Showing papers in "Journal of Cerebral Blood Flow and Metabolism in 1994"
TL;DR: Evidence has been presented suggesting that NO participates in the mechanisms of cerebral ischemic damage and the evidence for and against a role of NO is critically examined.
Abstract: There is increasing evidence that nitric oxide (NO) is an important molecular messenger involved in a wide variety of biological processes. Recent data suggest that NO is also involved in the regulation of the cerebral circulation. Thus, NO participants in the maintenance of resting cerebrovascular tone and may play an important role in selected vasodilator responses of the cerebral circulation. Furthermore, evidence has been presented suggesting that NO participates in the mechanisms of cerebral ischemic damage. Despite the widespread attention that NO has captured in recent years and the large number of studies that have been published on the subject, there is considerable controversy regarding the role of this agent in cerebrovascular regulation and in ischemic damage. In this paper the results of investigations on NO and the cerebral circulation are reviewed and the evidence for and against a role of NO is critically examined.
661 citations
TL;DR: The findings demonstrate that abnormal topographic covariance profiles exist in parkinsonism and have potential clinical application as neuroimaging markers inParkinsonism.
Abstract: We used [18F]fluorodeoxyglucose/positron emission tomography (18F-FDG/PET) and a statistical model of regional covariation to study brain topographic organization in parkinsonism. We studied 22 patients with Parkinson's disease (PD), 20 age-matched normal volunteers, and 10 age- and severity-matched patients with presumed striatonigral degeneration (SND). We used FDG/PET to calculate global, regional, and normalized metabolic rates for glucose (GMR, rCMRglc, rCMRglc/GMR). Metabolic parameters in the three groups were compared using an analysis of variance, with a correction for multiple comparisons, and discriminant analysis. The scaled subprofile model (SSM) was applied to the combined rCMRglc dataset to identify topographic covariance profiles that distinguish PD patients from SND patients and normals. GMR, rCMRglc, and rCMRglc/GMR were normal in PD; caudate and lentiform rCMRglc/GMR was reduced in the SND group (p < 0.01). SSM analysis of the combined group of patients and normals revealed a significan...
435 citations
TL;DR: In situ hybridization experiments suggest the neuroprotective action of brain-derived neurotrophic factor to be mediated via trkB – receptors in the hippocampus and a therapeutic potential for the treatment of cerebral ischemia.
Abstract: The neuroprotective action of brain-derived neurotrophic factor (BDNF) was evaluated in a rat model of transient forebrain ischemia. A continuous intraventricular infusion of BDNF for 7 days starting immediately before the onset of ischemia significantly increased the number of pyramidal cells in the vulnerable CA1 sector of the hippocampus. In situ hybridization experiments suggest the neuroprotection to be mediated via trkB – receptors in the hippocampus. The data indicate a therapeutic potential for the treatment of cerebral ischemia.
333 citations
TL;DR: It is suggested that the rapid production of TNFα and IL-6 following CHI is a local inflammatory response of brain tissue to primary insult.
Abstract: In a model of closed head injury (CHI) in the rat we have shown the activation of phospholipase A2 and the production of eicosanoids after injury: at 15 min, mainly 5-hydroxyeicosatetraenoic acid (5-HETE), and at 24 h, mainly prostaglandin E2. The present study was designed to test whether CHI can also trigger the production of cytokines in the brain. CHI was induced in ether-anesthesized rats by a weight-drop device falling over the exposed skull covering the left hemisphere, 1–2 mm lateral to the midline in the midcoronal plane. In the posttraumatic period (1–24 h), the rats were decapitated, cortical tissue from the injured zone of the contused and contralateral hemispheres was removed and sonicated, and cytokine activity was assessed. Whereas no tumor necrosis factor alpha (TNFα) activity was found in normal brain tissue, it was detectable in the contused hemisphere (∼72 ± 50 pg/mg protein) as early as 1 h post-CHI. TNFα levels increased at 2 h, peaked at 4 h, (-609 ± 540 pg/mg protein), and declined ...
328 citations
TL;DR: The data suggest that attenuated p53 expression may be protective after an ischemic event, and that grater protection was afforded by reduced expression of p53.
Abstract: Apoptosis or programmed cell death may be involved in neuronal death in the cerebral cortex after a permanent focal ischemic insult. Studies indicate that protein p53 is a major determinant of the cellular mechanism that leads to programmed cell death. Wild-type C57 mice and two groups of transgenic C57 mice, one homozygous and the other heterozygous for a p53 null gene, were subjected to middle cerebral artery occlusion. As expected, the wild-type mice had a large, consistent infarct volume (22.11 +/- 4.59 mm3; n = 10). Both transgenic groups had significantly less ischemic damage than the wild-type control group. However, unexpectedly, the heterozygous group had the least amount of ischemic damage (16.12 +/- 1.71 mm3, n = 11; 27% reduction in infarct size). The ischemic damage in the homozygous group (18.72 +/- 3.48 mm3, n = 9) was significantly less than in the wild-type control (15% reduction in infarct size) but significantly more than in the heterozygous group. Thus, although the absence of p53 expression was protective, greater protection was afforded by reduced expression of p53. These data suggest that attenuated p53 expression may be protective after an ischemic event.
304 citations
TL;DR: If the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion.
Abstract: We examined whether 7-nitroindazole (7-NI), a putative inhibitor of neuronal nitric oxide synthase (nNOS), decreases cerebral infarction 24 h after proximal middle cerebral artery (MCA) occlusion. In preliminary experiments, we determined that 7-NI (25, 50, and 100 mg/kg i.p.) decreased nitric oxide synthase (NOS) activity within cerebral cortex by 40-60% when measured up to 120 min, but not 240 min after administration. At 25 or 50 mg/kg, 7-NI did not alter the systemic arterial blood pressure or the dilation of pial arterioles after topical acetylcholine (10 and 100 microM). To examine the effect of 7-NI on infarct size, 55 Sprague-Dawley halothane-anesthetized rats were subjected to proximal MCA occlusion (modified Tamura method). Five minutes after occlusion, 7-NI (25 or 50 mg/kg i.p.) or vehicle was injected. Animals treated with 25 or 50 mg/kg showed 25 and 27% reductions in infarct volume, respectively. Coadministration of L-arginine (300 mg/kg i.p.) plus 7-NI (25 mg/kg i.p.) reversed the effect. If, indeed, the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion. The results also emphasize the importance of developing strategies to selectively inhibit the neuronal isoform inasmuch as we observed previously that administering the less selective NOS inhibitor, N omega-nitro-L-arginine (L-NA), in the same model either caused no change or increased the volume of ischemic injury.
303 citations
TL;DR: Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives >10 h, and the equilibrium analysis on day 2 is proposed as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial Plasma tracer concentrations.
Abstract: The in vivo kinetics of the dopamine (DA) transporter probe 123I-labeled 2 beta-carboxymethoxy-3 beta-(4-iodophenyl) tropane ([123I] beta-CIT) in striatum was investigated with single-photon emission computerized tomography (SPECT) in five healthy human subjects. The aim of this study was to derive an adequate measure of the DA transporter density that would not be affected by regional cerebral blood flow or peripheral clearance of the tracer. SPECT data were acquired on the day of injection (day 1) from 0 to 7 h and on the following day (day 2) from 19 to 25 h. Arterial sampling on day 1 was used to measure the input function. Graphical, kinetic, and equilibrium analyses were evaluated. Graphical analysis of day 1 data, with the assumption of negligible dissociation of the tracer-receptor complex (k4 = 0), was found to be blood flow-dependent. A three-compartment kinetic analysis of day 1 data were performed using a three (k4 = 0)- and a four (k4 > 0)-parameter model. The three-parameter model estimated the konBmax product at 0.886 +/- 0.087 min-1. The four-parameter model gave a binding potential (BP) of 476 ml g-1, a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspecific equilibrium partition coefficient (V3" = k3/k4 = 6.66 +/- 1.54). Results of day 1 kinetic analysis and day 2 equilibrium analysis were well correlated among subjects. Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives > 10 h. We propose the equilibrium analysis on day 2 as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial plasma tracer concentrations.
293 citations
TL;DR: It is demonstrated that oxygen requirements are not coupled to an appropriate flow response in the periinfarct zone with severely reduced blood flow and the resulting episodes of relative hypoxia could explain the previously documented relationship between the number of depolarizations and infarct volume.
Abstract: In the periphery of ischemic brain lesions, transient spreading depression-like direct current (DC) deflections occur that may be of pathophysiological importance for determining the volume of the ischemic infarct. The effect of these deflections on cerebral blood flow, tissue oxygen tension, and electrophysiology was studied in rats submitted to intraluminal thread occlusion of the middle cerebral artery (MCA) and compared with the changes following potassium chloride (KCl)-induced spreading depression of intact animals. Immediately after MCA occlusion, cortical laser-Doppler flow (LDF) in the periphery of the MCA territory sharply decreased to 35 +/- 14% of control (mean +/- SD; p < 0.05), tissue PO2 declined from 28 +/- 4 to 21 +/- 3 mm Hg (p < 0.05), and EEG power fell to approximately 80% of control. During 7-h occlusion, 3-11 DC deflections with a mean duration of 5.2 +/- 4.8 min occurred at irregular intervals, and EEG power gradually declined to 66 +/- 16% of control (p < 0.05). During the passage of DC deflections, LDF did not change, but PO2 further declined to 19 +/- 4 mm Hg (p < 0.05). KCl-induced depolarizations of intact rats were significantly shorter (1.4 +/- 0.5 min; p < 0.05) and were accompanied by a 43% increase in LDF (p < 0.05) and a slight but significant increase in tissue PO2 from 22 +/- 4 to 25 +/- 4 mm Hg (p < 0.05). The comparison of periinfarct and KCl-induced depolarizations demonstrates that oxygen requirements are not coupled to an appropriate flow response in the periinfarct zone with severely reduced blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
284 citations
TL;DR: It is demonstrated that mild intraischemic hypothermia reduces tissue injury after prolonged temporary ischemia, possibly by attenuating postischemi blood flow disturbances and by reducing vasogenic edema resulting from BBB disruption.
Abstract: Mild to moderate hypothermia (30–33°C) reduces brain injury after brief (<2-h) periods of focal ischemia, but its effectiveness in prolonged temporary ischemia is not fully understood. Thirty-two Sprague–Dawley rats anesthetized with 1.5% isoflurane underwent 3 h of middle cerebral artery occlusion under hypothermic (33°C) or normothermic (37°C) conditions followed by 3 or 21 h of reperfusion under normothermic conditions (n = 8/group). Laser–Doppler estimates of cortical blood flow showed that intraischemic hypothermia reduced both postischemic hyperperfusion (p ≤ 0.01) and postischemic delayed hypoperfusion (p ≤ 0.01). Hypothermia reduced the extent of blood-brain barrier (BBB) disruption as estimated from the extravasation of Evans blue dye at 6 h after the onset of ischemia (p ≤ 0.01). Hypothermia also reduced the volume of both brain edema (p ≤ 0.01) and neuronal damage (p ≤ 0.01) as estimated from Nissl-stained slides at both 6 and 24 h after the onset of ischemia. These results demonstrate that mil...
242 citations
TL;DR: The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia, and acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats.
Abstract: Experimental models of focal cerebral ischemia have provided important data on early circulatory and biochemical changes, but typically their correspondence with metabolic and hemodynamic findings in stroke patients has been poor. To fill the gap between experimental studies at early time points and rather late clinical studies, we repeatedly measured CBF, CMRO2, oxygen extraction fraction (OEF), cerebral blood volume (CBV), and CMRglc in six cats before and up to 24 h after permanent middle cerebral artery (MCA) occlusion (MCAO), using the 15O steady state and [18F]fluorodeoxy-glucose methods and a high-resolution positron emission tomography (PET) scanner. Likewise, three sham-operated control cats were studied during the same period. Final infarct size was determined on serial histologic sections. In the areas of final glucose metabolic depression that were slightly larger than the histologic infarcts, mean CBF dropped to approximately 40% of control values immediately on arterial occlusion. If further decreased to < 20% during the course of the experiment. This progressive ischemia was most conspicuous in border zones. CMRO2 fell to a lesser degree (55%), eventually reaching approximately 25% of its control level. At early stages, OEF increased mainly in the center of ischemia. With time, areas of increased OEF moved from the center to the periphery of the MCA territory. Concurrently, progressive secondary decreases in OEF in conjunction with further reductions of CBF and CMRO2 indicated the development of central necrosis. The findings are highly suggestive of a dynamic penumbra. In five cats with complete MCA infarcts, CBF decreased and OEF increased in the contralateral hemisphere after 24 h, suggesting whole-brain damage. This effect may be explained by the widespread brain edema found histologically in addition to the nonspecific CBF reductions and OEF elevations observed also in the sham-operated controls after 1 day in the experimental condition. In one cat, cortical OEF increased only transiently. Normal CMRO2 and CMRglc were eventually restored, and the final infarct was small. This study demonstrates that acute regional pathophysiologic changes can be repeatedly assessed by multivariate PET in cats. Viable tissue can be detected up to several hours after MCA occlusion, and the transition of misery-perfused regions into necrosis or preserved tissue can be followed over time. The present results support the concept of a dynamic penumbra, in which for up to 24 h tissue damage spreads progressively from the center to the periphery of ischemia. Sequential high-resolution PET provides insight into the dynamics of regional pathophysiology and may thus further the development of rational therapeutic strategies.
240 citations
TL;DR: No donors increase CBF to the ischemic territory and reduce the tissue damage resulting from focal ischemia and the findings suggest that NO donors may represent a new therapeutic strategy for the management of acute stroke.
Abstract: We studied whether administration of nitric oxide (NO) donors reduces the ischemic damage resulting from middle cerebral artery (MCA) occlusion in spontaneously hypertensive rats (SHRs). In halothane-anesthetized and ventilated SHRs, the MCA was occluded. CBF was monitored using a laser-Doppler flowmeter. Three to five minutes after MCA occlusion, the NO donors sodium nitroprusside (SNP; 3 mg/kg/h) or 3-morpholino-sydnonimine (SIN 1; 1.5–6 mg/kg/h) were administered into the carotid artery for 60 min. As a control, the effect of papaverine (3.6 mg/kg/h), a vasodilator that acts independently of NO, was also studied. The hypotension evoked by these agents was counteracted by intravenous infusion of phenylephrine. At the end of the infusion, rats were allowed to recover. Stroke size was determined 24 h later in thionin-stained sections. In sham occluded rats, SNP (n = 5), SIN 1 (n = 5), and papaverine (n = 5) produced comparable increases in CBF (p > 0.05 from vehicle). After MCA occlusion, SNP (n = 5) and ...
TL;DR: Hibernation appears to be actively regulated, and hormonal factors may be involved, and the identification and characterization of such factors and of the mechanisms used by hibernating species to increase ischemic tolerance and to blunt the destructive effects of ischemia may enable to prevent or minimize the loss of homeostatic control during and after cerebral ischemIA in other species.
Abstract: The breakdown of cellular homeostasis and progressive neuronal destruction in cerebral ischemia appears to be mediated by a complex network of causes that are intricately interrelated. We have investigated a physiological state existing normally in nature in which mammals appear to tolerate the ordinarily detrimental effects of ischemia with reduced oxygen availability and to resist activation of self-destructive processes, i.e., mammalian hibernation. Ground squirrels (Spermophilus tridecemlineatus) were chronically implanted with arterial and venous catheters and telemetry devices for electroencephalography, electrocardiography, and monitoring of body temperature. The animals were placed in an environmental chamber at an ambient temperature of 5 degrees C. Entrance into hibernation was characterized by a drop in heart rate followed by a gradual decline in body temperature and an isoelectric electroencephalogram. Cold-adapted active animals that were not hibernating served as controls. Cerebral blood flow (CBF) was measured in both groups with the autoradiographic [14C]iodoantipyrine method. Mean (+/- SD) mass-weighted CBF in the brain was 62 +/- 18 ml 100 g(-1) min (-1) (n = 4) in the control group but was reduced to ischemic levels, 7 +/- 4 ml 100 g(-1) min (-1) (n = 4), in the hibernating animals (p < 0.001) [corrected]. No neuropathological changes were found in similarly hibernating animals aroused from hibernation. Hibernation appears to be actively regulated, and hormonal factors may be involved. The identification and characterization of such factors and of the mechanisms used by hibernating species to increase ischemic tolerance and to blunt the destructive effects of ischemia may enable us to prevent or minimize the loss of homeostatic control during and after cerebral ischemia in other species.
TL;DR: Focal induction of ischemic tolerance in rat neocortex that may be related to expression of heat-shock proteins is demonstrated.
Abstract: The objective of this study was to determine whether brief focal ischemia induces ischemic tolerance in rat brain. Focal ischemia was produced in Wistar rats by occluding the middle cerebral artery (MCA) for 20 min at a distal site. Following recovery for 24 h, the animals were subjected to a 10-min episode of forebrain ischemia using a combination of bilateral carotid artery occlusion and systemic hypotension. Histologic injury, assessed after a survival period of 3–4 days, consisted of selective neuronal necrosis bilaterally in cerebral cortex, striatum, hippocampus, and thalamus superimposed upon a small cortical infarct adjacent to the site of MCA occlusion. However, the intensity of neuronal necrosis in the MCA territory of the neocortex ipsilateral to MCA occlusion was markedly less than that in the contralateral MCA cortex. In contrast, the extent of neuronal necrosis in subcortical structures was similar in both hemispheres Unexpectedly, animals in which the MCA was manipulated, but not occluded, ...
TL;DR: Findings are consistent with the hypothesis that the early onset of signal hyperintensity in diffusion-weighted MR images may reflect cellular edema associated with impaired membrane pump function and early in vivo detection of potentially reversible ischemic cerebral edema may have important research and clinical applications.
Abstract: Diffusion-weighted magnetic resonance (MR) images from rats during acute cerebral ischemia induced by middle cerebral artery occlusion were analyzed for correspondence with changes in brain water, ...
TL;DR: This is the first demonstration of elevated levels of endothelin in focal isChemic tissue and in the extracellular fluid in global ischemia and suggests a role of the peptide in ischemic and postischemic derangements of cerebral vascular function and tissue injury.
Abstract: Endothelin-1, a peptide exhibiting extremely potent cerebral vasoactive properties, is elevated in the cerebrospinal fluid after hemorrhagic stroke and implicated in cerebral vasospasm. The purpose of this study was to determine changes in endothelin in ischemic rat brain by assaying endothelin tissue and extracellular levels. Immunoreactive endothelin levels in ischemic brain tissue following permanent or transient focal ischemia produced by middle cerebral artery occlusion was determined. In addition, endothelin levels were assayed in striatal extracellular fluid collected by microdialysis before, during, and after global ischemia produced by two-vessel occlusion combined with hypotension. Twenty-four hours after the onset of permanent middle cerebral artery occlusion, the ischemic cortex level (0.58 +/- 0.27 fmol/mg protein) of immunoreactive endothelin was significantly (p < 0.05) increased, by 100%, over that in the nonischemic cortex (0.29 +/- 0.13 fmol/mg protein). Transient artery occlusion for 80 min with reperfusion for 24 h also resulted in a similar significant (p < 0.05) increase, 78%, in immunoreactive endothelin in the ischemic zone. Global forebrain ischemia significantly (p < 0.05) increased the level of immunoreactive endothelin collected in striatal microdialysis perfusate, from a basal level of 14.6 +/- 6.7 to 26.5 +/- 7.7 and 26.2 +/- 7.4 amol/microliters (i.e. 82 and 79%). These changes reflect the relative picomolar extracellular concentration increases during ischemia and following reperfusion, respectively. This is the first demonstration of elevated levels of endothelin in focal ischemic tissue and in the extracellular fluid in global ischemia and suggests a role of the peptide in ischemic and postischemic derangements of cerebral vascular function and tissue injury.
TL;DR: A clinically useful role for α-amino-3-hydroxy-5-methyl-4-isoxazole propionate antagonists in embolic stroke is envisaged if nontoxic drugs can be developed, since cerebroprotection was achieved with delayed treatment with both of these lead compounds.
Abstract: We tested the abilities of two potent non-N-methyl-d-aspartate (non-NMDA) glutamate antagonists [2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX)] and [1-(4-aminophenyl)-4-methyl-7,8-methylene-dioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466)] to reduce neocortical infarction following 2 h of transient middle cerebral artery occlusion in a hypertensive stroke model in the rat and compared these effects against, and in combination with, a potent NMDA antagonist [(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-amine maleate (MK-801)]. In Expt. 1, an already established cytoprotective dose of Na+-NBQX (30 mg/kg i.p. × 3) was compared with saline (1 ml), the NMDA antagonist MK-801 (1 mg/kg i.p. × 3), and a combination of the same doses of both NBQX and MK-801. Initial doses were delayed to 90 min following occlusion with subsequent injections at the time of reperfusion and 30 min following reperfusion. Saline-treated rats sustained 181 ± 32 mm3 (n = 15) of neocortical infarction (m...
TL;DR: The studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μM (perfused supracortically at 4 μl/h for 21 h) and suggest that calpain inhibitors may provide a unique and potentially powerful means of treating stroke and other ischemic brain incidents.
Abstract: Experiments were conducted to determine whether a potent, reversible calpain inhibitor could reduce the cortical ischemic brain damage associated with focal ischemia in the rat. AK275 (Z-Leu–Abu–CONH–CH2CH3), the active isomer of the diastereomeric mixture, CX275, was employed in conjunction with a novel method of perfusing drug directly onto the infarcted cortical surface. This protocol reduced or eliminated numerous, nonspecific pharmacokinetic, hemodynamic, and other potentially confounding variables that might complicate interpretation of any drug effect. Focal ischemia was induced using a variation of the middle cerebral artery occlusion method. These studies demonstrated a reliable and robust neuroprotective effect of AK275 over the concentration range of 10 to 200 μM (perfused supracortically at 4 μl/h for 21 h). Moreover, a 75% reduction in infarct volume was observed when initiation of drug treatment was delayed for 3 h postocclusion. Our data further support an important role of calpain in ische...
TL;DR: Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems and raising the possibility that other factors indirectly related to changes in blood flow (or Pco2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.
Abstract: To assess the stability of different measures of receptor occupancy from [11C]raclopride (a D2 antagonist) studies with positron emission tomography, we analyze data from five test/retest studies in normal volunteers in terms of individual model parameters from a three-compartment model, the distribution volume (DV) and the ratio of DVs from a receptor-containing region of interest to a non-receptor-containing region. Large variations were found in the individual model parameters, limiting their usefulness as an indicator of change in receptor systems. The DV ratio showed the smallest variation. Individual differences were reflected in the greater intersubject variation in DV than intrasubject variation. The potential effects of blood flow on these measurements were addressed both experimentally and by simulation studies using three models that explicitly incorporate blood flow into a compartmental model that also includes receptor-ligand binding. None of the models showed any variation in the DV with changes in blood flow as long as flow was held constant during the simulation. Experimentally, blood flow was significantly reduced by hyperventilation in a human subject. The DV was found to be reduced relative to baseline in the hyperventilation study, but the DV ratio remained unchanged. The effect of elevated and reduced flow was also tested in two baboon experiments in which PCO2 was varied. Some variability in the DV ratio was observed but was not correlated with changes in blood flow. This raises the possibility that other factors indirectly related to changes in blood flow (or PCO2) may cause changes in DV, and these effects need to be considered when evaluating experimental results.
TL;DR: These data represent the first detailed in vivo measurements of diffusion parameters α, λ, and k‘ during and after progressive ischemia and anoxia, which could affect the diffusion and aggravate the accumulation of ions, neurotransmitters, metabolic substances, and drugs used in therapy of nervous diseases.
Abstract: Extracellular space (ECS) volume fraction (alpha), ECS tortuosity (lambda), and nonspecific uptake (k'), three parameters affecting the diffusion of substances in nervous tissue, were studied during ischemia and anoxia in the rat spinal cord gray matter in vivo. Progressive ischemia evoked by exsanguination, as well as anoxia evoked by respiratory or cardiac arrest, produced prominent extracellular K+ and pH changes closely related to a decrease in blood pressure and amplitude of field potentials. With use of ion-selective microelectrodes, the changes in the diffusion parameters were measured by quantitative analysis of concentration-time profiles of tetramethylammonium (TMA+) applied by iontophoresis concomitantly with ionic shifts. Under normoxic conditions (in rats with blood pressure of 80-110 mm Hg) diffusion parameters in the dorsal horn gray matter at depth 500-900 microns were as follows: alpha = 0.20 +/- 0.019, lambda = 1.62 +/- 0.12, k' = 4.6 +/- 2.5 x 10(-3) s-1 (mean +/- SD, n = 39). Extracellular K+, pH, and diffusion properties gradually changed during progressive ischemia. As the blood pressure fell to 50-60 mm Hg and field potential amplitude to 20-60%, K+ rose to 6-12 mM, pHe fell by approximately 0.05-0.1 pH unit, and volume fraction of the ECS significantly decreased, to alpha = 0.16 +/- 0.019 (n = 22). Even though the tortuosity remained virtually constant, the nonspecific uptake significantly decreased to k' = 3.4 +/- 1.8 x 10(-3) s-1. As the blood pressure fell to 20-30 mm Hg and field potential amplitude to 0-6%, K+ rose to 60-70 mM, pHe fell by approximately 0.6-0.8 pH unit, and all three diffusion parameters significantly changed. The ECS volume fraction decreased to alpha = 0.05 +/- 0.021, tortuosity increased to lambda = 2.00 +/- 0.24, and TMA+ uptake decreased to k' = 1.5 +/- 1.6 x 10(-3) s-1 (n = 12). No further increase in extracellular K+ or changes in the alpha were found during and up to 120 min after the death of the animal. However, there was a further significant increase in lambda = 2.20 +/- 0.14 and decrease in k' = 0.4 +/- 0.3 x 10(-3) s-1 (n = 24). The acid shift reached its maximum level at approximately 5-10 min after respiratory arrest and then the pHe gradually increased by approximately 0.2 unit. Full recovery to "normoxic" diffusion parameters was achieved after reinjection of the blood or after an injection of noradrenaline during severe ischemia, if this resulted in a rise in blood pressure above 80 mm Hg and a decrease in extracellular K+ below 12 mM.(ABSTRACT TRUNCATED AT 400 WORDS)
TL;DR: Bradykinin, infused in low doses through the carotid artery ipsilateral to RG2 glioma in rats, significantly increased the permeability in tumor capillaries to six different tracers compared with intracarotid infusion of saline alone.
Abstract: Bradykinin, infused in low doses (10 μg/kg/min) through the carotid artery ipsilateral to RG2 glioma in rats, significantly increased the permeability in tumor capillaries to six different tracers of varying molecular weights compared with intracarotid infusion of saline alone. Permeability in normal brain capillaries was not significantly increased by intracarotid bradykinin infusion. Tracers used to examined permeability included radiolabeled α-aminoisobutyric acid (AIB; MW 103), sucrose (MW 342.3), inulin (MW 5000), and dextran (MW 70,000), horseradish peroxidase (HRP) and Evans blue (EB). Permeability was expressed as the unidirectional transfer constant Ki (μl/g/min). The permeabilities (Ki) of tumors in the bradykinin group versus the control saline group for AIB, sucrose, inulin, and dextran were 25.91 ± 6.78 vs. 13.95 ± 4.29 (p < 0.01), 17.90 ± 2.65 vs. 10.75 ± 4.55 (p < 0.01), 23.92 ± 6.99 vs. 6.20 ± 4.37 (p < 0.01), and 17.84 ± 1.00 vs. 1.47 ± 1.24 (p < 0.001), respectively (mean ± SD). Permeabi...
TL;DR: A magnetic resonance imaging brain mapping method was used to localize an activated volume of brain tissue in chloralose-anesthetized rats during electrical stimulation of the forepaw, which led to an increase in MR signal intensity of the contralateral frontal and parietal cortices, which corresponded to forelimb motor and somatosensory areas.
Abstract: A magnetic resonance (MR) imaging brain mapping method was used to localize an activated volume of brain tissue in chloralose-anesthetized rats during electrical stimulation of the forepaw. Physiologically-induced changes are characterized by alterations of the magnetic properties of blood as determined by the oxygenation state of hemoglobin. Stimulation of the left forepaw led to an increase in MR signal intensity of the contralateral frontal and parietal cortices, which corresponded to forelimb motor and somatosensory areas. The activation was contiguous in coronal planes between +5 and +2 mm anterior to the bregma, and its volume was calculated to be 20–30 mm3. Each activated region was revealed using a paired t-test statistical analysis method and the activated volume was calculated from regions exposed by thresholding at p < 0.005. Physiologically-induced fractional signal changes, ΔS/S, in the motor and somatosensory areas were 0.06 ± 0.04 and 0.17 ± 0.06, respectively.
TL;DR: The data show that changes in gene expression can occur in regions remote from an infarction, including ipsilateral medial striatum, most of thalamus, and hippocampus, which are not supplied by the MCA.
Abstract: Middle cerebral artery (MCA) occlusion in halothane-anesthetized rats induced c-fos, junB, and c-jun immediate early gene mRNAs and hsp70 heat shock gene mRNA in brain. In situ hybridization studies showed that c-fos and junB were induced throughout all of the cortex at 1 and 4 h following MCA occlusion. hsp70 was induced in the core and margins of the MCA ischemia. By 24 h, there was little expression of c-fos, junB, c-jun, and hsp70 in the core of the MCA infarct; there was modest induction of hsp70 at the margins of the infarct; and there was diffuse induction of c-fos, junB, and c-jun in all of the cortex outside the infarct. MCA occlusion also induced these genes in subcortical structures. c-fos, junB, and hsp70 were induced in ipsilateral medial striatum, most of thalamus including medial and lateral geniculate nuclei, substantia nigra, and hippocampus. Most of these structures, except for the striatum, are not supplied by the MCA. These data show that changes in gene expression can occur in regions remote from an infarction.
TL;DR: The data demonstrate that imaging of ADC provides reliable information about the metabolic state of the brain and can be used to monitor, with high temporal and regional resolution, the manifestation and reversal of ischemic brain injury.
Abstract: Adult normothermic cats were submitted to 1-h complete cerebrocirculatory arrest by intrathoracic occlusion of the internal mammary, the innominate, and the subclavian arteries in combination with pharmacologically induced hypotension. After ischemia, recirculation was initiated at different blood pressure levels to manipulate the postischemia resuscitation conditions. The resulting spectrum of postischemic recovery was studied by combining nuclear magnetic resonance imaging of the apparent diffusion coefficient (ADC) with pictorial assays of brain tissue pH, ATP, glucose, and lactate. Before ischemia, the mean ADC (average of seven coronal slices of five cats) was 713 +/- 40 x 10(-6) mm2/s. After 10-min ischemia, ADC declined to 68% of control and after 50 min slightly further to 63% of control. During recirculation after 1-h ischemia, recovery of ADC varied depending on the initial reperfusion pressure and other systemic variables. In two animals ADC only transiently increased followed by a secondary decline below the postischemic level. In three other animals ADC returned to near control within 1 h of recirculation. The comparison of ADC changes with previously reported changes in extracellular volume revealed a close relationship, supporting the notion that ADC is a function of the intra/extracellular water compartmentation. Recovery of ADC correlated closely with tissue pH and metabolic recovery, studied 3 h after the initiation of recirculation. Animals without recovery of ADC exhibited global depletion of ATP and glucose and severe lactacidosis, whereas animals with recovery of ADC showed replenishment of ATP and glucose to near control and a substantial reversal of lactacidosis.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is demonstrated that SPECT studies with an acetazolamide challenge can detect the Stage II hemodynamic failure in stroke patients with minimal or no infarction.
Abstract: Single photon emission computed tomography (SPECT) with acetazolamide challenge has increasingly been used for evaluating hemodynamic reserve in stroke patients. The accuracy of this test, however, has not been validated with positron emission tomography (PET). In 14 patients who had occlusive disease of the internal carotid artery or the trunk of the middle cerebral artery (MCA) with minimal or no infarction on computed tomography (CT) and magnetic resonance imaging (MRI), we compared acetazolamide reactivity on SPECT with N-isopropyl-p-[123I]-iodoamphetamine to hemodynamic parameters determined with gas inhalation labeled 15O steady-state PET studies. The asymmetry index (AI)--i.e., the percentage of the activity rate of the ischemic MCA territory versus the contralateral one, was determined by SPECT. Acetazolamide reactivity expressed as delta AI, or change in AI after acetazolamide challenge, was significantly lower in seven patients than -8.4%, the lower limit of the 95% confidence interval for the normal reactivity. Values of ipsilateral CBF, cerebral blood volume (CBV)/CBF, and oxygen extraction fraction (OEF) and contralateral OEF were significantly different between patients with normal and reduced acetazolamide reactivity. Values of delta AI were correlated with OEF (r = -0.87; p 0.52, the mean + 2 SD calculated from five normal volunteers, also had reduced acetazolamide reactivity, while the patients with normal OEF values had normal reactivity. The present study has demonstrated that SPECT studies with an acetazolamide challenge can detect the Stage II hemodynamic failure.
TL;DR: It is demonstrated that chloride is the principal anion that accompanies the accumulation of sodium in ischemic brain, but its rate of accumulation in brain is much less than its rates of movement into brain, and therefore inhibition of chloride uptake would have little effect on brain edema formation.
Abstract: Brain edema formation during the early stages of focal cerebral ischemia is associated with an increase in both sodium content and blood-brain barrier (BBB) sodium transport. The goals of this study were to determine whether chloride is the principal anion that accumulates in ischemic brain, how the rate of BBB transport of chloride compares with its rate of accumulation, and whether the stimulation seen in BBB sodium transport is also seen with other cations. Focal ischemia was produced by occlusion of the middle cerebral artery (MCAO) in anesthetized rats. Over the first 6 h after MCAO, the amount of brain water in the center of the ischemic cortex increased progressively at a rate of 0.15 +/- 0.02 (SE) g/g dry wt/h. This was accompanied by a net increase in brain sodium (48 +/- 12 mumol/g dry wt/h) and a loss of potassium (34 +/- 7 mumol/g dry wt/h). The net rate of chloride accumulation (16 +/- 1 mumol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions (22Na, 36Cl, and 86Rb) and two passive permeability tracers ([3H]alpha-aminoisobutyric acid ([3H]AIB) and [14C]urea) was determined. Permeability to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36Cl influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in ischemic brain.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Ca2+ fluxes through ω-conopeptide-sensitive N-type Ca2+ channels are critically involved in the pathogenesis of selective neuronal death up to 24 h after ischemia in the hippocampus and that this conopeptid protection extends, even when given late, to neocortical infarct reduction.
Abstract: SNX-111 (NEUREX Corporation, Menlo Park, CA, U.S.A.) an omega-conopeptide, was tested for cytoprotection following normothermic ischemia using both a four-vessel occlusion model of severe forebrain ischemia and a model of transient middle cerebral artery occlusion focal ischemia. Adult male Wistar rats were subjected to 10 min of forebrain ischemia followed by 7 days of reperfusion. A single dose of SNX-111 (5 mg/kg) was injected intravenously following delays of either 6 or 24 h after reperfusion. For 11 rats treated with saline, there was 78 +/- 13% CA1 neuronal injury (mean +/- SD); for 11 given SNX-111 delayed by 6 h, injury was reduced to 35 +/- 30% (p < 0.01); and remarkably, treatment delayed by 24 h (n = 10), still resulted in protection, with only 50 +/- 29% injury (p < 0.05). Adult male spontaneously hypertensive rats had transient occlusion of the right middle cerebral artery of 1.5- or 2-h duration followed by 22.5 or 22 h of reperfusion, respectively. Rats were randomly assigned to receive either saline or SNX-111 (5 mg/kg i.v.), with treatment starting immediately after reperfusion (1.5-h ischemic group) or at 1 h following the onset of ischemia (2-h ischemic group). In the 1.5-h ischemic group, saline-treated animals sustained 138 +/- 32 mm3 of neocortical infarction (n = 9), and SNX-111 treatment resulted in an infarct reduction to 76 +/- 25 mm3 (n = 9; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The present findings provide further evidence that the activation of IEGs forms part of the brain's metabolic response to ischemia, but no simple correlation appears to exist between the induction of the investigated IEGS and the phenomenon of selective vulnerability.
Abstract: The temporospatial expression pattern of four immediate early genes (IEGs) (c-fos, c-jun, junB, NGFI-B) following 30 min of global ischemia was investigated in rat brains by in situ hybridization and immunohistochemistry (c-fos). All examined IEG mRNAs, as well as Fos-like immunoreactivity, increased transiently in vulnerable and resistant brain regions following ischemia, but the induction profiles were distinct. Ischemia caused a post-ischemic early-onset, transient c-fos induction in widespread regions, as well as a late-onset induction restricted to vulnerable regions. Late-onset c-fos induction was observed in the CA1 region and the ventral thalamus but not in the striatum or neocortex, where neurons degenerate at a quicker pace. After recirculation, c-jun mRNA appeared to be initially coinduced with c-fos mRNA, but c-jun mRNA levels remained elevated or increased in various regions, including all vulnerable regions, when c-fos mRNA had already declined to near basal levels. Compared to c-fos and c-j...
TL;DR: The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cerebral energy requirements.
Abstract: During prolonged starvation, brain energy requirements are covered in part by the metabolism of ketone bodies. It is unknown whether short-term starvation of a few days' duration may lead to reduced brain glucose metabolism due to the change toward ketone body consumption. In the present study we measured the cerebral metabolism of glucose and ketone bodies in nine healthy volunteers before and after 3.5 days of starvation. Regional glucose metabolism was measured by dynamic positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. The mean value of K1* in gray and white matter increased by 12% (p < 0.05), whereas k2* and k3* were unchanged compared with control values. Regional glucose metabolism in cortical gray matter was reduced by 26% from 0.294 +/- 0.054 to 0.217 +/- 0.040 mumol g-1 min-1 (p < 0.001). White matter glucose metabolism decreased by 27% (p < 0.02). The decrease was uniform in gray and white matter with regional decreases ranging from 24 to 30%. A determination using Fick's principle confirmed the reduction in glucose metabolism yielding a decrease of 24% from 0.307 +/- 0.050 to 0.233 +/- 0.073 mumol g-1 min-1 (p < 0.05), whereas CBF did not change (0.57 +/- 0.07 vs. 0.57 +/- 0.06 ml g-1 min-1). The global net uptake of beta-hydroxybutyrate increased 13-fold from 0.012 +/- 0.024 to 0.155 +/- 0.140 mumol g-1 min-1 (p < 0.05). Net uptake of acetoacetate and net efflux of lactate and pyruvate did not change significantly during starvation. The present study shows that the human brain adapts to the changes in energy supply as early as 3 days following initiation of starvation, at which time ketone bodies account for approximately one-fourth of the cerebral energy requirements.
TL;DR: The results demonstrate that changes in intra-extracellular pH and bicarbonate concentrations modulated ischemic damage in an unexpected way, and hypothesize that the decisive event was an exaggerated decrease in extra- and intracellular pH.
Abstract: Although preischemic hyperglycemia is known to aggravate damage due to transient ischemia, it is a matter of controversy whether or not this is a result of the exaggerated acidosis. It has recently...
TL;DR: Results are consistent with the hypothesis that reduction of NAA measured by MRSI may be a sensitive marker of neuronal injury in vivo in a variety of disease states.
Abstract: N-acetylaspartate (NAA) has been proposed as a marker of neuronal density. Therefore, regional measurement of NAA by magnetic resonance spectroscopic imaging (MRSI) may provide a sensitive method for detection of selective neuronal loss, in contrast to conventional imaging techniques such as magnetic resonance imaging (MRI). To test this hypothesis, we produced selective neuronal injury by kainate-induced status epilepticus. Three days later three-dimensional 1H-MRSI was obtained and compared with conventional T2-weighted MRI and histological findings in normal and kainate-treated rats. Reduction of NAA determined by MRSI in piriform cortex, amygdala, and hippocampus correlated well with neuronal injury determined from histology. Changes of NAA, without any MRI changes in hippocampus, indicated greater sensitivity of MRSI for detection of neuronal injury. These results are consistent with the hypothesis that reduction of NAA measured by MRSI may be a sensitive marker of neuronal injury in vivo in a variety of disease states.