bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Carbohydrate Metabolism during Severe Ischemia in Fetal Sheep
Authors: Chao Conrad R. , Hohimer A. Roger , Bissonnette John M.
Published: April 2011

The effect of cephalic hypotension on brain metabolism was studied in 10 unanesthetized, normoxic (PaO2 >17 mm Hg), late-gestation fetal lambs. Perfusion pressure (cephalic arterial minus sagittal venous pressure) was 40 ±1 mm Hg (SEM) during control and was reduced to 10 ± 1 by occlusion of the Grachiocephalic artery. Cerebral blood flow was measured with microspheres, and arterial and sagittal vein blood samples were analyzed for oxygen content, glucose, and lactate. During the occlusion, oxygen consumption decreased from 125 ± 8 to 95 ± 4 (p < 0.05) (all values μmol 100 g−1 min−1), and glucose uptake increased from 20 ±3 to 25 ± 1 (p < 0.05). During the control period, there was no net lactate flux; during the occlusion, lactate excretion was 5.7 ± 1.4 (p < 0.005). The control glucose and oxygen uptakes demonstrated a normal 6:1 molar ratio; however, during the occlusion, 9.4 μmol 100 g−1 glucose min−1 were taken up in excess of expected aerobic glucose metabolism. If all of this glucose were anaerobically metabolized to lactate, three times the measured efflux would be produced. The transport properties of the fetal blood-brain barrier may be important factors in perinatal brain injury.
Nimodipine Prevents Hyperglycemia-Induced Cerebral Acidosis in Middle Cerebral Artery Occluded Rats
Authors: Berger Leo , Hakim Antoine M.
Published: April 2011

The effects of acute moderate hyperglycemia on local cerebral pH (LCpH) and local cerebral blood flow (LCBF) were studied in rats infused with glucose before middle cerebral artery (MCA) occlusion, and compared with findings in MCA occlusion alone. The effects of nimodipine infusion on LCBF and LCpH in MCA-occluded hyperglycemic rats were also studied. LCpH and LCBF were determined simultaneously by a double-label autoradiographic technique. Hyperglycemia was induced by an intraperitoneal injection of 2 g/kg D-glucose before MCA occlusion. Nimodipine-treated rats received the drug as an intravenous infusion of 0.5 μg/kg/min starting 15 min after occlusion, and ending at decapitation 4 h postocclusion. Cortical LCpH of five structures in the MCA territory of hyperglycemic rats varied between 6.64 ± 0.04 and 6.72 ± 0.02 (means ± SEM). These values were significantly lower than LCpH in the same ischemic structures in the control rats, which varied between 6.76 ± 0.04 and 6.82 ± 0.03 (p < 0.05 for four of five structures). Cortical LCpH of hyperglycemic nimodipine-treated rats ranged between 6.94 ± 0.02 and 7.05 ± 0.02, indicating significant elevations in LCpH (p < 0.001) compared with the untreated ischemic hyperglycemic animals. LCBF in the ischemic structures was not modified by hyperglycemia or nimodipine treatment. This suggests that nimodipine, by mechanisms other than improvement in blood flow, can prevent the enhanced cerebral tissue acidosis produced by hyperglycemia before incomplete focal ischemia.
Enhancement of Iron-Catalyzed Free Radical Formation by Acidosis in Brain Homogenates: Difference in Effect by Lactic Acid and CO2
Authors: Rehncrona Stig , Hauge Hans Nielsen , Siesjö Bo K.
Published: April 2011

The influence of lactic acidosis and of extreme hypercapnia on free radical generation and lipid peroxidation in brain tissues was studied. Cortical homogenates were prepared from the rat brain in a bicarbonate buffer and incubated for 60 min. Lipid peroxidation was evaluated by measurements of thiobarbituric acid reactive (TBAR) material and α-tocopherol analysis. The pH during incubations were decreased to 6.10–6.20 by either lactic acid administration or equilibration with 60% CO2 gas in paired experiments. In homogenates treated with lactic acid there was a 20-fold increase in TBAR material and the α-tocopherol concentration decreased to ∼60% of control. There was only a 10-fold increase in TBAR material and no change in α-tocopherol concentration if acidosis was induced by CO2. These differences between lactic acidosis and hypercapnic acidosis were statistically highly significant. The results indicate that lactic acidosis has a more pronounced effect in augmenting free radical generation in brain tissues than acidosis due to an increase in CO2 tension. It is suggested that this effect of lactic acid is mediated by increased dissociation of catalytic iron from proteins of the transferrin type.
Localisation in PET Images: Direct Fitting of the Intercommissural (AC—PC) Line
Authors: Friston K. J. , Passingham R. E. , Nutt J. G. , Heather J. D. , Sawle G. V. , Frackowiak R. S. J.
Published: April 2011

A technique is described for estimating the position of the intercommisural line (AC–PC line) directly from landmarks on positron emission tomographic (PET) images, namely the ventral aspects of the anterior and posterior corpus callosum, the thalamus, and occipital pole. The relationship of this estimate to the true AC–PC line, fitted through the centres of the anterior and posterior commissures, showed minimal vertical and angular displacement when measured on magnetic resonance imaging (MRI) scans. Using regression analysis, the ease and reliability of fitting to these points was found to be high. This directly derived AC–PC line estimate was validated in terms of the assumptions used in the method of Fox et al. The ratio of distance between the AC–PC line and a line passing through the base of the inion (GI line) to total brain height was 0.21, as predicted. The technique has been further validated by localizing focal activation of the sensorimotor cortex. The technique is discussed in terms of absolute limits to localization of structures in the brain using noninvasive tomographic techniques in general and PET in particular.
Systematic Studies on the Effects of the NMDA Receptor Antagonist MK-801 on Cerebral Blood Flow and Responsivity, EEG, and Blood-Brain Barrier following Complete Reversible Cerebral Ischemia
Authors: Stevens Mark K. , Yaksh Tony L.
Published: April 2011

The dose-dependent effects of MK-801, a glutamate receptor antagonist, on changes in CBF, CBF-Paco2 responsiveness (133Xe clearance), EEG, and blood-brain barrier (methylene blue) were examined after a 15-min period of reversible complete global ischemia induced in halothane-anesthetized cats by occlusion of the vertebral and carotid arteries. Pretreatment with doses of MK-801 of ≥0.5 mg/kg had no effect on resting CBF measures and produced a dose-dependent slowing of the dominant EEG frequency. In animals receiving this agent, there was an almost immediate return of baseline EEG patterns upon reinstitution of flow, no hypoperfusion after 2 h of reflow, preservation of CBF and CBF-Paco2 responsiveness, and maintenance of blood-brain barrier integrity. In contrast, parallel control animals and animals treated with MK-801 at a dose of 0.1 mg/kg exhibited poor recovery based on the above parameters. MK-801 also diminished in a dose-dependent manner the CSF levels of 6-keto-prostaglandin (PG) F1α (stable metabolite of PGI2) and thromboxane (Tx) B2 (stable metabolite of TxA2), which were otherwise elevated in vehicle-treated animals 2 h after reflow. Of particular interest, the CSF TxB2/6-keto-PGF1α ratio in vehicle-treated animals was near 2. In animals pretreated with MK-801, at doses of ≥0.5 mg/kg, this ratio was nearly 1. These observations are consistent with a possible triggering role of glutamate release in initiating at least part of the acute sequelae of ischemia. Such release in an electrically silent cell would increase Ca2+ influx and activate free fatty acid metabolism, leading to probable changes in vascular function and changes in blood-brain barrier permeability.
Heterogeneity of P2-Purinoceptors in Brain Circulation
Authors: Torregrosa Germán , Miranda J. , Salom Juan B. , Alabadí José A. , Alvarez Cristina , Alborch Enrique
Published: April 2011

The existence of P2-purinoceptors in the cerebrovascular bed was examined by testing the effects of ATP and its stable analog, α,β-methylene-ATP, on CBF in the unanesthetized goat as well as on isometric tension in isolated goat middle cerebral artery. When injected directly into the cerebral circulation, ATP increased and α,β-methylene-ATP decreased CBF. Indomethacin did not modify either of these effects. The vasoconstrictor action of α,β-methylene-ATP was reduced by nicardipine. “In vitro,” both ATP and α,β-methylene-ATP contracted the cerebral arteries at resting tone, but the analog was more potent than ATP. Repeated application of α,β-methylene-ATP as well as indomethacin significantly reduced the ATP-induced contractions. Nicardipine inhibited both the α,β-methylene-ATP- and the ATP-induced contractile response. In preconstricted arteries, ATP produced relaxation and α,β-methylene-ATP induced further contraction. The relaxant response to ATP was not modified by indomethacin. These results show the existence of two subtypes of P2-purinoceptors in brain circulation: P2x, more sensitive to α,β-methylene-ATP than to ATP, which elicits cerebral vasoconstriction; and P2y, sensitive to ATP, which elicits cerebral vasodilation.
Imaging Peripheral Benzodiazepine Receptors in Brain Tumors in Rats: In vitro Binding Characteristics
Authors: Ikezaki Kiyonobu , Black Keith L. , Toga Arthur W. , Santori Emily M. , Becker Donald P. , Smith Mayumi L.
Published: April 2011

Peripheral benzodiazepine binding constants for transplanted RG-2 gliomas and HK and LK Walker 256 tumors (metastatic breast carcinoma) were determined in Wistar rats using autoradiography. In addition, Kd and Bmax parameters for peripheral benzodiazepine receptors on RG-2 tumors were directly visualized using digital image analysis of autoradiograms. High specific binding of [3H]PK11195, a selective peripheral benzodiazepine ligand, had excellent topographical correlation to areas of histologically verified tumor. Scatchard analysis suggested a single class of peripheral binding sites with similar binding affinities in RG-2 and LK Walker 256 tumors and normal cortex. Bmax was 20-fold greater in glial tumors and 11.6- and 10.6-fold greater in LK and HK Walker 256 tumors, respectively, compared to normal cortex. The location of metastatic tumors, either intracerebrally or subcutaneously, did not effect their Kd or Bmax values. Kd and Bmax values for RG-2 tumors were similar whether determined densitometrically or by direct visualization with image analysis. Binding parameters within normal brain were difficult to visualize by image analysis due to the low level of specific binding. The ability to label specifically intracerebral tumor cells and to characterize the binding parameters shown in this study suggest that peripheral benzodiazepine receptor ligands could be utilized by PET to analyze directly a variety of tumors in humans.
Continuous Monitoring of Cerebrocortical Blood Flow during Stimulation of the Cerebellar Fastigial Nucleus: A Study by Laser-Doppler Flowmetry
Authors: Iadecola Costantino , Reis Donald J.
Published: April 2011

Laser–Doppler flowmetry was used to continuously monitor cortical CBF during electrical stimulation of the fastigial nucleus (FN). Rats were anesthetized with isoflurane (0.75–5%), paralyzed, and artificially ventilated. The LDF probe was placed over a target region of the parietal cortex through a burr hole. The hypertension associated with FN stimulation was prevented by spinal cord transection at C1 with arterial pressure maintained by i.v. infusion of phenylephrine. After cord transection, CBF changed linearly with changes in arterial pco2 ( r = 0.93; n = 23). FN stimulation (50–100 μA, 50 Hz, 1 s on/1 s off) produced sustained increases in CBF that developed slowly, reaching 50% of maximum within 24 ± 1 s of stimulation (n = 17). After stimulation, CBF returned to baseline gradually within a time period (84–540 s) proportional to the duration of the stimulation ( r = 0.93; n = 15). The CBF response was stimulus frequency and intensity dependent, was elicited only from restricted sites in FN, and was abolished by atropine (1 mg/kg, i.v.) or pentobarbital (30 mg/kg, i.v.). The slow temporal profile of the cerebrovasodilation is compatible with the hypothesis that in cerebral cortex local neurons mediate the vasodilation by interstitial release of vasoactive agents rather than by a direct action of neural processes on blood vessels. LDF is an effective technique for monitoring phasic change in CBF and may be useful in studies of the intrinsic neurogenic control of the cerebral circulation.
The Effect of Pentobarbital and Isoflurane on Glucose Metabolism in Thermally Injured Rat Brain
Authors: Archer David P. , Elphinstone Mary G. , Pappius Hanna M.
Published: April 2011

The effect of pentobarbital and isoflurane on cerebral glucose metabolism (CMRglc) was studied in thermally injured rat brain using quantitative autoradiography. In awake lesioned animals, CMRglc in cortical regions ipsilateral to the injury was reduced to 50% of normal while little if any decrease was observed in contralateral cortical regions and subcortical regions bilaterally. Treatment of lesioned animals with pentobarbital or isoflurane further reduced CMRglc, but more in the hemisphere contralateral to the injury than on the injured side. Thus, the side-to-side difference in cortical CMRglc present in the awake lesioned animals was abolished by the anesthetics. The results support the hypothesis that CMRglc depression associated with a focal cold injury is functional in nature. Reduction of metabolism by anesthetics in functionally depressed brain is limited by the decrease in CMRglc associated with the injury.
Quantifying Interictal Metabolic Activity in Human Temporal Lobe Epilepsy
Authors: Henry Thomas R. , Mazziotta John C. , Engel Jerome , Christenson Peter D. , Zhang Jing Xi , Phelps Michael E. , Kuhl David E.
Published: April 2011

The majority of patients with complex partial seizures of unilateral temporal lobe origin have interictal temporal hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG PET) studies. Often, this hypometabolism extends to ipsilateral extratemporal sites. The use of accurately quantified metabolic data has been limited by the absence of an equally reliable method of anatomical analysis of PET images. We developed a standardized method for visual placement of anatomically configured regions of interest on FDG PET studies, which is particularly adapted to the widespread, asymmetric, and often severe interictal metabolic alterations of temporal lobe epilepsy. This method was applied by a single investigator, who was blind to the identity of subjects, to 10 normal control and 25 interictal temporal lobe epilepsy studies. All subjects had normal brain anatomical volumes on structural neuroimaging studies. The results demonstrate ipsilateral thalamic and temporal lobe involvement in the interictal hypometabolism of unilateral temporal lobe epilepsy. Ipsilateral frontal, parietal, and basal ganglial metabolism is also reduced, although not as markedly as is temporal and thalamic metabolism.
Angiotensin Peptide Regulation of Fluid-Phase Endocytosis in Brain Microvessel Endothelial Cell Monolayers
Authors: Guillot François L. , Audus Kenneth L.
Published: April 2011

An in vitro model comprised of primary cultures of brain microvessel endothelial cells was used to investigate angiotensin II (Ang II) effects on blood–brain barrier fluid-phase endocytosis. The effects of Ang II, saralasin, sarathrin, bradykinin (BK), and phorbol myristate acetate (PMA) on brain microvessel endothelial cell fluid-phase endocytosis were determined using the fluorescent marker, Lucifer yellow. Nanomolar concentrations of saralasin (a partial Ang II agonist) stimulated brain microvessel endothelial cell endocytosis by 30% whereas Ang II treatment enhanced Lucifer yellow uptake by 20%. Sarathrin (an Ang II antagonist) had no effect on Lucifer yellow uptake. Nanomolar concentrations of BK and PMA also stimulated Lucifer yellow uptake by the brain microvessel endothelial cell by 40 and 95%, respectively. Stimulatory effects of Ang II and saralasin on Lucifer yellow uptake by brain microvessel endothelial cells could be completely blocked by pretreatment with either sarathrin or indomethacin (an inhibitor of prostaglandin synthesis). In contrast, the effects of neither BK nor PMA on brain microvessel endothelial cell uptake of Lucifer yellow were altered by indomethacin pretreatment. Results indicated that Ang II, saralasin, BK, and PMA produce similar stimulatory effects on brain microvessel endothelial cell fluid-phase endocytosis with only Ang II and saralasin, producing increases in brain microvessel endothelial cell fluid-phase endocytosis that appeared to be mediated by prostaglandins.
Cortical Spreading Depression is Associated with Arachidonic Acid Accumulation and Preservation of Energy Charge
Authors: Lauritzen Martin , Hansen Anker Jon , Kronborg Dorte , Wieloch Tadeusz
Published: April 2011

The present study aimed to study the relation between the release of arachidonic acid (AA) and the energy state in cerebral cortices of rats during single episodes of cortical spreading depression (CSD). The changes in concentrations of AA, labile phosphate compounds [ATP, ADP, AMP, and phosphocreatine (PCr)], and glycolytic metabolites (lactate, pyruvate, glucose, and glycogen) were studied during and following the large change of the local direct current (DC) potential. Free AA increased markedly during the DC shift, continued to increase during the subsequent 3 min, and returned to control levels at 4–5 min after CSD. PCr decreased by 38% in the first minutes following the DC shift, while ADP increased by 38%. Both returned to normal within a few minutes. ATP, AMP, and energy charge remained constant throughout the experimental period. Glucose decreased by 47% and glycogen by 34% for a few minutes following CSD, while lactate increased by 105% at 2–3 min and by 77% at 4–5 min after CSD. The metabolites returned to control levels at 10 min after CSD. Considering the constant energy charge at all time points during CSD, it is suggested that the AA rise reflects augmented phospholipase activity due to either increased intracellular [Ca2+] or receptor stimulation or both. The possibility that N-methyl-d-aspartate receptors play a role in the release of AA, and that free AA in turn could be part of the mechanism of CSD, is discussed.
The Two Patterns of Reactive Astrocytosis in Postischemic Rat Brain
Authors: Petito Carol K. , Morgello Susan , Felix Juan C. , Lesser Martin L.
Published: April 2011

The distribution and time course of postischemic astrocyte hypertrophy and hyperplasia and the relationship to neuronal viability or necrosis was studied in rats subjected to 30 min of carotid and vertebral artery occlusion followed by reperfusion from 3 h to 5 weeks. Intermediate filaments (IFs) were evaluated by electron microscopy, IF proteins by immunohistochemistry, and astrocyte division by [3H]thymidine uptake. Glial fibrillary acidic protein (GFAP) increased in damaged and nondamaged brain regions by 2 days and was associated with cell enlargement, increases in IF, and transformation of GFAP-negative into GFAP-positive glia. Cell hypertrophy and increased GFAP persisted only in regions of neuronal necrosis whereas the number and size of GFAP-positive astrocytes returned to control levels in nondamaged regions by 2 weeks. Astrocyte hyperplasia was not seen until 3 days and was confined to damaged brain regions. Vimentin-positive astrocytes were numerous by 2 days in damaged brain and remained only in those regions at 5 weeks. The data demonstrate that reactive astrocytosis develops in undamaged brain, but is reversible with prolonged survival, whereas reactive astrocytosis that accompanies structural brain damage persists for prolonged periods and is associated with hyperplasia, as well as hypertrophy. In addition, the results show that astrocyte expression of vimentin is more specific than GFAP in identifying regions of permanent ischemic injury during the early postischemic period.
Time Course of Postischemic Intracellular Alkalosis Reflects the Duration of Ischemia
Authors: Chopp Michael , Chen Hua , Vande Linde Ana M. Q. , Brown Eileen , Welch K. M. A.
Published: April 2011

We investigated the long-term (up to 1 week) relationships between the duration of cerebral ischemia and postischemic energy metabolic profile, pH, and tissue edema in the rat. Ten rats each were subjected to 8 or 12 min of forebrain ischemia induced by bicarotid occlusion concurrent with systemic hypotension, and the results were compared with those of 10 sham-operated rat controls. In vivo 31P nuclear magnetic resonance spectroscopy was performed prior to ischemia and at intervals up to 168 h after ischemia. Cerebral edema (measured by specific gravity) was assessed prior to ischemia and at 24, 72, and 168 h after ischemia. The data revealed significant differences in the brain tissue pH profile over time between the ischemic groups (p < 0.03). The 12-min ischemic animals exhibited brain tissue alkalosis (pH = 7.27 ± 0.12) at 24 h compared with both sham (pH = 7.09 ± 0.08) at 24 h and preischemic (pH = 7.06 ± 0.04) pH values. The pH remained alkalotic (pH = 7.23 ± 0.15) through the 48-h time period. In contrast, in the 8-min group, the onset of alkalosis was delayed until 48 h after ischemia (pH = 7.24 ± 0.15), and pH remained alkalotic for only 24 h. No difference in high-energy phosphate metabolism was detected between groups. A different time dependence of tissue pH and specific gravity changes after 12 min of ischemia was detected. The present study suggests that the duration of an ischemic event marks the time of onset of brain tissue alkalosis and its duration and that cerebral edema alone cannot explain the pH changes.
MK-801 Attenuates Capillary Bed Compression and Hypoperfusion following Incomplete Focal Cerebral Ischemia
Authors: Meyer Fredric B. , Anderson Robert E. , Friedrich Patricia F.
Published: April 2011

The effects of the N-methyl-d-aspartate (NMDA) antagonist MK-801 on capillary beds and CBF following 1 h of transient incomplete focal cerebral ischemia were studied by examining 133Xe CBF, capillary diameter, and area of perfused vasculature. Capillary diameter increased from a control of 5.24 ± 0.37 to 8.62 ± 0.57 μm (p < 0.001) and area of perfused vasculature from 20,943 ± 1,151 to 30,442 ± 1,691 μm2/×10 magnification field (p < 0.001) with MK-801 1.0 mg/kg administered 30 min prior to ischemia. After flow restoration in control animals, there was a relative hypoperfusion with eventual normalization of CBF over 60 min. Alternatively, in MK-801 1.0 mg/kg animals, there was rapid normalization of CBF upon flow restoration without the postischemic hypoperfusion observed in controls. On histological analysis, there was consistently less neuronal edema in MK-801-treated animals. These results support the hypothesis that hypoperfusion following incomplete focal cerebral ischemia may be due in part to NMDA-mediated cellular edema with subsequent extravascular capillary bed compression.
Kinetic Studies on Uptake of Serotonin and Noradrenaline into Pial Arteries of Rats
Authors: Chang Jing-Yu , Hardebo J. E. , Owman Ch.
Published: April 2011

A population of cerebrovascular nerve fibers have recently been found to store serotonin (5-hydroxytryptamine; 5-HT). There is reason to assume that these 5-HT-containing fibers have a sympathetic rather than an intracerebral origin. This was further elucidated in the present study in which the uptake mechanisms of 5-HT and noradrenaline (NA) were characterized and compared in rat pial arteries by measuring the accumulation of [3H]5-HT and [14C]NA under various experimental conditions in vitro. Sympathectomized vessels served as blanks. The uptake into the perivascular sympathetic nerves was dependent on time as well as concentration and was saturable. The Km values were similar, 0.17 μ M for 5-HT and 0.15 μ M for NA, but the Vmax value was 10 times higher for NA (2.38 and 25 pmol/mg/15 min, respectively). The two amines competed with each other in the sympathetic uptake, as studied by inhibition of the accumulation of one labeled amine by the other nonlabeledamine. Corticosterone, acting on the extraneuronal process, significantly inhibited the 5-HT uptake but had no substantial effect on NA. Reserpine, blocking the intraaxonal vesicular stores, markedly attenuated the accumulation of NA, but not of 5-HT. The selective uptake blocker paroxetine reduced the 5-HT uptake with much higher potency than the NA uptake, whereas desipramine predominantly inhibited NA uptake. The pial 5-HT uptake was not significantly affected by lesion of the raphe complex, whereas it was reduced to half following superior cervical ganglionectomy. The results suggest that the 5-HT present in nerves associated with pial vessels at the base of the brain is taken up through an efficient axonal mechanism, functionally related but not identical to the uptake process for NA.
Regional Neuroprotective Effects of the NMDA Receptor Antagonist MK-801 (Dizocilpine) in Hypoglycemic Brain Damage
Authors: Papagapiou M. P. , Auer R. N.
Published: April 2011

Current evidence points to an important role of N-methyl-d-aspartate (NMDA) receptor activation in the pathogenesis of hypoglycemic neuronal death. MK-801 {dizocilpine maleate, (+)-5-methyl-10,11-dihydro-5 H-di[ a,d]cyclohepten-5,10-imine} is an anticonvulsant compound also known to be a potent noncompetitive antagonist at NMDA receptors, readily crossing the blood–brain barrier after parenteral administration. Treatment of rats with dizocilpine (1.5–5.0 mg/kg) injected intravenously during profound hypoglycemia (blood glucose levels 1.5–2.0 m M) at the stage of δ-wave (1–4 Hz) slowing of the EEG mitigated selective neuronal necrosis in the hippocampus and striatum, assessed histologically after 1-week survival. The degree of neuroprotection in the striatum and in the CA1 pyramidal cells of the hippocampus was dose dependent. Because of concern for a possible hypothermic mechanism of brain protection by MK-801, core temperature was closely monitored and was found not to decrease significantly. Since CBF is normal or increased in hypoglycemia, a fall in brain temperature during hypoglycemia is unlikely to play a role in the mechanism of the neuroprotection seen with the drug. The findings indicate that in profound hypoglycemia, intravenous administration of the NMDA antagonist dizocilpine, even after the appearance of δ-wave EEG slowing, can reduce the number of necrotic neurons in several brain regions and suggest that the neuroprotective effect of MK-801 is not related to hypothermia.
Eicosanoids in Rat Brain during Ischemia and Reperfusion—Correlation to DC Depolarization
Authors: Tegtmeier F. , Weber C. , Heister U. , Haker I. , Scheller D. , Nikolov R. , Höller M.
Published: April 2011

The effects of complete ischemia on cerebral arachidonic acid (AA) metabolism were investigated in the isolated perfused rat brain. During 12.5 min of ischemia, AA, 5-hydroxy-6,8,11,14-eicosatetraenoic acid, and 15-hydroxy-5,8,11,13-eicosatetraenoic acid increased 129-, 4-, and 10-fold, respectively, while subsequent reperfusion for 30 min resulted in normalized levels independently of the duration of preceding ischemia. Prostaglandin (PG) F2α, PGE2, PGD2, 6-keto-PGF1α, and thromboxane (Tx) B2 remained at preischemic levels during 12.5 min of complete ischemia. However, at the end of subsequent reperfusion for 30 min, the levels of the prostanoids PGF2α, PGE2, PGD2, 6-keto-PGF1α, and TxB2 increased according to the preceding ischemic time. The levels reached a maximum after 7.5 min of ischemia and were elevated by 7-, 14-, 48-, 3-, and 30-fold, respectively. A prolongation of ischemia of up to 12.5 min was not associated with further increases of prostanoids at the end of reperfusion. The mechanisms underlying the metabolism of eicosanoids are discussed in relation to the changes of cortical direct current potential.
Selective Electrical Stimulation of Postganglionic Cerebrovascular Parasympathetic Nerve Fibers Originating from the Sphenopalatine Ganglion Enhances Cortical Blood Flow in the Rat
Authors: Suzuki Norihiro , Hardebo Jan Erik , Kåhrström Jan , Owman Christer
Published: April 2011

Recently, the origins and pathways of cerebrovascular acetylcholine- and vasoactive intestinal polypeptide-containing nerves have been elucidated in detail in the rat: The sphenopalatine ganglion is the major source for postganglionic parasympathetic fibers to the vascular beds of the cerebral hemispheres. To clarify the functional role of the nerves on cerebral blood vessels in vivo, brain cortical microvascular blood flow was measured in rats during electrical stimulation of these particular postganglionic fibers. Animals were subjected to transection of the right nasociliary nerve 2 weeks before the flow measurements to eliminate activation of peptidergic sensory fibers. Relative change in microvascular blood flow was continuously recorded by a laser-Doppler flowmeter system under α-chloralose anesthesia. The postganglionic fibers were electrically stimulated just proximal to the ethmoidal foramen by a bipolar platinum electrode (5 V; 0.5 ms; 3, 10, 30, 60 Hz; as a continuous stimulation for 90 s). Stimulation at 10 Hz induced a marked increase of the cortical blood flow (CoBF) on the ipsilateral side, whereas no change was observed on the contralateral side. It reached a maximum mean value of 42.5% at 46 s, and then slightly declined during the remaining stimulation period. No significant changes were observed in the mean arterial blood pressure or blood gases during or after stimulation. Both atropine and scopolamine failed to alter this flow increase. Electrical stimulation of the postganglionic fibers at different frequencies revealed a maximal increase in the CoBF at 30 Hz in the control situation (47.2%), but at 10 Hz after scopolamine administration (51.6%). This provides the first report showing that selective postganglionic stimulation of the parasympathetic nerve fibers markedly enhances blood flow in the brain, and it supports the view that the neurogenic vasodilatation is primarily noncholinergic.
Postischemic Canine Cerebral Blood Flow Appears to Be Determined by Cerebral Metabolic Needs
Authors: Michenfelder John D. , Milde James H.
Published: April 2011

Following a period of complete global cerebral ischemia and reperfusion there ensues a low flow state referred to as the delayed postischemic hypoperfusion state. It is unknown whether this low flow state contributes to neuronal injury or whether the magnitude of hypoperfusion correlates with the duration of ischemia. The latter question was addressed in 20 dogs in which complete global ischemia was induced by cerebrospinal fluid (CSF) compression for periods of 3, 9, 12, or 18 min. Following reperfusion, CBF (by sagittal sinus outflow) and CMRO2 were determined for 90 min, and results were correlated with the duration of ischemia. At 90 min postischemia the magnitude of decrease in CBF correlated crudely with the duration of ischemia ( r = – 0.67, p < 0.01). For CMRO2 correlation of the magnitude of decrease with the duration of ischemia was more evident ( r = –0.74, p < 0.001). Furthermore, the postischemic ratio of CBF to CMRO2 was virtually identical for all dog groups regardless of the ischemic time. The adequacy of the ratio of CBF to CMRO2 was reflected by adequate oxygen levels in the sagittal sinus blood of all dogs. The authors conclude that the delayed postischemic hypoperfusion state is probably not an important determinant of neuronal injury since its magnitude appears to be primarily determined by the metabolic needs of the brain.
Glucose Utilization in Rat Hippocampus after Long-Term Recovery from Ischemia
Authors: Beck Thomas , Wree Andreas , Schleicher Axel
Published: April 2011

The influence on hippocampal glucose utilization of a transient 10-min forebrain ischemia was quantified in male Wistar rats after 2 and 3 weeks as well as after 3 months by application of the [14C]2-deoxyglucose technique. Ischemia was induced by occlusion of the carotid arteries and simultaneous lowering of the blood pressure to 40 mm Hg. For identification of the hippocampal architecture, sections were stained for perikarya (cresyl violet) and for acetylcholinesterase. The hippocampal regions clearly showed different responses to the ischemic insult. The necrotic pyramidal cells being almost completely removed, significant increases in glucose utilization occurred in most layers of the CA1 sector at 2 and 3 weeks post ischemia, while widespread reductions prevailed in all other sectors and the dentate gyrus. At 3 months after the ischemic insult, glucose utilization was reduced in all hippocampal structures including the CA1 region. The increases in glucose utilization in the CA1 sector are suggested to indicate long-lasting presynaptic hyperexcitation, while the widespread reductions in glucose utilization demonstrate that neuronal activity is also altered in hippocampal areas that do not show major histological damage.
Measurement of Cerebral Monoamine Oxidase B Activity Using L-[11C]Deprenyl and Dynamic Positron Emission Tomography
Authors: Lammertsma A. A. , Bench C. J. , Price G. W. , Cremer J. E. , Luthra S. K. , Turton D. , Wood N. D. , Frackowiak R. S. J.
Published: April 2011

A tracer kinetic procedure was developed for the measurement of monoamine oxidase type B (MAO-B) activity using L-[11C]deprenyl and positron emission tomography (PET). The kinetic model consisted of two tissue compartments with irreversible binding to the second compartment (three rate constants). In addition, a blood volume component was included. Special attention was given to the accurate measurement of the plasma and whole blood input functions. The method was applied to the measurement of the dose-response curve of a reversible MAO-B inhibitor (Ro 19–6327). From the results, it followed that the rate constant for irreversible binding ( k3) appeared to be a better index of MAO-B activity than the net influx constant Ki Furthermore, regional analysis demonstrated that Ki but not k3, was flow dependent. This implies that full kinetic analysis is required for an accurate assessment of MAO-B activity.
Tachykinins (Substance P, Neurokinin A, Neuropeptide K, and Neurokinin B) in the Cerebral Circulation: Vasomotor Responses in vitro and in situ
Authors: Jansen I. , Alafaci C. , McCulloch J. , Uddman R. , Edvinsson L.
Published: April 2011

The vasomotor responses of tachykinins have been studied in the cerebral vasculature of human, pig, cat, and guinea pig. Substance P (SP), neurokinin A (NKA), neurokinin B (NKB), and neuropeptide K (NPK) induced concentration-dependent relaxations of precontracted cerebral arteries in all species when examined by a sensitive in vitro technique. In addition, the relaxant responses to SP, NKA, and NKB were studied in cat pial arterioles by peptide microapplication in situ. In human pial vessels, the order of relaxant potency was SP > NKB > NKA > NPK; in the pig middle cerebral artery, there was no difference in potency between the tachykinins; in the cat middle cerebral artery, SP = NKB > NKA = NPK; and in the guinea pig basilar artery, SP » NPK = NKA > NKB. Responses induced by SP, NKA, and NKB in the cat were comparable in vitro and in situ. Removal of the endothelium abolished relaxation induced by all four tachykinins. The relaxant responses of guinea pig basilar arteries to SP, NKA, and NPK were competitively antagonized by the SP antagonist Spantide. However, Spantide lowered the Imax of the NKB concentration–response curve without any rightward shift, suggesting action at a different site than the other tachykinins. In the guinea pig basilar artery, the relaxation seems to be exerted via a NK-1 receptor subtype while the receptor subtype is more unclear in cerebral arteries from human, cat, and pig. It is concluded that relaxations induced by SP, NKA, NKB, and NPK are dependent on the endothelium, and are antagonized either competitively or non-competitively by the SP antagonist Spantide. The origin of tachykinins acting through the endothelium is discussed.
Acidosis-Induced Ischemic Brain Damage: Are Free Radicals Involved?
Authors: Lundgren Johan , Zhang Hui , Agardh Carl-David , Smith Maj-Lis , Evans Patrica J. , Halliwell Barry , Siesjö Bo K.
Published: April 2011

Substantial evidence exists that reactive oxygen species participate in the pathogenesis of brain damage following both sustained and transient cerebral ischemia, adversely affecting the vascular endothelium and contributing to the formation of edema. One likely triggering event for free radical damage is derealization of protein-bound iron. The binding capacity for some iron-binding proteins is highly pH sensitive and, consequently, the release of iron is enhanced by acidosis. In this study, we explored whether enhanced acidosis during ischemia triggers the production of reactive oxygen species. To that end, enhanced acidosis was produced by inducing ischemia in hyperglycemic rats, with normoglycemic ones serving as controls. Production of H2O2, estimated from the decrease in catalase activity after 3-amino-1,2,4-triazole (AT) administration, was measured in the cerebral cortex, caudoputamen, hippocampus, and substantia nigra (SN) after 15 min of ischemia followed by 5, 15, and 45 min of recovery, respectively (in substantia nigra after 45 min of recovery only). Free iron in cerebrospinal fluid (CSF) was measured after ischemia and 45 min of recovery. Levels of total glutathione (GSH + GSSH) in cortex and hippocampus, and levels of α-tocopherol in cortex, were also measured after 15 min of ischemia followed by 5, 15, and 45 min of recovery. The results confirm previous findings that brief ischemia in normoglycemic animals does not measurably increase H2O2 production in AT-injected animals. Ischemia under hyperglycemic conditions likewise failed to induce increased H2O2 production. No difference in free iron in CSF was observed between animals subjected to ischemia under hyper- and normoglycemic conditions. The moderate decrease in total glutathione or α-tocopherol levels did not differ between normo- and hyperglycemic animals in any brain region or at any recovery time. Thus, the results failed to give positive evidence for free radical damage following brief periods of ischemia complicated by excessive acidosis. However, it is possible that free radical production is localized to a small subcellular compartment within the tissue, thereby escaping detection. Also, the results do not exclude the possibility that free radicals are pathogenetically important after ischemia of longer duration.
Intracarotid Infusion of Leukotriene C4 Selectively Increases Blood-Brain Barrier Permeability after Focal Ischemia in Rats
Authors: Baba Takehiko , Black Keith L. , Ikezaki Kiyonobu , Chen Kangnian , Becker Donald P.
Published: April 2011

Intracarotid infusions of leukotriene C4 (LTC4) were used to open selectively the blood–brain barrier (BBB) in ischemic tissue after middle cerebral artery (MCA) occlusion in rats. BBB permeability was determined by quantitative autoradiography using [14C]aminoisobutyric acid. Seventy-two hours after MCA occlusion, LTC4 (4 μg total dose) infused into the carotid artery ipsilateral to the MCA occlusion selectively increased the unidirectional transfer constant for permeability K1 approximately threefold within core ischemic tissue and tissue adjacent to the ischemic core. No effect on BBB permeability was seen within nonischemic brain tissue or in ischemic tissue after only 24 h after MCA occlusion. γ-Glutamyl transpeptidase (γ-GTP) activity was decreased in capillaries in ischemic tissue at 48 and 72 h after infarction, compared to high γ-GTP in normal brain capillaries and moderate γ-GTP in capillaries in the ischemic tissue at 24 h after infarction. These findings suggest that normal brain capillaries resist the vasogenic effects of LTC4. In contrast, LTC4 increases permeability in capillaries of ischemic tissue, where γ-GTP is decreased. γ-Glutamyl transpeptidase, an enzyme that inactivates LTC4 to LTD4 and LTE4 to LTF4, may act as an “enzymatic barrier” in normal brain capillaries to leukotrienes.
The Effect of Bile Salts on the Permeability and Ultrastructure of the Perfused, Energy-Depleted, Rat Blood-Brain Barrier
Authors: Greenwood J. , Adu J. , Davey A. J. , Abbott N. J. , Bradbury M. W. B.
Published: April 2011

The action of bile salts upon the rat blood–brain barrier (BBB) was assessed in the absence of energy-yielding metabolism. Brains were perfused in situ with a Ringer solution for 5 min followed by a 1 min perfusion containing either sodium deoxycholate (DOC), taurochenodeoxycholate (TCDC), or Ringer/DNP. The integrity of the BBB was then determined by perfusing with the radiotracer [14C]mannitol for 2.5 min. Alternatively, the brains were perfusion fixed for ultrastructural assessment. At 0.2 m M DOC, the BBB remained intact and the cerebral ultrastructure was similar to the controls. At 1 m M and above, disruption of the BBB became evident. At 2 m M, the cerebral cortex became severely vacuolated, with damaged endothelium and collapsed capillaries. With TCDC, BBB disruption occurred at 0.2 m M without any apparent ultrastructural damage to the micro vasculature. Following 2 m M TCDC, similar, but less widespread, structural changes to the 2 m M DOC-perfused animals was apparent. Opening of the BBB occurred at a concentration lower than that required to cause lysis of either red blood cells or cultured cerebral endothelial cells. It is proposed that the effect of bile salts at concentrations of 1.5 m M and above is largely due to their lytic action as strong detergents on endothelial cell membranes, but that at lower concentrations a more subtle modification of the BBB occurs.
Distribution and Kinetics of 3-O-Methyl-6-[18F]fluoro-L-DOPA in the Rhesus Monkey Brain
Authors: Doudet Doris J. , McLellan Catherine A. , Carson Richard , Adams H. Richard , Miyake Hitoshi , Aigner Thomas G. , Finn Ronald T. , Cohen Robert M.
Published: April 2011

Most attempts to model accurately [18F]-DOPA imaging of the dopamine system are based on the assumptions that its main peripheral metabolite, 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]3-OM-DOPA), crosses the blood-brain barrier but is present as a homogenous distribution throughout the brain, in part because it is not converted into [18F]DOPA in significant quantities. These assumptions were based mainly on data in rodents. Little information is available in the primate. To verify the accuracy of the above assumptions, we administered 18F-labeled 3-OM-DOPA to normal rhesus monkeys and animals with lesions of the DA nigrostriatal system. No selective 18F regional accumulation in brain was apparent in normal or lesioned animals. The plasma metabolite analysis revealed that only the negatively charged metabolites (e.g., sulfated conjugates) that do not cross the blood-brain barrier were found in significant quantities in the plasma. A one-compartment, three-parameter model was adequate to describe the kinetics of [18F]3-OM-DOPA. In conclusion, assumptions concerning [18F]3-OM-DOPA's behavior in brain appear acceptable for [18F]DOPA modeling purposes.
In vivo Binding of Nimodipine in the Brain: II. Binding Kinetics in Focal Cerebral Ischemia
Authors: Hogan Matthew J. , Gjedde Albert , Hakim Antoine M.
Published: April 2011

We report the binding characteristics of [3H]nimodipine to normal and ischemic brain in vivo. We used the 1,4-dihydropyridine, nimodipine, to label the L-type voltage-sensitive calcium channel in focal cerebral ischemia after occlusion of both the middle cerebral and ipsilateral common carotid arteries in rats. Varying concentrations of [3H]nimodipine were infused 3.5 h after the onset of ischemia and circulated for 30 min before the brain was obtained for autoradiography and determination of regional nimodipine content. In separate sets of experiments, the metabolites of nimodipine were determined and the conditions for equilibrium of nimodipine distribution were established. Increased nimodipine uptake was observed in ischemic regions. This increased binding was saturable and specific with an affinity constant, KD, of 0.45 n M and a maximal regional binding capacity, Bmax, ranging from 3.1 to 10.9 pmol/g. Only binding to ischemic tissue was specific and saturable whereas that in nonischemic tissue was nonspecific. In vivo binding of nimodipine may be used to identify cell membrane depolarization and calcium channel activation in focal cerebral ischemia.
Cerebral Blood Flow and Oxygen Consumption in Cortical Spreading Depression
Authors: Mayevsky Avraham , Weiss Harvey R.
Published: April 2011

We determined the effects of spreading depression on local cerebral O2 supply, oxygenation, and O2 consumption in the anesthetized rat. Spreading depression was induced by application of 0.5 M KCl to the frontal cortex. Regional cerebral blood flow was determined with [14C]iodoantipyrine and regional O2 extraction was determined microspectrophotometrically. The passage of the spreading depression wave was determined with a multiprobe assembly that recorded NADH redox state (surface fluorometry), extracellular K+ activity, and DC steady potential (surface minielectrodes). As the wave of spreading depression passed, there was an increase in extracellular K+ and a decrease in NADH. Cerebral blood flow was significantly increased (120 ± 51 ml/min/100 g, mean ± SD) during the wave as compared with other regions. In the affected cortex, blood flow was not different from that in the contralateral cortex (69 ± 28 ml/min/100 g) either before or after the wave of spreading depression passed. Arterial and venous O2 saturation were unaffected by the wave and the histogram of O2 saturations of examined veins followed a similar normal distribution in all regions. Oxygen extraction was not altered by the wave of spreading depression. Oxygen consumption was significantly increased during the wave to 7.4 ± 3.7 ml O2/min/100 g compared with the contralateral cortex (5.1 ± 2.6 ml/min/100 g) and other regions. It can be concluded that spreading depression caused an increase in cerebral O2 consumption that was adequately matched by an increase in local blood flow. Oxygen delivery was not limited during spreading depression and its effects were quickly over as evidenced by the lack of alteration in oxygenation after the wave of spreading depression passed.
Effects of Focal Cortical Freezing Lesion on Regional Energy Metabolism
Authors: Buczek Marek , Ratcheson Robert A. , Lust W. David , McHugh Michael , Pappius Hanna M.
Published: April 2011

Freezing lesions have been shown to cause a depression in glucose use, particularly in cortical areas of the brain ipsilateral to the lesion, and this effect was interpreted to be caused by a depressed functional activity in these regions. The metabolic status of the affected areas has not been previously examined and could be a factor in the observed changes in local CMRglc. In frozen-cut and dried sections taken from brains 3 days after freeze lesioning, discrete pieces of the median and lateral parietal cortex, striatum, hippocampus, and hypothalamus were dissected and analyzed for ATP, P-creatine, glucose, and lactate. CMRglc measurements were also made in the same animals. The concentrations of the four metabolites were significantly increased in the lesioned hemisphere, with the most predominant effects observed in the cortical areas that exhibited the greatest depression in CMRglc. The enriched metabolite profile, particularly in the cortical areas, is consistent with the hypothesis that decreased glucose use in the traumatized brain is caused by diminished need rather than by decreased supply of energy. Because the lumped constant in the operational equation of the deoxyglucose method for determination of CMRglc is a function of brain glucose content and decreases gradually in hyperglycemia, the degree of metabolic depression in cortical areas of lesioned hemisphere probably have been somewhat overestimated in this and previous publications. However, provisionally recalculated local CMRglc in the lesioned hemisphere remain significantly lower than in the contralateral hemisphere and in the normal brain.