bluuebunny/crossref_metadata_2025 huggingface dataset:
A Relationship between Metabolism in Frontal Lobes and Cerebellum in Normal Subjects Studied with PET
Authors: Junck Larry , Gilman Sid , Rothley Jill R. , Betley Annette T. , Koeppe Robert A. , Hichwa Richard D.
Published: April 2011

Lesions of one cerebral hemisphere are associated with decreased glucose metabolism, oxygen metabolism, and blood flow in the contralateral cerebellar hemisphere. We used positron emission tomography to look for a functional relationship in cerebral metabolism between the cerebral cortex and the contralateral cerebellum in normal human subjects. Twenty-four normal subjects were scanned with [18F]fluoro-2-deoxy-D-glucose while in a resting state. Asymmetry in local CMRglu (LCMRglu) in the frontal cortex was strongly correlated with asymmetry in LCMRglu in the opposite direction in the cerebellar hemispheres ( r = −0.60, p < 0.001). Widespread subregions of the frontal cortex were found to contribute to this relationship. Considering these results together with previous studies demonstrating that frontal lesions are associated with decreased metabolism in the contralateral cerebellum, we conclude that the frontal cortex exerts a strong modulating influence on metabolism in the contralateral cerebellum in normal subjects, and that this influence may be asymmetrical.
Calcium Uptake Evoked by Electrical Stimulation is Enhanced Postischemically and Precedes Delayed Neuronal Death in CA1 of Rat Hippocampus: Involvement of N-Methyl-D-Aspartate Receptors
Authors: Andiné Peter , Jacobson Ingemar , Hagberg Henrik
Published: April 2011

Extracellular calcium concentration changes in the CA1 of the hippocampus during burst activity were measured during postischemic reflow, and the involvement of N-methyl-D-aspartate (NMDA) receptors was evaluated, In adult Wistar rats global ischemia was induced by four-vessel occlusion for 20 min, After 6 h of postischemic reflow, the animals were halothane-anesthetized and reintubated, A double-barrelled calcium-sensitive microelectrode was advanced through stratum oriens, pyramidale, and radiatum in 50-μm steps. At each step the perforant pathway was stimulated (15 Hz, 30 s), and changes in extracellular calcium concentration were recorded. High-frequency stimulation elicited burst firing and transient decreases in extracellular calcium concentration, which are interpreted as neuronal calcium uptake. In control hippocampus, the extracellular calcium decreases were maximal in the stratum pyramidale. Six to eight hours after ischemia, a threefold enhancement of extracellular calcium decreases was found in the dendritic layers of the CA1. The NMDA-receptor antagonist ketamine (15–30 mg/kg intraperitoneally) reduced these electrically evoked calcium decreases. Seven days after ischemia, there was a 60–90% loss of pyramidal cells in the CA1. In conclusion, the cellular calcium uptake, possibly through NMDA receptors evoked by neuronal activity, is enhanced during early postischemia and precedes delayed neuronal death.
The Effects of Dipyridamole and Theophylline on Rat Pial Vessels during Hypocarbia
Authors: Ibayashi Setsuro , Ngai Al C. , Meno Joseph R. , Winn H. Richard
Published: April 2011

Hypocarbia results in an increase in brain adenosine concentrations, presumably because of brain hypoxia associated with hypocarbic vasoconstriction. It was hypothesized that adenosine limits the degree of hypocarbic vasoconstriction. To test this hypothesis, the effects of dipyridamole and theophylline on CO2 reactivity during hypocarbia were investigated in anesthetized rats. Dipyridamole should reduce the vasoconstriction by potentiating adenosine action, whereas theophylline should increase the vasoconstriction by blocking adenosine receptors. Cortical pial arterioles of mechanically ventilated and anesthetized rats were displayed on a video monitor system through a closed cranial window. Arterial blood pressure and oxygen tension were stable. CO2 reactivity, formulated as 100 x [Δ diameter (μm)/resting diameter (μm)]/Δ PaCO2 (mmHg), in the hypocarbic phase was calculated before and after topical superfusion of dipyridamole (10−6 M; n = 7) and theophylline (5 × 10−5 M; n = 6). CO2 reactivity was significantly decreased after superfusion of dipyridamole (0.57 ± 0.08; mean ± SEM) as compared with mock cerebrospinal fluid (CSF) (0.97 ± 0.17, p < 0.05, n = 7). On the other hand, CO2 reactivity after superfusion of theophylline was increased (1.63 ± 0.28) as compared with mock CSF (1.00 ± 0.20, p < 0.05, n = 6), indicating that adenosine is involved in hypocarbic vasoconstriction.
Ornithine Decarboxylase Activity and Immunohistochemical Location in Postischemic Brain
Authors: Dempsey Robert J. , Maley Bruce E. , Cowen David , Olson Jack W.
Published: April 2011

Ornithine decarboxylase, rate-limiting in polyamine formation, has been found to be necessary for the development of vasogenic edema after cryogenic cerebral injury and is postulated to be of importance in late ischemic brain edema formation. Ornithine decarboxylase activity and accompanying edema was studied after transient cerebral ischemia in Mongolian gerbils. Bilateral carotid artery occlusion was utilized to produce dense forebrain ischemia. After 4 h of reperfusion a significant elevation in ornithine decarboxylase activity was present (72.5 ± 24.7 vs 8.5 ± 2 pmoles/mg protein/h, p < 0.05). Immunohistochemical localization of ornithine decarboxylase indicated its presence in cortical neurons of ischemic gerbils. This was typically located in the perinuclear cytoplasm and extended into proximal dendrites. Nonischemic animals did not contain ornithine decarboxylase immunoreactivity. These studies show the presence and location of ornithine decarboxylase in cerebral tissue sUbjected to transient ischemia. The increase in this marker of polyamine activity paralleled previous studies in this model of cerebral edema formation and reperfusion deficit in blood flow and evoked potential, suggesting that ornithine decarboxylase is a marker for and may be associated with those late metabolic events leading to progressive functional deterioration after incomplete cerebral ischemia.
Absence of N-Methyl-D-Aspartate Receptors on Ovine Cerebral Microvessels
Authors: Beart P. M. , Sheehan K-A. M. , Manallack D. T.
Published: April 2011

Radioreceptor methods were used to quantitate the N-methyl-D-aspartate (NMDA) receptor-complex of ovine cerebral microvessels and cerebral gray matter. Specific binding of D[3H]2-amino-5-phosphonopentanoate and [3H]1-[1-(2-thienyl)cyclohexyl]piperidine, ligands for the NMDA primary acceptor site and ionophore, respectively, was found in cerebral gray matter but was not detectable in membranes prepared from brain microvessels enriched in capillaries. Sigma receptors, another locus of action for phencyclidine congeners, were also not present on microvessels but were found in cortical homogenates. On the other hand, cerebral microvessels and gray matter contained significant numbers of β-adrenoceptors. Our results indicate the NMDA receptors and NMDA antagonists are unlikely to regulate the function of the cerebral microvasculature.
Simple Staining for Heat-Fixed Brain Sections after Topographical pH Analysis or Autoradiographic Studies
Authors: Parkinson N. A. , Christofi G. , Obrenovitch T. P. , Symon L.
Published: April 2011

Powerful topographic techniques are now available, among which autoradiographic and fluorescent mapping are the most prevalent. These techniques produce images that usually do not correlate with brain anatomy; subsequent staining is required to allow a precise association between the parameter(s) investigated and brain structures. A simple staining procedure is described, compatible with heat-fixed brain sections, and that was found particularly valuable in association with topographical tissue pH studies using the fluorescent pH indicator umbelliferone.
Intravascular Streaming and Variable Delivery to Brain following Carotid Artery Infusions in the Sprague-Dawley Rat
Authors: Saris Stephen C. , Wright Donald C. , Oldfield Edward H. , Blasberg Ronald G.
Published: April 2011

Intracarotid artery infusions in animals are commonly performed in studies of the blood–brain barrier and in chemotherapy trials. Implicit in the analysis of these experiments is that the infusate will be distributed to the territory of the internal carotid artery in a manner that is proportional to blood flow. Fifteen Sprague-Dawley rats were studied to determine if poor infusate mixing with blood due to intravascular streaming occurred during intracarotid artery drug infusions and if it could be eliminated with fast retrograde infusion. In three experimental groups, a radiolabeled flow tracer—14C-iodoantipyrine (IAP)—was infused retrograde through the external carotid artery into the common carotid artery at slow, medium, and fast rates (0.45, 1.5, and 5.0 ml/min). In a control group, IAP was injected intravenously (i.v.). Local isotope concentrations in the brain were determined by quantitative autoradiography, and the variability of isotope delivery was assessed in the frontoparietal cortex, temporal cortex, and caudate putamen of all animals. Streaming phenomena were manifest in all selected anatomic areas after the slow and medium rates of intraarterial infusion. After fast intracarotid infusion or i.v. injection, there was uniform distribution of isotope in the same brain regions.
Measurement of Local Cerebral Blood Flow with [14C]Iodoantipyrine in the Mouse
Authors: Jay Therese M. , Lucignani Giovanni , Crane Alison M. , Jehle Jane , Sokoloff Louis
Published: April 2011

Local cerebral blood flow was measured in the mouse by means of the [14C]iodoantipyrine method. This method has been previously used in the monkey, dog, cat, and rat, but its application to small mammals such as the mouse requires special attention to potential sources of error. The small size of the mouse brain requires special attention to the rapid removal and freezing of the brain to minimize effects of postmortem diffusion of tracer in the tissue. Because of the relatively low diameter/length ratios of the catheters needed for arterial sampling in small animals, substantial errors can occur in the determination of the time course of the [14C]iodoantipyrine concentration in the arterial blood unless corrections for lag time and dead space washout in the catheter are properly applied. Local cerebral blood flow was measured in seven awake mice with appropriate care to minimize these sources of error. The values were found to vary from 48 ml/100 g/min in the corpus callosum to 198 ml/100 g/min in the inferior colliculus. The results demonstrate that the [14C]iodoantipyrine method can be used to measure local cerebral blood flow in the mouse and that the values in that species are, in general, somewhat higher than those in the rat.
Initial Cerebral HM-PAO Distribution Compared to LCBF: Use of a Model Which Considers Cerebral HM-PAO Trapping Kinetics
Authors: Lear James L.
Published: April 2011

The cerebral uptake of [99mTc]– d,l-hexamethylpropyleneamine oxime complex (HM-PAO) was compared to LCBF determined simultaneously with [14C]iodoantipyrine (IAP) using double radionuclide quantitative digital autoradiography. Awake male rats were given intravenous injections of a mixture of 50 μCi IAP and 15 mCi of HM-PAO and killed 20 s after tracer activity had first reached the brain. Two separate autoradiograms were produced from each 20 μm brain section. The autoradiograms were digitized, corrected for cross-contamination, and then converted into images of individual tracer concentration. The diffusible tracer model was used to convert the IAP concentration images into LCBF images. Regional HM-PAO concentration was found not to be linearly related to LCBF as determined with the IAP, and therefore a simple microsphere type model was inadequate in relating HM-PAO uptake to LCBF. A better HM-PAO uptake–LCBF correlation was obtained when the HM-PAO arterial input function was corrected for very rapidly produced, non-cerebrally extracted, metabolites and a kinetic model was used that considered the rate of intracerebral metabolism of HM-PAO to a retained metabolite. Even using this model, however, some differences between HM-PAO uptake and LCBF occurred in certain brain regions. Because these differences were small and the HM-PAO uptake pattern has been shown to be constant for many minutes, HM-PAO can probably be used to estimate LCBF in patients with single positron emission computed tomography (SPECT) imaging.
Retention of [99mTc]-d,l-HM-PAO in Rat Brain: An Autoradiographic Study
Authors: Hoffman Timothy J. , Corlija Melvin , Chaplin Susan B. , Volkert Wynn A. , Holmes Richard A.
Published: April 2011

The regional cerebral distribution pattern of [99mTc]- d,l-HM-PAO in rat brain was studied by autoradiography. The regional cerebral uptake of this tracer is related to regional cerebral blood flow (rCBF); however, the ratio of retained radioactivity (determined by digital imaging techniques) in gray matter compared to white matter is lower than that reported for the blood flow ratio. Considerable inhomogeneity is observed in cortical gray matter for at least 60 min postinjection, demonstrating that minimal, if any, cerebral redistribution of this agent occurs.
High Energy Phosphate Metabolism in Experimental Permanent Focal Cerebral Ischemia: An in vivo 31P Magnetic Resonance Spectroscopy Study
Authors: Germano Isabelle M. , Pitts Lawrence H. , Berry Isabelle , de Armond Stephen J.
Published: April 2011

Relative levels of phosphate metabolites in the brain were examined in vivo by 31P magnetic resonance spectroscopy (MRS) in 50 Sprague-Dawley rats before, during, and after induction of focal permanent cerebral ischemia. After acquisition of baseline spectra, rats were subjected to injury within the core of the MR spectrometer, and 31P spectra were collected for 60 min after injury: in 7 rats, permanent, acute focal cerebral ischemia was induced (ischemia group); in 6 rats, mild hypoxia (FiO2 14%) was induced at the time of the ischemic insult and was maintained for 20 min (ischemia-hypoxia group); in 6 rats, mild hypoxia (FiO2 14%) only was induced for 20 min (hypoxia group). Control studies were performed in 25 rats. Cerebral intracellular pH, calculated from the chemical shift of inorganic phosphate (Pi), decreased immediately after injury in the ischemia and ischemia-hypoxia groups. The first 31P spectrum obtained after injury was characterized by an increase in Pi and a decrease in phosphocreatine (PCr) in the ischemia and ischemia-hypoxia groups; these changes in spectra were significantly greater in the ischemia-hypoxia group. No significant changes in adenosine triphosphate (ATP) were found in either group. Within 60 min of occlusion, 31P spectra returned toward baseline spectra in both ischemia-hypoxia and ischemia groups. No significant changes were seen in spectra of rats subjected to hypoxia alone. These results confirm that 31P MRS is a sensitive measure of early changes of high energy metabolites in focal cerebral ischemia. The return of spectra toward baseline values within 1 h of injury despite the presence of permanent ischemic damage, however, suggests that caution should be used in attempts to interpret “recovery” of 31P MRS.
Stability of Arterial Concentrations during Continuous Inhalation of C15O2 and 15O2 and the Effects on Computed Values of CBF and CMRO2
Authors: Lammertsma Adriaan A. , Correia John A. , Jones Terry
Published: April 2011

Stability of arterial whole blood and plasma concentrations is a basic requirement in the application of the oxygen-15 (15O2) steady-state inhalation technique for measuring regional cerebral blood flow and oxygen use. The level of stability obtainable in practice is reported in the form of retrospectively analysed blood data from 626 consecutive studies in patients with a range of clinical conditions. Serial arterial whole blood and plasma concentrations were measured during both C15O2 and 15O2 inhalations, and coefficients of variation were calculated. In addition, these concentrations were compared with the corresponding values recorded at the start of each study and maximum variations were calculated. For all four concentrations, mean and median coefficients of variation were around 5 and 4%, respectively. Mean and median maximum variations were around 9 and 7%, respectively. The effects of these variations on the calculations of regional cerebral blood flow, oxygen extraction, and oxygen use were estimated. Mean expected errors were found to be between 4 and 9%, and median expected errors between 3 and 6%. Inherent blood sampling errors were assessed from blood volume studies using 11CO-labeled red cells. These errors were found to be <3%.
Prevention of Ischemic and Postischemic Brain Edema by a Novel Calcium Antagonist (PN200-110)
Authors: Abe Koji , Kogure Kyuya , Watanabe Takao
Published: April 2011

The effect of PN200-110, a novel calcium antagonist, on the formation of brain edema was examined with rats using a middle cerebral artery (MCA) occlusion model. PN200-110 was effective in preventing the formation of brain edema in 6-h ischemia and in 3-h reperfusion following 3-h ischemia, which were cases in which great accumulations of calcium were autoradiographically observed. Furthermore, PN200-110 diminished the excessive accumulation of calcium in the MCA area involved. These results indicate that an inhibition of the massive influx of calcium into brain cells by PN200-110 may partially ameliorate cell damage, resulting in prevention of brain edema.
Functional Activation of Cerebral Blood Flow and Metabolism before and after Global Ischemia of Rat Brain
Authors: Ueki M. , Linn F. , Hossmann K.-A.
Published: April 2011

The effect of somatosensory stimulation on the local CBF (LCBF), CMRglu (LCMRglu), tissue pH, and tissue content of ATP, glucose, and lactate was studied in chloralose-anesthetized rats before and after 30 min of near-complete forebrain ischemia. In nonischemic rats LCBF in primary somatosensory cortex increased by 33%, LCMRglu increased by 55%, tissue glucose content decreased by 21%, and lactate increased by 30%. Local ATP and tissue pH did not change. Functional activation of the intact chloralose-anesthetized rat, in consequence, is associated with the stimulation of “aerobic” glycolysis but does not result in disturbances of energy or acid-base homeostasis. After 30-min ischemia and 3-h recirculation, somatosensory stimulation did not evoke any metabolic or hemodynamic alterations, although EEG and primary somatosensory evoked potentials recovered. The maintenance of normal energy state despite constant metabolic rate suggests that the postischemic generation of evoked potentials does not require measurable amounts of energy. Stimulation of glycolysis in the intact animal, therefore, may serve other purposes than fueling the energy requirements of evoked cortical activity.
Regional Cerebral Glucose Utilization Transiently Increases during Mild Hypoxia
Authors: MacNeill Colin , Bryan Robert M.
Published: April 2011

Regional cerebral glucose utilization (rCMRglu) was studied during mild hypoxic hypoxia in awake free-ranging rats. Rats were prepared with chronic arterial and venous catheters and placed in individual chambers for 4 days to recover from surgery before the experiments. The catheters were accessible by passing them through the top of the chambers. Hypoxia was induced by filling the chambers with a gas mixture consisting of 11% o2 in a balance of N2. Regional CMRglu and physiological parameters were measured in normoxic controls and in rats that had been hypoxic for 2 and 17 min before beginning the measurements. Regional CMRglu was measured in 17 brain regions using [6-14C]glucose. Pao2 decreased from 88 mm Hg in the controls to ∼40 mm Hg during hypoxia. In the early stages of hypoxia (2–12 min), rCMRglu increased ∼10–25% above the control rates. In later stages of hypoxia (17–27 min), rCMRglu was not different from that in the normoxic controls. The increase in rCMRglu in the early hypoxia was not blocked by propranolol (1.4 mg/kg), indicating that beta-adrenergic receptors were not involved with the increase in rCMRglu. It was concluded that mild hypoxia is associated with an increased rate of cerebral glucose utilization; however, the increase is transitory, with glucose utilization returning to control rates before 17 min.
Reproducibility of Cerebral Glucose Metabolic Measurements in Resting Human Subjects
Authors: Bartlett Elsa J. , Brodie Jonathan D. , Wolf Alfred P. , Christman David R. , Laska Eugene , Meissner Morris
Published: April 2011

Positron emission tomography with 11C-2-deoxyglucose was used to determine the test-retest variability of regional cerebral glucose metabolism in 22 young normal right-handed men scanned twice in a 24-h period under baseline (resting) conditions. To assess the effects of scan order and time of day on variability, 12 subjects were scanned in the morning and afternoon of the same day (a.m.-p.m.) and 10 in the reverse order (p.m.-a.m.) with a night in between. The effect of anxiety on metabolism was also assessed. Seventy-three percent of the total subject group showed changes in whole brain metabolism from the first to the second measurement of 10% or less, with comparable changes in various cortical and subcortical regions. When a scaling factor was used to equate the whole brain metabolism in the two scans for each individual, the resulting average regional changes for each group were no mote than 1%. This suggests that the proportion of the whole brain metabolism utilized regionally is stable in a group of subjects over time. Both groups of subjects had lower morning than afternoon metabolism, but the differences were slight in the p.m.-a.m. group. One measure of anxiety (pulse at fun 1) was correlated with run 1 metabolism and with the percentage of change from run 1 to run 2. No significant run 2 correlations were observed. This is the first study to measure test-retest variability in cerebral glucose metabolism in a large sample of young normal subjects. It demonstrates that the deoxyglucose method yields low Intrasubject variability and high stability over a 24-h period.
Accumulation of Calcium and Loss of Potassium in the Hippocampus following Transient Cerebral Ischemia: A Proton Microprobe Study
Authors: Martins Eduardo , Inamura Kenji , Themner Klas , Malmqvist Klas G. , Siesjö Bo K.
Published: April 2011

This study explored (a) whether postischemic accumulation of calcium in hippocampal neurons precedes or occurs pari passu with light microscopical signs of delayed neuronal necrosis, and (b) whether calcium initially accumulates in dendritic domains, presumed to have a high density of agonist-operated calcium channels. Transient ischemia of 10-min duration was induced in rats, and the animals were studied after 1, 2, 3, and 4 days of recovery. We measured total calcium and potassium contents in the stratum oriens, pyramidale, radiatum, and moleculare of the CA1 and CA3 sectors, using particle induced x-ray emission (PIXE) in the proton microprobe mode. The results showed significant accumulation of calcium and loss of potassium after 3 and 4 days of recovery in the CA1 sector, which developed neuronal necrosis, but not in the CA3 sector, which showed only occasional damage. In a few animals, calcium accumulation (and loss of potassium) was observed with no or only mild visible damage, but in the majority of animals the accumulation of calcium correlated to signs of neuronal necrosis. Since calcium accumulation was similar in all strata examined, the results failed to reveal preferential accumulation in dendritic or somal regions. Based on our results and those of Dux et al., we emphasize the possibility that delayed neuronal death is, at least in part, caused by increased calcium cycling of plasma membranes and gradual calcium overload of mitochondria.
Transient Blood-Brain Barrier Permeability following Profound Temporary Global Ischaemia: An Experimental Study Using 14C-AIB
Authors: Dobbin Jonathan , Crockard H. Alan , Ross-Russell Ralph
Published: April 2011

The influence of reperfusion after profound incomplete forebrain ischaemia on blood–brain barrier (BBB) permeability to a small protein tracer was studied in male Sprague-Dawley rats, The mean cortical blood to brain transfer constant ( Ki) for 14C-amino isobutyric acid (AIB) was significantly greater at 3 and 6 h of reperfusion, 2.5 times the mean values of controls (p < 0.05) (2.5 μl g−1 min−1 and 1.0 μl g−1 min−1 respectively), but had returned to control values after reperfusion for 24 h. Analysis of distribution of Ki values showed that following 15 min and 30 min of profound ischaemia, there was a significant increase in transfer of AIB across the blood–brain barrier (BBB) after recirculation for up to 6 h, though there was no evidence of protein extravasation as assessed by Evans Blue (EB) dye. After 24 h of reperfusion, the BBB to AIB was restored, and Ki values had returned to control values. It is concluded that following transient global ischaemia, the BBB may recover rapidly.
3-(2'-[18F]Fluoroethyl)Spiperone: In vivo Biochemical and Kinetic Characterization in Rodents, Nonhuman Primates, and Humans
Authors: Barrio Jorge R. , Satyamurthy Nagichettiar , Huang Sung-Cheng , Keen Randy E. , Nissenson Charna H. K. , Hoffman John M. , Ackermann Robert F. , Bahn Mark M. , Mazziotta John C. , Phelps Michael E.
Published: April 2011

3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50 = 1.5 n M) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1–10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 μg/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (∼90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat > monkey > human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET.
Evaluation of the 11CO2 Positron Emission Tomographic Method for Measuring Brain pH. II. Quantitative pH Mapping in Patients with Ischemic Cerebrovascular Diseases
Authors: Senda Michio , Alpert Nathaniel M. , Mackay Bruce C. , Buxton Richard B. , Correia John A. , Weise Steven B. , Ackerman Robert H. , Dorer David , Buonanno Ferdinando S.
Published: April 2011

A practical method has been developed that, using 11CO2 and positron emission tomography (PET), computes and maps (a) “effective pH” (pHt), a weighted average of intra- and extracellular pH, and (b) “clearance” ( K1), product of blood flow and 11CO2 extraction. This method, together with measurements of cerebral blood flow (CBF) and oxygen extraction fraction (OEF), was applied to 12 patients with cerebral ischemia or stroke. The regional K1 was positively correlated with CBF ( n = +0.78). The k1/CBF ratio, representing the extraction fraction ratio of 11CO2 to H215O, was negatively correlated with CBF ( r = –0.54), suggesting that 11CO2 extraction decreases as flow increases. In five acute stroke patients within 2 days of onset, the injured cortex had lower CBF (20.6 ml/min/100 g), higher OEF (78.1%), and lower pHt (6.96) than the contralateral cortex (CBF = 41.4 ml/min/100 g, OEF = 53.3%, pHt = 7.00), suggesting intracellular acidosis with intact cell membranes. In three stroke patients 5–8 days after onset, the injured cortex had higher CBF (60.9 ml/min/100 g), lower OEF (32.0%), and higher pHt (7.12) than the contralateral cortex (CBF = 45.3 ml/min/100 g, OEF = 58.0%, pHt = 7.06), which suggested an increase in extracellular volume compartment reflecting loss of cell membrane integrity. This method provides information on the regional tissue acid–base status and cell membrane integrity, which may be prognostic of tissue viability.
Measurement of Blood—Brain Hexose Transport with Dynamic PET: Comparison of [18F]2-Fluoro-2-Deoxyglucose and [11C]O-Methylglucose
Authors: Herholz K. , Wienhard K. , Pietrzyk U. , Pawlik G. , Heiss W.-D.
Published: April 2011

Blood-to-tissue transport of [18F]2-fluoro-2-deoxyglucose (FDG) and [11C]O-methylglucose (CMG) was compared by dynamic positron emission tomography in four patients with recent ischemic infarcts and in three patients with intracerebral tumors. Local blood volume, tracer transport from tissue to blood, and FDG phosphorylation rates were also determined. A regional analysis of parametric images showed a close correlation of FDG and CMG transport rate constants in pathological tissue. Transport rates of FDG and CMG showed correspondingly less asymmetric remote effects than FDG phosphorylation rates. Transport rate constants were consistently higher for FDG than for CMG in pathological and normal tissue, in accordance with the higher affinity of carrier enzymes to FDG. There was a significant correlation between fitted regional blood volume values and correspondence of average absolute values with both tracers. It is concluded that dynamic FDG PET for measurement of cerebral glucose metabolism is also useful to measure alterations of hexose transport and local blood volume in pathological tissue.
Effects of Traumatic Brain Injury on Regional Cerebral Blood Flow in Rats as Measured with Radiolabeled Microspheres
Authors: Yamakami Iwao , McIntosh Tracy K.
Published: April 2011

To clarify the effect of experimental brain injury on regional CBF (rCBF), repeated rCBF measurements were performed using radiolabeled microspheres in rats Subjected to fluid-percussion traumatic brain injury. Three consecutive microsphere injections in six uninjured control rats substantiated that the procedure induces no significant changes in hemodynamic variables or rCBF. Animals were subjected to left parietal fluid-percussion brain injury of moderate severity (2.1–2.4 atm) and rCBF values were determined (a) prior to injury and 15 min and 1 h following injury (n = 7); and (b) prior to injury and 30 min and 2 h following injury (n = 7). At 15 min post injury, there was a profound reduction of rCBF in all brain regions studied (p < 0.01). Although rCBF in the hindbrain had recovered to near-normal by 30 min post injury, rCBF in both injured and contralateral (uninjured) forebrain areas remained significantly suppressed up to 1 h post injury. At 2 h post injury, recovery of rCBF to near-normal values was observed in all brain regions except the focal area of injury (left parietal cortex) where rCBF remained significantly depressed (p < 0.01). This prolonged focal oligemia at the injury site was associated with the development of reproducible cystic necrosis in the left parietotemporal cortex at 4 weeks post injury. Our results demonstrate that acute changes in rCBF occur following experimental traumatic brain injury in rats and that rCBF remains significantly depressed up to 2 h post injury in the area circumscribing the trauma site.
Cerebral Superoxide Anion Generation during Seizures in Newborn Pigs
Authors: Armstead W. M. , Mirro R. , Leffler C. W. , Busija D. W.
Published: April 2011

Cerebral superoxide anion generation during bicuculline-induced seizures was measured in newborn pigs. Using two closed cranial windows inserted over the parietal cortices, superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined during 20 min of seizure activity induced by bicuculline, 5 mg/kg i. v. A modest increase in SOD-inhibitable NBT reduction was observed in piglets subjected to bicuculline-induced seizure activity (2.4 ± 0.6 pmol/mm2 in 20 min) when compared to control piglets (0.4 ± 0.3 pmol/mm2 in 20 min). Pretreatment with indomethacin (5 mg/kg i.v.) reduced SOD-inhibitable NBT reduction during seizures to the control level (0.5 ± 0.4 pmol/mm2 in 20 min). We conclude that small quantities of superoxide anion radical are produced by newborn pig brain during bicuculline-induced seizures and that cyclooxygenase metabolism of arachidonic acid appears to be a major source.
Alterations in Serotonin and Neuropeptide Y Content of Cerebrovascular Sympathetic Nerves following Experimental Subarachnoid Hemorrhage
Authors: Jackowski A. , Crockard A. , Burnstock G. , Lincoln J.
Published: April 2011

The effect of an experimental subarachnoid hemorrhage (SAH) upon neurotransmitter content in sympathetic nerves supplying the major cerebral arteries of the rat has been examined by immunohistochemical analysis and high performance liquid chromatography with electrochemical detection (HPLC–ECD). In particular, changes that occur in sympathetic nerve content of the vasoconstrictor agents serotonin (5-HT) and neuropeptide Y (NPY), which are colocalized with noradrenaline, were assessed. Subarachnoid hemorrhage was induced by a single injection of autologous arterial blood into the cerebrospinal fluid (CSF) space of the cisterna magna. The density of 5-HT-containing and NPY-containing perivascular nerve fibers per unit area of vessels was measured at defined intervals from 15 min to 5 days post-SAH. In addition, an HPLC study was performed to quantify the actual amounts of 5-HT and noradrenaline present in circle of Willis vessels at 3 h post-SAH. Comparison was made with sham-operated animals and animals that received a cisternal injection of buffered saline in place of blood. Our results reveal a major increase in cerebrovascular sympathetic nerve content of serotonin, arising by uptake, presumably from subarachnoid blood clot, within the first 3 h post-SAH. Neuropeptide Y content, however, decreased from 3 up to 48 h posthemorrhage. By 3 days post-SAH, when the majority of subarachnoid clot had resorbed, the sympathetic nerve content of both NPY and 5-HT was restored to normal. This pattern of change was not observed in either sham-operated or saline-injected controls.
Refinement of the Kinetic Model of the 2-[14C]Deoxyglucose Method to Incorporate Effects of Intracellular Compartmentation in Brain
Authors: Schmidt K. , Lucignani G. , Mori K. , Jay T. , Palombo E. , Nelson T. , Pettigrew K. , Holden J. E. , Sokoloff L.
Published: April 2011

A translocase to transport hexose phosphate formed in the cytosol into the cisterns of the endoplasmic reticulum, where the phosphatase resides, is absent in brain (Fishman and Karnovsky, 1986). 2-Deoxyglucose-6-phosphate (DG-6-P) may therefore have limited access to glucose-6-phosphatase (G-6-Pase), and transport of the DG-6-P across the endoplasmic reticular membrane may be rate limiting to its dephosphorylation. To take this compartmentation into account, a five-rate constant (5K) model was developed to describe the kinetic behavior of 2-deoxyglucose (DG) and its phosphorylated product in brain. Loss of DG-6-P was modeled as a two-step process: (a) transfer of DG-6-P from the cytosol into the cisterns of the endoplasmic reticulum; (b) hydrolysis of DG-6-P by G-6-Pase and subsequent return of the free DG to the precursor pool. Local CMRglc (LCMRglc) was calculated in the rat on the basis of this model and compared with values calculated on the basis of the three-rate constant (3K) and the four–rate constant (4K) models of the DG method. The results show that under normal physiological conditions all three models yield values of LCMRglc that are essentially equivalent for experimental periods between 25 and 45 min. Therefore, the simplest model, the 3K model, is sufficient. For experimental periods from 60 to 120 min, the 4K and 5K models do not correct completely for loss of product, but the 5K model does yield estimates of LCMRglc that are closer to the values at 45 min than those obtained with the 3K and 4K models.
Direct Chemical Measurement of the λ of the Lumped Constant of the [14C]Deoxyglucose Method in Rat Brain: Effects of Arterial Plasma Glucose Level on the Distribution Spaces of [14C]Deoxyglucose and Glucose and on λ
Authors: Mori Kentaro , Cruz Nancy , Dienel Gerald , Nelson Thomas , Sokoloff Louis
Published: April 2011

The lumped constant in the operational equation of the 2-[14C]deoxyglucose (DG) method contains the factor λ that represents the ratio of the steady-state tissue distribution spaces for [14C]DG and glucose. The lumped constant has been shown to vary with arterial plasma glucose concentration. Predictions based mainly on theoretical grounds have suggested that disproportionate changes in the distribution spaces for [14C]DG and glucose and in the value of λ are responsible for these variations in the lumped constant. The influence of arterial plasma glucose concentration on the distribution spaces for DG and glucose and on λ were, therefore, determined in the present studies by direct chemical measurements. The brain was maintained in steady states of delivery and metabolism of DG and glucose by programmed intravenous infusions of both hexoses designed to produce and maintain constant arterial concentrations. Hexose concentrations were assayed in acid extracts of arterial plasma and freeze-blown brain. Graded hyperglycemia up to 28 m M produced progressive decreases in the distribution spaces of both hexoses from their normoglycemic values (e.g., ∼ – 20% for glucose and – 50% for DG at 28 m M). In contrast, graded hypoglycemia progressively reduced the distribution space for glucose and increased the space for [14C]DG. The values for λ were comparatively stable in normoglycemic and hyperglycemic conditions but rose sharply (e.g., as much as 9–10-fold at 2 m M) in severe hypoglycemia.
The Role of Cerebral Metabolism in Determining the Local Cerebral Blood Flow Effects of Volatile Anesthetics: Evidence for Persistent Flow-Metabolism Coupling
Authors: Hansen Thomas D. , Warner David S. , Todd Michael M. , Vust Laverle J.
Published: April 2011

The effects of equipotent doses of halothane (1.05%) versus isoflurane (1.38%) anesthesia on CMRglc were determined autoradiographically using the 2-[14C]deoxyglucose technique in the rat. Eight anatomically standardized coronal sections were selected and digitized from the autoradiographs. Mean CMRglc was determined for hemispheric, neocortical, and subcortical regions at each anatomic level, and a neocortical/subcortical CMRglc ratio was calculated. In addition, the current CMRglc autoradiographs, as well as previous CBF autoradiographs obtained under identical experimental conditions were examined to characterize and compare flow/metabolism relationships for the two anesthetics. For this analysis, CBF was determined in 80 selected anatomic areas, and the values from each area were plotted against CMRglc values obtained from identical areas. In all major regions, mean CMRglc was greater with halothane than with isoflurane. The neocortical/subcortical ratio, reflecting the pattern of CMRglc distribution, was also greater during halothane anesthesia. This suggests that isoflurane has a disproportionate effect on neocortical metabolism resembling patterns previously seen for CBF. Analysis of CBF versus CMRglc plots for each anesthetic group showed two parallel lines with nearly identical slopes, but different Y intercepts. We conclude that the distribution of CMRglc observed during 1 MAC (minimum alveolar concentration) halothane and isoflurane anesthesia parallels the distribution of CBF. This finding supports the conclusion that flow-metabolism coupling is intact during halothane and isoflurane anesthesia, and that drug induced changes in cerebral metabolism may play an important role in determining the CBF response to that drug. Furthermore, there is evidence that, at a given level of CMRglc, isoflurane may have greater vasodilating capabilities than halothane.
Rapid Reduction in [3H]Prazosin Binding to Gerbil Forebrain Membranes during Bilateral Common Carotid Artery Occlusion
Authors: Nishino Katsuhiro , Davis James N.
Published: April 2011

Transient cerebral ischemia results in selective neuronal cell death. The mechanisms underlying this selective vulnerability to ischemia are only beginning to be elucidated. We studied the effect of ischemia on α1-adrenergic receptor binding by measuring [3H]prazosin binding in gerbil forebrain membranes after 10 min of bilateral carotid occlusion. Binding was reduced from 62 ± 3 to 33 ± 4 fmol/mg protein. Binding in the same membranes to β2-adrenergic receptors were also decreased, but not to the extent of that to β1-adrenergic receptors. Binding to muscarinic cholinergic ([3H]quinuclydil benzilate) and β1-adrenergic receptors were only slightly depressed. Surprisingly, the protein content was significantly increased in the membrane fraction studied from ischemic forebrain (68 ± 4 mg/g wet weight) compared with sham operated controls (57 ± 4). The dramatic decrease in α1-adrenergic receptor binding during ischemia is consistent with receptor binding studies of membranes pretreated with phospholipase A2 in vitro. It is not clear what effect this change in α1-adrenergic receptor binding has on subsequent selective neuronal death. The recent demonstration that catecholamines and locus ceruleus neurons influence the loss of CA1 neurons in the hippocampus suggests that it may play an important modulatory role.
Relative Cerebral Ischemia in SHR Due to Hypotensive Hemorrhage: Cerebral Function, Blood Flow and Extracellular Levels of Lactate and Purine Catabolites
Authors: Skarphedinsson Jon O. , Sandberg Mats , Hagberg Henrik , Carlsson Stefan , Thorén Peter
Published: April 2011

Cerebral blood flow (CBF, by laser Doppler flowmetry) and extracellular cortical concentrations (by microdialysis) of adenosine, inosine, xanthine, hypoxanthine, and lactate were measured together with somatosensory evoked potentials (SEP) in chloralose-anaesthetized spontaneously hypertensive rats (SHR) during relative cerebral ischemia induced by hypotensive hemorrhage. Reduction of mean arterial blood pressure (MABP) to 40–50 mm Hg, which decreased SEP to about 50% of prebleeding control level, decreased CBF only to about 75% of control due to cerebrovascular “autoregulation.” A secondary, marked rise in cerebrovascular resistance (CVR) occurred after about 15 min in parallel with a striking increase in heart rate (after initial bradycardia). This late rise in heart rate is probably elicited by relative ischemia in medullary centers. The increase in CVR might indicate increased sympathetic nerve activity to the circle of Willis and large cerebral arteries. Cortical lactate increased initially but started to decline after about 30 min, and after 2 h it was not significantly higher than control. Cortical adenosine, inosine, hypoxanthine, and xanthine increased slowly and were significantly elevated after 50 min of hemorrhage. After 80 min, adenosine and inosine had returned to initial levels, while hypoxanthine and xanthine were further elevated. Despite the apparent partial recovery of metabolic disturbances during late hemorrhage, and with a blood flow maintained at 75% of resting control, SEP did not improve. It is suggested that the depression of SEP is not primarily caused by circulatory-metabolic derangements, but instead by activation of specific inhibitory systems.
Cerebral Enzyme Antioxidant System. Influence of Aging and Phosphatidylcholine
Authors: Benzi G. , Pastoris O. , Marzatico F. , Villa R. F.
Published: April 2011

To obtain a comprehensive profile of the age-related changes of the antioxidant enzyme system in discrete brain regions (cortex, caudate-putamen, substantia nigra, thalamus), the present study involved practically the total life span of male Wistar rats (from 5 to 35 months of age). The activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase increase from 5 to 25 months of life and remain relatively constant or decrease scantily thereafter. In thalamus, the activity of total superoxide dismutase (SOD) increases from 5 to 20 months of rat life and decreases thereafter. Conversely, in both substantia nigra and caudate-putamen, enzyme activity declines steadily with age, while in parietotemporal cortex enzyme activity deteriorates from the 25th month onward. In both caudate-putamen and parietotemporal cortex, the activity of glutathione peroxidase increases from 5 to 20 months of life and remains relatively constant thereafter, while in substantia nigra the enzyme activity is practically unmodified during the life span. Furthermore, the activity of glutathione reductase in parietotemporal cortex declines from the 20th month onward, while in caudate-putamen and thalamus, enzyme activity deteriorates after an increase from 5 to 20 months of life. The interference of phosphatidylcholine and/or its metabolite(s) with the cerebral enzyme antioxidant system shows a characteristic specificity as regards both the time of onset and the enzyme activities involved, namely, SOD and glutathione reductase. The interference with SOD is related to the cytosolic form of the enzyme and affects the cortex only of 5-month-old animals and also extends to the thalamus of 15-month-old rats and all regions in 25-month-old ones. The interference of phosphatidylcholine and/or its metabolite(s) with glutathione reductase is found in the brain of 25-month-old rats.
The Deoxyglucose Method in the Ferret Brain. II. Glucose Utilization Images and Normal Values
Authors: Redies C. , Diksic M. , Yamamoto Y. L.
Published: April 2011

To measure cerebral glucose utilization with the autoradiographic deoxyglucose method, the tracer transfer rate constants and lumped constants must be known. 2-Deoxyglucose (2-DG) and fluorodeoxyglucose (FDG) constants were determined in 18 gray and white matter brain structures of the anesthetized ferret. The ferret is a domestic carnivore particularly suitable for deoxyglucose studies because of its small brain size and low body weight. The average gray matter rate constants for tracer transfer across the blood-brain barrier are similar for 2-DG and FDG in the ferret brain ( K*1 = 0.21 ml/g/min and k*2 = 0.39 min−1). The rate constant for the rate-limiting step of tracer phosphorylation, k*3, is 1.6 times higher for FDG than for 2-DG (0.21 vs. 0.13 min−1). Loss of metabolized tracer is about 1–1.5%/min throughout the ferret brain for both tracers as estimated for a 180 min experimental period. Taking into account this loss, the lumped constant is 0.92 for FDG and 0.68 for 2-DG. Glucose utilization values in the brain of the anesthesized ferret range from 33 μmol/100 g/min in the corpus callosum to 104 μmol/100 g/min in the caudate nucleus. Representative glucose utilization images of coronal sections of the ferret brain are shown. Brain structures are identified on the same slices counterstained with thionin.