bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Cerebellar Glucose Metabolism in Microvascular White Matter Disease: Normal Aging and Alzheimer's Disease
Authors: Klinger A. , de Leon M. J. , George A. E. , Miller J. D. , Wolf A. P.
Published: April 2011

Young normal, elderly, and clinically diagnosed Alzheimer disease subjects who had undergone positron emission tomography (PET) and computed tomography (CT) examinations were studied to determine the effect of periventricular white matter lesions on cerebellar glucose metabolic rates. PET-determined cerebellar metabolic rates were elevated in subjects with periventricular white matter lesions. These results suggest the cautious use of cortical-to-cerebellar ratios in future PET or single-photonemission CT (SPECT) studies.
Cerebrovascular and Cerebrometabolic Effects of Intracarotid Infused Platelet-Activating Factor in Rats
Authors: Kochanek Patrick M. , Nemoto Edwin M. , Melick John A. , Evans Rhobert W. , Burke David F.
Published: April 2011

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 ±4 (x ± SEM) to 77 ± 6 mm Hg and CBF from 159 ± 12 to 116 ± 14 ml/100 g/min (p < 0.002). In contrast, CMRO2 increased from 9.7 ± 0.9 to 11.7 ± 1.1 ml/100 g/min after 15 min (p < 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.
Retrograde Catheterization of the Right Internal Jugular Vein for Serial Measurements of Cerebral Venous Oxygen Content
Authors: Jakobsen Mogens , Enevoldsen Erna
Published: April 2011

Serial measurements of CBF and metabolism require multiple cerebral venous blood samples. Retrograde catheterization of the right internal jugular vein is easily performed at a point 2.5–3 cm lateral to, and 2 cm above, the medial end of the right clavicula. Complications are few and minor. In 1/80 (1.25%) cases the carotid artery was punctured during cannulation. Insertion of the catheter for 16–18 cm reduces contamination with extracerebral blood to a minimum.
Mechanisms of Action of Endothelin on Isolated Feline Cerebral Arteries: In vitro Pharmacology and Electrophysiology
Authors: Jansen I. , Fallgren B. , Edvinsson L.
Published: April 2011

Vascular endothelium has been found to produce a strong and potent vasoconstrictor peptide, endothelin. In this study, we have examined basic mechanisms underlying the contractile response of cerebral vessels to endothelin using in vitro pharmacology and electrophysiology. It was found that endothelin produced strong concentration-dependent contractions of circular segments of the feline middle cerebral artery. The response was slow in onset and long lasting. The vessels showed a remarkably strong tachyphylactic reaction upon repeated exposure to endothelin. The contractile effect of endothelin was not modified by the α-adrenoceptor antagonist phen-tolamine (10−6 M) or the 5-hydroxytryptamine antagonist ketanserin (10−6 M). Mechanical removal of the endothelium decreased potassium contractions while the maximum response to endothelin was only slightly reduced. There was no change in sensitivity of the cerebral artery to endothelin. The addition of a calcium antagonist (10−6 M diltiazem or 3 × 10−8 M nimodipine) or removal of extracellular calcium from the buffer solution did not change the sensitivity of the artery to endothelin but the maximum response to endothelin was reduced by between 40 and 60% by these procedures. The resting membrane potential of the cat middle cerebral artery was –62.8 ± 3.5 mV. There was no significant depolarization in conjunction with cumulative administration of endothelin in concentrations below 1 × 10−9 M. However, bursts of excitatory junction potentials were occasionally seen in response to high concentrations of endothelin (5 × 10−9 M). The findings suggest that the contractile response to endothelin of cat cerebral arteries involved influx of extracellular calcium through voltage-sensitive calcium channels and is in part mediated via a voltage-insensitive mechanism. Further work is necessary to define the intracellular actions of endothelin.
The Effects of the GABA Agonist Muscimol upon Blood Flow in Different Vascular Territories of the Rat Cortex
Authors: Kelly Paul A. T. , Faulkner Amanda J. , Burrow Andrew P.
Published: April 2011

Local cerebral blood flow was measured in five regions of rat cortex immediately following intravenous administration of the γ-aminobutyric acid (GABA) agonist muscimol. In contrast to recent observations, no increases in blood flow were found at either of the two time points analysed, and the data revealed that decreases in blood flow previously reported 30 min after muscimol treatment were in evidence as early as 30 s. These results are totally consistent with the conclusion that the overall effects of GABA agonists in the intact animal are to reduce blood flow in line with reduced metabolic demand in the neuropil. However, the heterogeneity of the reductions in cortical blood flow found here possibly suggests a biological role for vascular GABA systems in providing a mitigating influence on fluctuating tissue perfusion.
Glycolysis-Induced Discordance between Glucose Metabolic Rates Measured with Radiolabeled Fluorodeoxyglucose and Glucose
Authors: Ackermann Robert F. , Lear James L.
Published: April 2011

We have developed an autoradiographic method for estimating the oxidative and glycolytic components of local CMRglc (LCMRglc), using sequentially administered [18F]fIuorodeoxyglucose (FDG) and [14C]-6-glucose (GLC). FDG-6-phosphate accumulation is proportional to the rate of glucose phosphorylation, which occurs before the divergence of glycolytic ( GMg) and oxidative ( GMo) glucose metabolism and is therefore related to total cerebral glucose metabolism GMt: GMg + GMo = GMt. With oxidative metabolism, the 14C label of GLC is temporarily retained in Krebs cycle-related substrate pools. We hypothesize that with glycolytic metabolism, however, a significant fraction of the 14C label is lost from the brain via lactate production and efflux from the brain. Thus, cerebral GLC metabolite concentration may be more closely related to GMo than to GMt If true, the glycolytic metabolic rate will be related to the difference between FDG- and GLC-derived LCMRglc. Thus far, we have studied normal awake rats, rats with limbic activation induced by kainic acid (KA), and rats visually stimulated with 16-Hz flashes. In KA-treated rats, significant discordance between FDG and GLC accumulation, which we attribute to glycolysis, occurred only in activated limbic structures. In visually stimulated rats, significant discordance occurred only in the optic tectum.
MK-801, an Excitatory Amino Acid Antagonist, Does Not Improve Neurologic Outcome following Cardiac Arrest in Cats
Authors: Fleischer Jerry E. , Tateishi Akio , Drummond John C. , Scheller Mark S. , Grafe Marjorie R. , Zornow Mark H. , Shearman Gary T. , Shapiro Harvey M.
Published: April 2011

The excitatory amino antagonist MK-801 was administered to cats following resuscitation from cardiac arrest to evaluate its effect on neurologic and neuropathology outcome in a clinically relevant model of complete cerebral ischemia. In 29 cats studied, cardiac arrest (ventricular fibrillation) was maintained for 18 min and resuscitation was successfully performed in 21 cats. Four animals underwent a sham arrest. MK-801 or placebo was administered in a blinded, randomized manner. Beginning at 5 min post resuscitation (PR), MK-801 330 μg/kg over 2 min followed by 73 μg/kg/h for 10 h or the same volume of placebo was administered. Resuscitated animals remained paralyzed and sedated in an intensive care setting for 24–30 h PR. Neurologic examinations were performed at 2, 4, and 7 days PR by observers blinded to the treatment groups. Seventeen cats were entered into data analysis (nine MK-801-treated and eight placebo-treated). MK-801-treated animals had a significantly greater neurologic deficit score (NDS) rank (0 = normal, 100 = brain death) 2 days PR (mean rank 12.1 vs. 5.6; p = 0.008). This difference is most likely due to ongoing sedative actions of MK-801. There were no significant differences in NDS rank at 4 (10.3, MK-801 vs. 7.5, placebo) and 7 (9.6, MK-801 vs. 8.3, placebo) days PR. There were no significant differences in frontal cortex, hippocampus, occipital cortex, or cerebellar neuropathology between groups. Sham-arrested cats had normal neurologic and neuropathologic evaluations. In the circumstance of complete cerebral ischemia as employed in the current study, MK-801 had no beneficial effect upon neurologic or neuropathologic outcome.
Immunohistochemical Determination of Calcium—Calmodulin Binding Predicts Neuronal Damage after Global Ischemia
Authors: Picone Carmela M. , Grotta James C. , Earls Rosa , Strong Roger , Dedman John
Published: April 2011

Since ionic Ca2+ binds with intracellular calmodulin (CaM) before activating proteases, kinases, and phospholipases, demonstration of persistent Ca2+ –CaM binding in neurons destined to show ischemic cellular injury would support the concept that elevated intracellular Ca2+ plays a causative role in ischemic neuronal damage. In order to characterize Ca2+ –CaM binding, we used a sheep anti-CaM antibody (CaM-Ab) which recognizes CaM that is not bound to Ca2+ or brain target proteins. Therefore, immunohistochemical staining of brain sections by labeled CaM-Ab represented only unbound CaM. Six normal rats were compared to 15 animals rendered ischemic for 30 min by a modification of the four-vessel occlusion model. Animals were killed immediately after ischemia, and after 2 and 24 h of reperfusion. Brain sections through hippocampus were incubated in CaM-Ab, and a diaminobenzadiene labeled anti-sheep secondary antibody was added to stain the CaM-Ab. Staining in the endal limb of dentate, dorsal CA1, lateral CA3, and parietal cortex was graded on a 4-point scale. All normal animals had grade 4 staining indicating the presence of unbound CaM in all four brain regions. Ischemic animals demonstrated reduced (grade 0 to 2) staining in the CA1 and CA3 regions immediately and 2 and 24 h after ischemia (p < 0.01 for both regions at all three time intervals) indicating persistent binding of CaM with Ca2+ and target proteins in these regions. Staining decreased in dentate and cortex up to 2 h after ischemia (p = 0.02 for both regions) but returned toward normal by 24 h. We conclude that while most brain regions demonstrate increased Ca2+ –CaM binding immediately after ischemia, this binding returns to normal in brain regions destined to recover, such as cortex and dentate, but persists beyond 24 h in selectively vulnerable CA1 and partially vulnerable CA3, which are destined to undergo irreversible damage. These findings support the hypothesis that calcium entry into neurons and consequent persistent activation of Ca2+ -dependent enzyme systems leads to irreversible cell damage.
Seizure-Induced Damage to Substantia Nigra and Globus Pallidus is Accompanied by Pronounced Intra- and Extracellular Acidosis
Authors: Inamura Kenji , Smith Maj-Lis , Hansen Anker J. , Siesjö Bo K.
Published: April 2011

Status epilepticus of >30-min duration in rats gives rise to a conspicuous lesion in the substantia nigra pars reticulata (SNPR) and globus pallidus (GP). The objective of the present study was to explore whether the lesion, which encompasses necrosis of both neurons and glial cells, is related to intra- and extracellular acidosis. Using the flurothyl model previously described to produce seizures, we assessed regional pH values with the autoradiographic 5,5-dimethyl[2-14C]oxazolidine-2,4-dione technique. Regional pH values were assessed in animals with continuous seizures for 20 and 60 min, as well as in those allowed to recover for 30 and 120 min after seizure periods of 20 or 60 min. In additional animals, changes in extracellular fluid pH (pHe) were measured with ion-selective microelectrodes, and extracellular fluid (ECF) volume was calculated from the diffusion profile for electrophoretically administered tetramethylammonium. In structures such as the neocortex and the hippocampus, which show intense metabolic activation during seizures, status epilepticus of 20- and 60-min duration was accompanied by a reduction of the “composite” tissue pH (pHt) of 0.2–0.3 unit. Recovery of pHt was observed upon termination of seizures. In SNPR and in GP, the acidosis was marked to excessive after 20 and 60 min of seizures (ΔpHt ≈ 0.6 after 60 min). In these structures, recovery of pHt was observed after 20 min of seizures, but after 60 min of seizures, a lingering acidosis was observed in SNPR. During the seizures, pHe in the neocortex fell by ∼0.2 unit. In SNPR and GP, pHe fell to much lower values (mean ΔpHe ∼ 0.5–0.6), but ECF volume was essentially unaltered. For SNPR we calculated an average intracellular pH of 6.2 after 60 min of seizures. We conclude that lactic acidosis is one important pathogenic factor in the development of the pannecrotic lesion in SNPR and GP.
Endothelium-Dependent Dilation of Feline Cerebral Arteries: Role of Membrane Potential and Cyclic Nucleotides
Authors: Brayden Joseph E. , Wellman George C.
Published: April 2011

The objective of this study was to characterize the role of membrane potential and cyclic nucleotides in endothelium-dependent dilation of cerebral arteries. Middle cerebral arteries isolated from cats were depolarized and constricted in response to serotonin or when subjected to transmural pressures >50 mm Hg. Acetylcholine (ACh) and ADP caused vasodilation and a sustained, dose-dependent hyperpolarization of up to 20 mV in this artery. The membrane potential change preceded the vasodilation by ∼6 s. Hyperpolarizations and dilations to ACh and ADP did not occur in preparations without endothelium. The hyperpolarizations were abolished by ouabain (10−5 M), which also blocked the dilator response to ACh. However, dilations to ADP were unaffected by ouabain. Methylene blue (5 × 10−5 M), a guanylate cyclase inhibitor, had no effect on the responses to ACh or ADP in the presence or absence of ouabain. Cyclic guanosine monophosphate (cGMP) levels were not altered in cerebral arteries exposed to ACh or ADP. However, ADP did increase cyclic adenosine monophosphate levels in these blood vessels. We conclude that although membrane hyperpolarizations may be adequate to cause vasodilation, at least one other pathway of endothelium-dependent vasodilation also is present in feline cerebral arteries. Cyclic GMP does not appear to be involved in this alternate pathway of dilation.
Demonstration of Acid Hydrolase Activity in Primary Cultures of Bovine Brain Microvessel Endothelium
Authors: Baranczyk-Kuzma Anna , Raub Thomas J. , Audus Kenneth L.
Published: April 2011

The existence of lysosomes and acid hydrolase activity was demonstrated in an in vitro blood–brain barrier (BBB) model comprising primary cultures of bovine brain microvessel endothelial cell (BMEC) monolayers. BMEC lysosomes were observed by the uptake of acridine orange and fluorophore-labeled acetylated low-density lipoprotein by fluorescence microscopy. Cytochemical localization of the acid hydrolase, sulfatase, and acid phosphatase (AcP) activities with light microscopy also revealed hydrolase-positive vacuoles or lysosomes that varied in number from cell to cell. BMEC monolayers were fractionated and biochemical assays of the sulfatase, AcP, and β-galactosidase were performed. Significant activities of the acid hydrolases were found to be associated with lysosome and microsome fractions (69–77%). The majority of β-galactosidase (≈48%) and total sulfatase (≈58%) activity was associated with the lysosome fraction of the BMECs. In contrast, ≈52% of AcP activity was associated with the microsome fraction of the cells. The results of this study are consistent with the demonstration in vivo of acid hydrolases as potential factors in the endocytic pathway for transport of proteins through the BBB and as contributors to the BBB's enzymatic barrier function.
Acute Thrombotic Infarction Suppresses Metabolic Activation of Ipsilateral Somatosensory Cortex: Evidence for Functional Diaschisis
Authors: Ginsberg Myron D. , Castella Yamile , Dietrich W. Dalton , Watson Brant D. , Busto Raul
Published: April 2011

To study the effects of focal infarction on the capacity for functional activation of an ipsilateral somatosensory system remote from the lesion, we produced a small thrombotic infarct in the left frontal pole of male Wistar rats by a photochemical method. Five days later, the awake, restrained rats received tactile stimulation of the large whiskers (vibrissae) of the right side of the face, while a double-label 14C-autoradiographic study of local CMRglc (lCMRglc) and local CBF (lCBF) was performed. Unlesioned and unstimulated animals served as controls. In rats without frontal infarct, vibrissae stimulation led to activation of lCMRglc in the three synaptic relay stations of the barrel-field pathway (ipsilateral trigeminal medullary nucleus, contralateral ventrobasal thalamus, and contralateral barrel-field cortex). The mean increment in lCMRglc was 42% in lamina IV of barrel-field cortex and 49% in ventrobasal thalamus. Normalized lCBF tended to increase in superficial cortical laminae. In unstimulated animals with frontal infarct, lCMRglc was reduced by 20–30% throughout the ipsilateral barrel-field cortex as well as other ipsilateral cortical regions, but not in ventrobasal thalamus or other subcortical areas. In animals with frontal infarct subjected to contralateral vibrissae stimulation, a remarkable suppression of activation was observed throughout the barrel-field cortex so that left-less-than-right hemispheral lCMRglc asymmetry persisted despite stimulation. The ventrobasal thalamus, similarly, failed to increment its lCMRglc with vibrissae stimulation, whereas activation of the trigeminal nucleus was not suppressed. Similar trends were observed in the normalized lCBF data. These observations, which establish that a small frontal infarct is capable of suppressing normal physiological activation in remote ipsilateral brain structures, may have important implications with respect to suppression and recovery of function in human ischemic stroke.
Neuronal pH Regulation: Constant Normal Intracellular pH is Maintained in Brain during Low Extracellular pH Induced by Acetazolamide—31P NMR Study
Authors: Vorstrup Sissel , Jensen Karl Erik , Thomsen Carsten , Henriksen Ole , Lassen Niels A. , Paulson Olaf B.
Published: April 2011

The intracellular pH in the brain was studied in six healthy volunteers before and immediately after the administration of 2 g of acetazolamide. Phosphorus-31 nuclear magnetic resonance spectroscopy by a 1.5 tesla whole-body scanner was used. The chemical shift between the inorganic phosphate and the phosphocreatine resonance frequencies was used for indirect assessment of the intracellular pH. The mean baseline intracellular pH was 7.05 ± 0.04 (SD). The mean pH changes obtained at 15-min intervals within the first hour of acetazolamide administration were −0.03 ± 0.04 (SD), −0.02 ± 0.03 (SD), and 0.00 ± 0.04 (SD), i.e., no statistically significant pH decrease was observed during the period where extracellular pH is known to drop markedly. Although several factors contribute to the lack of change of the intraneuronal pH, we will discuss that this observation in addition might suggest a direct intracerebral effect of acetazolamide.
Cerebral Blood Flow before and after Cardioversion of Atrial Fibrillation
Authors: Petersen Palle , Kastrup Jens , Videbæk Regitze , Boysen Gudrun
Published: April 2011

In nine patients with atrial fibrillation (AF) of <3 months' duration, CBF was measured the day before and after and again 30 days after electrical cardioversion therapy to sinus rhythm. The day before cardioversion therapy, median CBF (expressed as initial slope index 1, ml/100 g · min−1) was 35.8 and the day after it was 37.1. After 30 days in sinus rhythm, CBF was 39.4 (NS), although the end-tidal Pco2 values were lower than the pretreatment values. After correction for changes in end-tidal Pco2, the median CBF had increased significantly from 35.8 to 40.3 on day 1 and to 46.7 on day 30. The reduced CBF during AF could be a contributing factor in the development of cerebrovascular complications in patients with AF.
Mixing in the Human Carotid Artery during Carotid Drug Infusion Studied with PET
Authors: Junck Larry , Koeppe Robert A. , Greenberg Harry S.
Published: April 2011

The safety and efficacy of drug infusion into the carotid artery require adequate mixing of the infused solution with carotid blood. Using positron emission tomography (PET), we studied the mixing of solutions infused into the human carotid artery in seven patients by analyzing the distribution of [15O]H2O infused into the carotid artery and by vein. At four infusion rates ranging from 0.5 to 10 ml/min, the variability in distribution averaged 16.5–17.8% among the pixels in a large volume of interest, without dependence on the infusion rate. The overall correlation between [15O]H2O influx with arterial infusion and [15O]H2O influx with venous injection was 0.78–0.82 at the four infusion rates, with no trend toward higher correlations at the faster infusion rates. The distribution into the anterior, middle, and posterior cerebral artery territories differed from distribution throughout the entire carotid territory by an average of 6.2–9.6% at the four infusion rates, with no trend toward smaller differences at the faster infusion rates. Infusions performed into a vinyl tube simulating the carotid artery indicated that at 0.5 ml/min, the velocity of fluid exiting the catheter makes no apparent contribution to mixing. We conclude that with infusions at the carotid bifurcation, mixing in the human carotid artery is complete or nearly complete over a wide range of infusion rates. The mixing appears to result from the patterns of blood flow within the artery, and not from jet effects at the catheter tip.
Continuous Nimodipine Treatment Attenuates Cortical Infarction in Rats Subjected to 24 Hours of Focal Cerebral Ischemia
Authors: Jacewicz Michael , Brint Steve , Tanabe Jody , Pulsinelli William A.
Published: April 2011

Focal cerebral infarction and edema were measured in rats (Wistar, Fisher 344, and spontaneously hypertensive strains) pretreated with nimodipine (2 μg/kg/min i.v.) or its vehicle and subjected to the tandem occlusion of the middle cerebral and common carotid arteries. Animals awoke from anesthesia 10–15 min after onset of ischemia and continued to receive treatment over a 24-h survival period. Cortical infarction and edema were quantified by image analysis of frozen brain sections processed for histology. Nimodipine-treated rats developed 20–60% smaller cortical infarct volumes than controls (p < 0.002). Cortical edema was reduced proportionately to the decrease in infarct volume and constituted ∼36% of the infarct volume. Nimodipine caused a mild hypotensive response that did not aggravate ischemic brain damage. The results indicate that continuous nimodipine treatment, started before induction of focal cerebral ischemia, can attenuate ischemic brain damage and edema as late as 24 h after the onset of ischemia.
Involvement of Perivascular Sensory Fibers in the Pathophysiology of Cerebral Vasospasm following Subarachnoid Hemorrhage
Authors: Edvinsson L. , Delgado-Zygmunt T. , Ekman R. , Jansen I. , Svendgaard N-Aa , Uddman R.
Published: April 2011

The involvement of perivascular sensory fibers containing substance P (SP) and calcitonin gene-related peptide (CGRP) in the events occurring in conjunction with subarachnoid hemorrhage (SAH) has been studied in a rat model. Two days after blood injection, the time point at which maximum vasoconstriction is occurring in this model, immunocytochemistry and radioimmunoassay showed a reduction in SP- and CGRP-like immunoreactivity (LI). The quantitative measurements revealed a significant 50% reduction of CGRP-LI and a slight reduction of SP-LI in SAH as compared to controls. This partial reduction in neurotransmitter content (denervation) caused no change in the sensitivity of the rat basilar artery to SP or CGRP as studied using a sensitive in vitro method. However, the maximum relaxant response to CGRP was increased from 52 to 81% ( p < 0.05), while there was no change in the maximum SP-induced relaxations. It is suggested that not only a pre-, but also a postsynaptic modulation of perivascular sensory fibers may occur in experimental SAH.
Effects of Unilateral Lesion of the Nucleus Basalis of Meynert on Brain Glucose Utilization in Callosotomized Baboons: A PET Study
Authors: Yamaguchi Tatsuo , Kunimoto Masayuki , Pappata Sabina , Chavoix Chantal , Brouillet Emmanuel , Riche Danielle , Mazière Mariannick , Naquet Robert , MacKenzie Eric T. , Baron Jean-Claude
Published: April 2011

Prior work has demonstrated that unilateral lesions of the nucleus basalis of Meynert (NbM) in baboons induce a marked reduction in glucose utilization of the ipsilateral cerebral cortex, linearly proportional to the depression in cortical choline acetyltransferase (ChAT) activity achieved. Unexpectedly, there was also marked hypometabolism of the contralateral cerebral cortex, and glucose utilization recovered gradually on both sides despite persistent deficit in cortical ChAT activity. To investigate the role of the corpus callosum (CC) in this bilateral metabolic effect and subsequent recovery, three baboons were subjected to unilateral electrolytic NbM lesion >3 months following section of the anterior CC. Brain glucose utilization was sequentially studied by positron emission tomography; ChAT activity was measured and histological sections obtained after death. In these animals, the NbM lesion also induced significant metabolic depression over the ipsilateral cortex, proportional to the reduction in ChAT activity. Corpus callosotomy did not prevent the contralateral metabolic effects, suggesting that the latter do not normally operate through the CC. However, there was no significant recovery of glucose utilization, suggesting that, following unilateral NbM lesion, the CC normally mediates, at least in part, the recovery of cortical glucose utilization.
Cerebral Blood Flow, Glucose Utilization, Regional Glucose, and ATP Content during the Maturation Period of Delayed Ischemic Injury in Gerbil Brain
Authors: Mies G. , Paschen W. , Hossmann K.-A.
Published: April 2011

Coupling between local perfusion and metabolism was examined in Mongolian gerbils during the development of delayed neuronal death using a combination of double-tracer autoradiography and imaging of local energy state. Animals were anesthetized with 1.5% halothane and forebrain ischemia was produced by occluding both common carotid arteries. After 5 min of ischemia, brains were recirculated for 6 h and 1, 2, or 4 days. At the end of the experiment, regional cerebral blood flow (CBF) and glucose utilization (CMRglc) were determined in identical brain sections with [131I]iodoantipyrine and [14C]deoxyglucose, respectively. Adjacent sections were taken for imaging of ATP and glucose using substratespecific bioluminescence reactions. In the CA1 subfield of control animals, CBF and CMRglc amounted to 81 ± 8 ml 100g−1 min−1 and 69 ± 2 μmol 100 g−1 min-1, respectively, and the calculated CBF/CMRglc ratio was 1.18 ± 0.12 ml/μmol (mean ± SD). After ischemia, the CBF/CMRglc ratio increased to 1.31 ± 0.14, 1.43 ± 0.16, 1.45 ± 0.16, and 1.56 ± 0.18 ml/μmol following 6 h and 1, 2, or 4 days recirculation, respectively. Glucose levels did not change during the 6 h to 4 day recirculation period in the hippocampal CA1 subfield. In the same region, ATP levels were unchanged during 6 h to 2 day postischemic recovery but reduced to about 70% after 4 days of recirculation. The results indicate that a mismatch of the flow-metabolism couple following transient ischemia does not appear to contribute to the postischemic maturation of delayed neuronal death in selectively vulnerable brain regions.
Protective Effect of Nimodipine against Ischemic Neuronal Damage in Rat Hippocampus without Changing Postischemic Cerebral Blood Flow
Authors: Nuglisch Jörg , Karkoutly Chourouk , Mennel Hans Dieter , Roßberg Christine , Krieglstein Josef
Published: April 2011

The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.
Asymmetrical Transport of Amino Acids across the Blood—Brain Barrier in Humans
Authors: Knudsen G. Moos , Pettigrew K. D. , Patlak C. S. , Hertz M. M. , Paulson O. B.
Published: April 2011

Blood–brain barrier permeability to four large neutral and one basic amino acid was studied in 30 patients with the double indicator technique. The resultant 64 venous outflow curves were analyzed by means of two models that take tracer backflux and capillary heterogeneity into account. The first model considers the blood–brain barrier as a double membrane where amino acids from plasma enter the endothelial cell. When an endothelial cell volume of 0.001 ml/g was assumed, permeability from the blood into the endothelial cell was, for most amino acids, about 10–20 times larger than the permeability for the reverse direction. The second model assumes that the amino acids, after intracarotid injection, cross a single membrane barrier and enter a well-mixed compartment, the brain extracellular fluid, i.e., the endothelial cell is assumed to behave as a single membrane. With this model, for large neutral amino acids, the permeability out of the extracellular fluid space back to the blood was between 8 to 12 times higher than the permeability from the blood into the brain. Such a difference in permeabilities across the blood–brain barrier can almost entirely be ascribed to the effect of a nonlinear transport system combined with a relatively small brain amino acid metabolism. The significance of the possible presence of an energy-dependent A system at the abluminal side of the blood–brain barrier is discussed and related to the present findings. For both models, calculation of brain extraction by simple peak extraction values underestimates true unidirectional brain uptake by 17–40%. This raises methodological problems when estimating blood to brain transfer of amino acids with this traditional in vivo method.
Differential Effects of Electrical Stimulation of the Dorsal Raphe Nucleus and of Cervical Sympathectomy on Serotonin and Noradrenaline Concentrations in Major Cerebral Arteries and Pial Vessels in the Rat
Authors: Bonvento G. , Lacombe P. , MacKenzie E. T. , Rouquier L. , Scatton B. , Seylaz J.
Published: April 2011

The levels of noradrenaline (NA), serotonin (5-HT), and 5-hydroxyindoleacetic acid were measured by HPLC and compared between the large arteries of the circle of Willis and the small pial vessels in the rat, following either electrical stimulation of the dorsal raphe nucleus or bilateral superior cervical ganglionectomy. With electrical stimulation, the 5-HT concentrations were reduced (– 48%) in the small pial vessels, but were unchanged in the major cerebral arteries. NA concentrations were dramatically reduced following cervical sympathectomy in the large arteries (– 77%), though the reduction was less pronounced (– 34%) in the small vessels. Sympathectomy caused a significant decrease in the 5-HT concentration of the major cerebral arteries (–33%), but was without effect on the 5-HT levels of the small pial vessels. These results show that an appreciable fraction of the perivascular 5-HT measured in the small pial and the large cerebral arteries originates from different sources.
Postischemic Glucose Metabolism is Modified in the Hippocampal CA1 Region Depleted of Excitatory Input or Pyramidal Cells
Authors: Jørgensen Martin Balslev , Wright Donald C. , Diemer Nils H.
Published: April 2011

During early postischemic reperfusion, the vulnerable brain regions (e.g., hippocampal CA1) show a relatively high deoxyglucose accumulation. To investigate if this accumulation is a marker for the later-occurring regional cell death and to determine its cellular localization, we studied the glucose metabolism in the CA1 region post ischemia after removal of its pre- or postsynaptic components. A 20-min period of cerebral ischemia was used for selective removal of the main postsynaptic component in CA1 pyramidal cells, and a bilateral intraventricular injection of kainic acid for removal of the majority of presynaptic axon terminals in this region (and postsynaptic terminals and cell bodies in CA3). The glucose metabolism was studied in these two lesion types and in sham-operated animals before and after a period of ischemia. There was a 60% reduction of metabolism after ischemia in the nonvulnerable regions, whereas CA1 and sometimes CA3 showed a columnar pattern of high and low metabolism. CA1 and CA3 devoid of the postsynaptic component showed increased postischemic metabolism. The latter was due to the presence of macrophages, as demonstrated by an enzyme histochemical stain for nonspecific esterase. CA1 with no presynaptic component showed a postischemic depression of the glucose metabolism similar to the rest of the brain. It is suggested that the level of the postischemic glucose metabolism in the ischemia-vulnerable regions is determined by the presence of both synaptic components. The presence of macrophages in a region gives rise to apparently normal values of glucose metabolism.
A Semiautomated Method for Measuring Brain Infarct Volume
Authors: Swanson Raymond A. , Morton Matthew T. , Tsao-Wu George , Savalos Robert A. , Davidson Charisse , Sharp Frank R.
Published: April 2011

An accurate, reproducible method for determining the infarct volumes of gray matter structures is presented for use with presently available image analysis systems. Areas of stained sections with optical densities above that of a threshold value are automatically recognized and measured. This eliminates the potential error and bias inherent in manually delineating infarcted regions. Moreover, the volume of surviving normal gray matter is determined rather than that of the infarct. This approach minimizes the error that is introduced by edema, which distorts and enlarges the infarcted tissue and surrounding white matter.
Acute Sympathetic Denervation Does Not Eliminate the Effect of Angiotensin Converting Enzyme Inhibition on CBF Autoregulation in Spontaneously Hypertensive Rats
Authors: Waldemar Gunhild
Published: April 2011

The effect of angiotensin converting enzyme inhibition with captopril (10 mg/kg i.v.) on CBF autoregulation was studied in 16 spontaneously hypertensive rats (8 control and 8 treated with captopril) subjected to acute cervical sympathectomy. CBF was measured repetitively by the intra-arterial 133Xe injection method, during the manipulation of MABP by norepinephrine or hemorrhagic hypotension. Prior to the administration of drugs, baseline MABP was 112 ± 10 mm Hg in the control group and 119 ± 11 mm Hg in the captopril group. Baseline CBF was 99 ± 19 ml/100 g/min, with no difference in the two groups. In agreement with previous findings in rats with intact sympathetic nerves, the lower limit of CBF autoregulation was reduced from the MABP interval of 70–89 to 50–69 mm Hg by captopril.
Effect of γ-Hydroxybutyrate on Local and Global Glucose Metabolism in the Anesthetized Cat Brain
Authors: Haller C. , Mende M. , Schuier F. , Schuh R. , Schröck H. , Kuschinsky W.
Published: April 2011

This study addresses three topics in the chloralose-anesthetized cat: (a) distribution of local CMRglc: values ranging from 5 to 109 μmol/100 g/min were found in 37 brain structures and the mean CMRglc over all examined structures was 30.6 μmol/100 g/min; (b) effect of γ-hydroxybutyrate (GHB, 250 mg/kg i.v.) on local CMRglc, which was significantly ( p < 0.05) depressed in 16 of 37 structures, most prominently in the auditory system, and the mean CMRglc over all structures after GHB was 20.4 μmol/100 g/min; and (c) global values of CMRglc, CMRO2, and CBF before and after GHB: in these experiments, a modified Kety–Schmidt technique was employed measuring saturation/desaturation of inhaled H2 and concentrations of glucose and oxygen in aortic and sagittal sinus blood. CBF and CMRO2 were not altered after GHB, whereas CMRglc was significantly decreased from 35.7 to 28.8 μmol/100 g/min. The values of CMRglc obtained with both techniques (autoradiography and the Kety–Schmidt technique) are concordant, especially when considering the different sampling areas of both methods. The main finding of the present study is a reduction in cerebral glucose consumption after GHB, irrespective of the technique of measurement. This reduction occurs at an unchanged CMRO2 and CBF.
Preischemic Hyperglycemia and Postischemic Alteration of Rat Brain Pyruvate Dehydrogenase Activity
Authors: Lundgren Johan , Cardell Monika , Wieloch Tadeusz , Siesjö Bo K.
Published: April 2011

Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20–25 m M). The results were compared with those obtained in normoglycemic animals (plasma glucose 5–10 m M). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19–25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1–4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC. The relative increase in the fraction of activated PDHC in the early recovery phase in hyperglycemic animals probably reflects either increased intramitochondrial calcium levels or persistent increases in the NADH/NAD and/or ADP/ATP ratios.
Metabolic and Hemodynamic Activation of Postischemic Rat Brain by Cortical Spreading Depression
Authors: Kocher M.
Published: April 2011

Following transient ischemia of the brain, the coupling between somatosensory activation and the hemodynamic-metabolic response is abolished for a certain period despite the partial recovery of somatosensory evoked responses. To determine whether this disturbance is due to alterations of the stimulus-induced neuronal excitation or to a breakdown of the coupling mechanisms, cortical spreading depression was used as a metabolic stimulus in rats before and after ischemia. Adult rats were subjected to 30 min of global forebrain ischemia and 3–6 h of recirculation. EEG, cortical direct current (DC) potential, and laser-Doppler flow were continuously recorded. Local CBF (LCBF), local CMRglc (LCMRglc), regional tissue contents of ATP, glucose, and lactate, and regional pH were determined by quantitative autoradiography, substrate-induced bioluminescence, and fluorometry. Amplitude and frequency of the DC shifts did not differ between groups. In control animals, spreading depression induced a 77% rise in cortical glucose consumption, a 66% rise in lactate content, and a drop in tissue pH of 0.3 unit. ATP and glucose contents were not depleted. During the passage of DC shifts, transient increases (<2 min) in laser-Doppler flow were observed, followed by a post-spreading depression hypoperfusion. A comparable although less expressed pattern of hemodynamic and metabolic changes was observed in the postischemic rats. Although baseline LCMRglc was depressed after ischemia, it was activated 47% during spreading depression. Lactate increased by 26%, pH decreased by 0.3 unit, and ATP and glucose remained unchanged. The extent of the transient increase in laser-Doppler flow did not differ from that of the control group, and a post–spreading depression hypoperfusion was also found. The results demonstrate that the postischemic brain may, although to a lesser degree, cover additional energy demands. The previously observed suppression of functional activation after ischemia is probably caused by both alterations in afferent synaptic transmission and subsequent neuronal excitation and the diminution of the metabolic response to a local stimulus as observed during spreading depression.
Compartmental Analysis of Diprenorphine Binding to Opiate Receptors in the Rat in vivo and its Comparison with Equilibrium Data in vitro
Authors: Cunningham Vincent J. , Hume Susan P. , Price Gary R. , Ahier Randall G. , Cremer Jill E. , Jones Anthony K. P.
Published: April 2011

The regional binding of the opiate receptor ligand diprenorphine has been examined in rat brain both in vivo and in vitro. The time course of total label in specific brain regions was followed up to 2 h after intravenous bolus injection of [3H]diprenorphine, with or without a pulse chase of unlabelled diprenorphine at 30 min. In addition, total label was measured 30 min after injection of labelled diprenorphine at nontracer concentrations over a range of specific activities. Total data sets for each region were fitted simultaneously to a compartmental model to give estimates of maximal binding capacity (Bmax), the second-order apparent association rate constant, and the first-order dissociation rate constant of the receptor-ligand complex. The model incorporated the use of a reference region with low specific binding (cerebellum). The binding of diprenorphine to rat brain homogenates was measured in vitro under equilibrium conditions at 37°C, pH 7.4, in the presence and absence of naloxone, to give corresponding regional estimates of Bmax and the half-saturation constant Kd The results showed a close correlation between in vitro and in vivo regional estimates of Bmax over a wide range. There were no significant interregional differences either in Kd in vitro or in the Kd derived from the in vivo analysis, although in vitro and in vivo estimates differed by an order of magnitude. This work was carried out as part of a validation study with a view to the application of the compartmental model to data obtained in vivo in humans using positron emission tomography, when successive studies over a range of specific activities are not feasible. Restriction of the rat data to tracer alone and pulse chase protocols showed that the compartmental model gave regional estimates of the combined forward rate constant consistent with estimates obtained using the complete data set.
Postischemic Canine Cerebral Blood Flow is Coupled to Cerebral Metabolic Rate
Authors: Michenfelder John D. , Milde James H. , Katušić Zvonimir S.
Published: April 2011

Following complete global cerebral ischemia and reperfusion, a brief period of reactive hyperemia is followed by a prolonged period of low flow commonly referred to as the delayed postischemic hypoperfusion state. It is generally assumed that this low-flow state may be injurious because of inadequate substrate delivery, thus implying that flow is no longer coupled to metabolic needs. This relationship of CBF to CMRO2 was examined in six anesthetized dogs that were subjected to 12 min of complete ischemia induced either by CSF compression or aortic occlusion. Following reperfusion and onset of the low-flow state, which stabilized at 45 min postischemia, control normothermic (37°C) measurements of CBF and CMRO2 were determined. Thereafter, femoral arterial blood was circulated through a heat exchanger (42.5°C), and brain temperature was increased to 40°C and measurements were repeated. The brain was then cooled back to 37°C for a final set of normothermic measurements. Thereafter, brain biopsies were taken to determine the energy state of the brain. CMRO2 changed ∼6%/°C. CBF paralleled the change in CMRO2. Accordingly, the ratio of CBF to CMRO2 remained constant throughout at a value of 8 to 9, demonstrating maintained coupling. The brain energy state was normal at the end of the study. The authors conclude that postischemic CBF is modulated by the brain's metabolic needs.
Heat Shock Protein hsp72 Induction in Cortical and Striatal Astrocytes and Neurons following Infarction
Authors: Sharp Frank R. , Lowenstein Daniel , Simon Roger , Hisanaga Kinya
Published: April 2011

Transient global and transient focal ischemia induced the 72 kDa heat shock protein (hsp72) in neurons in cortex, striatum, and other regions known to be injured during transient ischemia. A novel finding was the induction of hsp72 in islands (cylinders in three dimensions) of cells composed of astrocytes around the perimeter and neurons in the interior. Since histology showed pale staining in these regions, it is proposed that these islands represent areas of focal infarction in the distribution of small cortical and lenticulostriate arteries. Although the factors responsible for hsp72 induction during ischemia and infarction are unknown, these results suggest differences in mechanisms of hsp72 induction in astrocytes compared to neurons.