)4.9 ± 1.5/7.1 ± 3.1. and 42 h (N = 6) 3.4 ± 0.4/6.6 ± 2.1. Concurrent serum fibrinogen values were baseline 142 ± 12, sham (18 h) 141 ±14, 2 h 166 ± 21, 18 h 512 ± 43 (p < .01), and 42 h 580 ± 86 (p < .01). These results suggest that neutrophil adherence is increased after acute central nervous system ischemia. There appears to be a limited period of increased adherence that occurs earlier than other acute phase reactants.

Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia.

Delayed deterioration of neurological function after central nervous system ischemia is a well-documented clinical problem. The purpose of our study was to elucidate the role of spinal cord blood flow and spinal cord-blood barrier integrity in the evolution of delayed neurological deterioration after transient spinal cord ischemia in rabbits. Anesthetized rabbits were subjected to lumbar spinal cord ischemia (25 minutes) and variable periods of reperfusion (30 minutes to 48 hours after ischemia). Regional spinal cord blood flow was monitored by carbon-14-labeled iodoantipyrine autoradiography; vascular permeability was assessed by quantitative microhistofluorescence of Evans blue-albumin in frozen sections of spinal cord. Hindlimb motor function was assessed by standard scoring system and tissue edema by wet/dry weight method. Hindlimb motor function indicated complete paralysis during ischemia and partial gradual recovery upon reperfusion (up to 8 hours), followed by progressive deterioration to severe deficits over 48 hours. Severe vascular permeability disruption was noticed early (30 minutes) after reperfusion, but almost complete recovery reestablished at 8 hours was followed by a secondary progressive increase in vascular permeability. Blood flow was reduced by 20-30% (p less than 0.01) 4 hours after ischemia in the gray matter, but hyperemia (200-300%, p less than 0.01) was observed 12-24 hours after ischemia. Spinal cord water content increased by 5.7% (p less than 0.05) 24 hours after ischemia. This study demonstrates that delayed neurological and motor deterioration after spinal cord ischemia is associated with severe progressive breakdown of spinal cord-blood barrier integrity that develops late (hours) after the injury. Our data suggest that no ischemic insult in early or late reperfusion is associated with delayed motor deterioration.